@article {pmid41887928,
year = {2026},
author = {Zhao, X and Wang, X and Sheng, Y and Lin, S and Xu, S and Hu, Z and Ling, X and Chen, C and Cao, M and Cui, H and Lu, Y},
title = {Rational Engineering of Phospholipase D Unlocks Robust Catalysis for Phosphatidylserine Formation.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c17951},
pmid = {41887928},
issn = {1520-5118},
abstract = {Phosphatidylserine (PS), a major brain phospholipid, supports the central nervous system's health and may alleviate cognitive decline, including in Alzheimer's disease. A key challenge in green enzymatic PS synthesis is the suppression of hydrolysis while enhancing PLD-catalyzed transphosphatidylation. Here, we developed a mechanism-guided engineering strategy for Streptomyces antibioticus phospholipase D (SaPLD). The substitution of W187I increased the PS yield to 58.3%, while V380W improved thermostability. Combining beneficial mutations generated SaPLD-R7 (W187I/V380W/G381A), which overcame the activity-stability trade-off and achieved up to 95.8% PS yield using the enzyme produced by 5 L scale fermentation. Molecular dynamics simulations showed that SaPLD-R7 enhanced substrate binding and catalysis by shortening the key active site distances and reducing local flexibility. Solvent contact and energy analyses further indicated improved stability. This work establishes a structure-mechanism-function framework for enhancing PLD transphosphatidylation and provides a robust enzymatic route for high-efficiency PS production as a valuable functional food ingredient.},
}

@article {pmid41888060,
year = {2026},
author = {Mao, KL and Fu, JX and Chen, J and Liao, YL and Huang, ML and Chen, Z and Lin, LM and Shi, Q and Gao, BM},
title = {From marine predator to pharmacology: Conotoxin diversity, discovery, and therapeutic potential.},
journal = {Zoological research},
volume = {47},
number = {2},
pages = {378-403},
doi = {10.24272/j.issn.2095-8137.2025.553},
pmid = {41888060},
issn = {2095-8137},
mesh = {*Conotoxins/chemistry/pharmacology/therapeutic use/genetics ; Animals ; *Conus Snail/chemistry ; Drug Discovery ; Humans ; },
abstract = {Cone snails (Conus spp.) biosynthesize a highly specialized venom comprising a vast arsenal of neurotoxic peptides, termed conotoxins. These peptides exhibit exceptional structural and functional diversity, characterized by unique disulfide-bond architectures, highly variable amino acid sequences, and precise interactions with defined molecular targets. This review presents a comprehensive synthesis of current knowledge on conotoxin biology, beginning with evolutionary origin and proceeding through the classification systems used to define their gene superfamilies and pharmacological families. Advances in discovery methodologies are also examined, with particular emphasis on the transformative role of high-throughput multi-omics in expanding conotoxin identification and characterization. Furthermore, this review analyzes the pharmacological properties of representative conotoxins acting on key ion channels and receptors and evaluates the structure-activity relationships that determine their potency, selectivity, and functional profile. Mechanistic insights derived from these studies have established conotoxins as powerful neuropharmacological tools and a rich reservoir for drug discovery. Their significant therapeutic potential is underscored by efficacy in chronic pain management, exemplified by the US FDA-approved drug ziconotide, and by growing evidence supporting applications in neuroprotection in disorders such as Alzheimer's disease and Parkinson's disease, as well as in selected cardiovascular conditions. Future perspectives are also discussed, with progress likely dependent on the integration of computational design, peptide engineering, and bioengineering platforms to accelerate the translation of these marine peptides into next-generation clinical therapeutics.},
}

*Conotoxins/chemistry/pharmacology/therapeutic use/genetics
Animals
*Conus Snail/chemistry
Drug Discovery
Humans

@article {pmid41888300,
year = {2026},
author = {Sanchez-Mico, MV and Calvo-Rodriguez, M and Bacskai, BJ},
title = {Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.},
journal = {Nature reviews. Neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41888300},
issn = {1471-0048},
abstract = {Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca[2+] dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca[2+] signalling pathways are progressively remodelled during ageing and become profoundly dysregulated in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. Importantly, astrocyte Ca[2+] alterations are heterogeneous and context-dependent, ranging from aberrant spontaneous activity to loss of signalling in specific subcellular domains, reflecting the disease stage, brain region and molecular pathology. Disruption of astrocyte Ca[2+] homeostasis compromises core homeostatic functions and contributes to neuronal vulnerability, circuit dysfunction and impaired neurovascular regulation. By integrating current evidence across physiological, ageing and disease contexts, this Review highlights astrocytic Ca[2+] signalling as a central node in neurodegenerative pathophysiology and underscores its potential as a target for therapeutic intervention.},
}

@article {pmid41888327,
year = {2026},
author = {Zeng, Y and Shao, Y and Zhou, D and Qiu, M and Wang, Z and Xi, Q},
title = {Whole-Brain Static Functional Connectivity Disruptions Based on the Default Mode Network in Patients with Mild Cognitive Impairment.},
journal = {Brain topography},
volume = {39},
number = {3},
pages = {},
pmid = {41888327},
issn = {1573-6792},
support = {Grant No. 20254Y0168//the Commission of Shanghai Municipal Health/ ; Grant No. PWRl2022-05//the Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai/ ; Grant No. 23Y11907500//the Science and Technology Commission of Shanghai Municipality/ ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; Male ; Female ; Magnetic Resonance Imaging/methods ; Aged ; *Brain/physiopathology/diagnostic imaging ; *Default Mode Network/physiopathology/diagnostic imaging ; Middle Aged ; Brain Mapping ; Retrospective Studies ; Neural Pathways/physiopathology/diagnostic imaging ; *Nerve Net/physiopathology/diagnostic imaging ; Alzheimer Disease/physiopathology ; },
abstract = {Mild cognitive impairment (MCI) is regarded a potential early stage of Alzheimer's disease (AD) and associated with a significantly increased risk of progression to AD. This study aims to evaluate whole-brain static functional connectivity (SFC) disruptions with the default mode network (DMN) seed points in patients with MCI by resting-state functional magnetic resonance imaging (rs-fMRI), and to explore whether these disruptions could serve as potential markers for MCI progression to AD. Retrospective rs-fMRI data with MCI (n = 36) and corresponding matched healthy controls (HCs) (n = 26) were collected for comparison. Independent component analysis (ICA) was used to extract DMN regions, and SFC was calculated for four seed points within the DMN. Two-sample t-tests were performed to compare group differences in SFC strength between the MCI and HC groups, and Pearson correlation analyses were conducted. Compared to HCs, the MCI group showed both increased and decreased SFC between four subregions and multiple brain regions, decreased SFC was more widely distributed than increased SFC. Abnormal connectivity was more prominent in the first two key nodes compared to the latter two. Affected regions primarily located in the precuneus, frontal gyri, temporal gyri, postcentral gyrus, caudate nucleus, lingual gyrus, and fusiform gyrus. The SFC value between the right angular gyrus and the right insula was significantly negatively correlated with MoCA scores (r = - 0.385, p < 0.05, FDR-corrected). It reveals a decline in the functional integration capacity within the DMN, as well as complex reorganization and abnormal connectivity patterns between the DMN and other brain networks. The altered interactions between DMN subregions and abnormal brain areas are significantly associated with episodic memory disturbance in MCI.},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnostic imaging
Male
Female
Magnetic Resonance Imaging/methods
Aged
*Brain/physiopathology/diagnostic imaging
*Default Mode Network/physiopathology/diagnostic imaging
Middle Aged
Brain Mapping
Retrospective Studies
Neural Pathways/physiopathology/diagnostic imaging
*Nerve Net/physiopathology/diagnostic imaging
Alzheimer Disease/physiopathology

@article {pmid41888480,
year = {2026},
author = {Xu, Z and Mijalkov, M and Sun, J and Chang, YW and Sala, A and Volpe, G and Severino, M and Veronese, M and Garcia-Ptacek, S and Pereira, JB and , },
title = {Mapping individual molecular connectomes in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71310},
doi = {10.1002/alz.71310},
pmid = {41888480},
issn = {1552-5279},
support = {W81XWH-12-2-0012//U.S. Department of Defense/ ; //National Institutes of Health Grant/ ; //Gun och Bertil Stohnes Stiftelse/ ; //KI Foundations/ ; //Gamla Tjänarinnor Foundation/ ; //Karolinska Institute Consolidator Position grant/ ; //Strategic Research Area Neuroscience/ ; //Kung Gustav:S & Viktorias Stiftelse/ ; //Swedish Alzheimer Foundation/ ; //Blomquist family/ ; //European Union - NextGenerationEU and the Romanian Government/ ; //KI Research Incubator/ ; 2022-01108//Swedish Research Council/ ; 2025-03210//Swedish Research Council/ ; AF-1032782//Alzheimer Foundation/ ; 2-3980/2025//Blomqvist Foundation/ ; FO2025-0059//Swedish Brain Foundation/ ; 760250/28.12.2023//Romania's National Recovery and Resilience Plan/ ; PNRR-C9-I8-CF109/31.07.2023//Romania's National Recovery and Resilience Plan/ ; //Omanian Ministry of Research, Innovation and Digitalization/ ; //StratNeuro/ ; //KI Consolidator Grant/ ; //King Gustaf V and Queen Victoria's Foundatio/ ; //Dementia Foundation/ ; //Lars Hierta Memorial Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/genetics/pathology ; *Connectome/methods ; Positron-Emission Tomography ; Male ; Female ; Aged ; tau Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Progression ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Mapping individual differences is crucial to improve personalized medicine approaches in Alzheimer's disease (AD), which is characterized by strong inter-individual variability in the accumulation patterns of tau and amyloid beta pathology.

METHODS: We assess the progression of AD across the disease continuum by building individual molecular connectomes using longitudinal positron emission tomography (PET) data.

RESULTS: We demonstrate that these connectomes constitute a unique fingerprint, capable of identifying a single individual from a large group of subjects. Alterations in the connectomes discriminate different diagnostic groups and predict cognitive decline to a higher extent than conventional PET measures. We introduce a novel gene-specific transcription network analysis that linked individual tau and amyloid connectomes to a common transcriptomic profile of apoptosis, with the tau connectome being specifically related to pyrimidine metabolism, and the amyloid connectome to histone acetylation.

DISCUSSION: Individual molecular connectome mapping provides a novel and sensitive framework to monitor AD progression.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/genetics/pathology
*Connectome/methods
Positron-Emission Tomography
Male
Female
Aged
tau Proteins/metabolism
*Brain/diagnostic imaging/metabolism
Amyloid beta-Peptides/metabolism
Disease Progression
Aged, 80 and over
Longitudinal Studies

@article {pmid41888691,
year = {2025},
author = {Dwarkanth, PS and Anitha, R and Babu, GH and Ahammad, SKH and Karamati, H and Kumar, A and Oza, AD and Moges, DM},
title = {An efficient Alzheimer's disease detection by NV classifier with BWTDL approach using MRI image.},
journal = {BMC medical imaging},
volume = {26},
number = {1},
pages = {},
pmid = {41888691},
issn = {1471-2342},
}

@article {pmid41888907,
year = {2026},
author = {Tsai, AP and Martin, AK and Mi, A and Yeh, AE and Ramirez Lopez, E and Wyss-Coray, T},
title = {PLCG2 signaling and genetic resilience in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {41888907},
issn = {1750-1326},
}

@article {pmid41888956,
year = {2026},
author = {Li, M and Yu, Q and Yu, S and Cheng, Q and Wu, S and Jin, Y and Cui, Z and Chen, H and Zhao, X and Wu, X and Lu, Z},
title = {Plasma EV LINE-1 mRNA as a diagnostic biomarker for differentiating Alzheimer's disease from non-Alzheimer's dementias.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02034-3},
pmid = {41888956},
issn = {1758-9193},
support = {ZR2025QC1673//Natural Science Foundation of Shandong Province/ ; tsqnz20240852//Taishan Scholars Program of Shandong Province/ ; 82502804//National Natural Science Foundation of China/ ; },
}

@article {pmid41888976,
year = {2026},
author = {Li, M and Qiu, N and Niu, W and Qian, C and Zhang, Y and Yang, W and Ding, F and Wang, H and Xu, X and Xia, J and Zhang, X},
title = {A novel PGK1 activator improves Alzheimer's disease by regulating glycolysis.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02029-0},
pmid = {41888976},
issn = {1758-9193},
support = {2021-I2M-1-069//CAMS Innovation Fund for Medical Sciences/ ; },
}

@article {pmid41889068,
year = {2026},
author = {Wang, P and Xue, M and Mao, Y and Wang, C and Yao, X and Biswal, BB},
title = {Dynamic Alterations of Functional Systems in Alzheimer's Disease: A Co-Activation Pattern Analysis.},
journal = {Human brain mapping},
volume = {47},
number = {5},
pages = {e70509},
doi = {10.1002/hbm.70509},
pmid = {41889068},
issn = {1097-0193},
support = {NSFC62401106//National Natural Science Foundation of China/ ; NSFC62171101//National Natural Science Foundation of China/ ; 2024NSFSC1661//Sichuan Province Science and Technology Support Program/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging ; Male ; Magnetic Resonance Imaging ; Female ; Aged ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; *Nerve Net/diagnostic imaging/physiopathology ; *Connectome/methods ; Middle Aged ; Aged, 80 and over ; *Default Mode Network/diagnostic imaging/physiopathology ; *Brain/physiopathology/diagnostic imaging ; },
abstract = {While resting-state brain dysfunctions have been extensively investigated in Alzheimer's disease (AD), the dynamic alterations of functional systems remain poorly understood. We employed co-activation pattern (CAP) analysis to characterize the functional-state alterations in 243 participants using resting-state fMRI data and applied graph theory analysis to estimate corresponding topological properties. The CAP analysis identified five distinct brain states across groups: State 1 (limbic network dominated), State 2 (dorsal attention network (DAN) and central executive network dominated), State 3 (default mode network and central executive network dominated), State 4 (somatomotor network and ventral attention network dominated), and State 5 (DAN, sensorimotor, and visual networks dominated). Compared to cognitively unimpaired individuals, State 3 demonstrated significantly reduced persistence and resilience in both mild cognitive impairment (MCI) and AD groups. Additionally, both clinical groups (MCI and AD) exhibited decreased transitions from State 2 to State 5 and reduced self-transitions within State 3. Graph theory analysis revealed that compared to cognitively unimpaired individuals, MCI and AD individuals had increased node degree centrality and node efficiency, alongside decreased node local efficiency in regions within the default mode network (DAN) and visual network, which corresponded well with CAP analysis results. Our findings provide a multiscale framework linking dynamic state instability to static network reorganization, advancing understanding of the dynamic functional alterations underlying cognitive decline in AD spectrum disorders.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging
Male
Magnetic Resonance Imaging
Female
Aged
*Cognitive Dysfunction/physiopathology/diagnostic imaging
*Nerve Net/diagnostic imaging/physiopathology
*Connectome/methods
Middle Aged
Aged, 80 and over
*Default Mode Network/diagnostic imaging/physiopathology
*Brain/physiopathology/diagnostic imaging

@article {pmid41889233,
year = {2026},
author = {Santos, LRC and de Almeida, JNB and Frias, CC and Almeida, WP and Maistro, EL},
title = {Evaluation of DNA/Chromosome Integrity and Cell Death in Human Metabolically Noncompetent and Competent Cells Exposed to N'-(3,5-Difluorobenzylidene)Pyridine-4-Carbohydrazide.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70171},
pmid = {41889233},
issn = {1099-1263},
support = {Finance code 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 303604/2021-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Universidade Estadual Paulista/ ; },
abstract = {The N-acylhydrazone scaffold is recognized as a privileged structure for the design of bioactive substances with increasing applications in medicinal chemistry research. Ensuring the safety of newly developed molecules is a critical step for both human health and environmental protection. Accordingly, this study aimed to evaluate the cytotoxic and genotoxic properties of N'-(3,5-difluorobenzylidene)pyridine-4-carbohydrazide in two cellular models: nonmetabolizing leukocytes and metabolically active hepatic cells (HepG2/C3A). The resazurin-based cytotoxicity analysis, performed with concentrations between 1 and 600 μg/mL, indicated that only the uppermost concentration caused a marked decrease in viability of both cell populations after 48 h of incubation. Regarding genotoxicity at 50, 100, and 200 μg/mL concentrations, no DNA damage was detected in the comet assay, but in the micronucleus test, a significant increase in chromosome alterations in leukocytes at 200 μg/mL concentration was detected, with a decrease in cell proliferation in both cell types. The data indicate that, at the concentrations where the biological effects of acylhydrazone were previously observed, the substance appeared to be safe, but at higher concentrations and/or during chronic exposure, caution and further studies are needed.},
}

@article {pmid41889331,
year = {2026},
author = {Nelvagal, HR and Chiraki, N and Curless, T and Cullinane, PW and Rockliffe, A and Pimparkar, S and Kawamura, H and Ollerenshaw, S and Elahi, I and Brandner, S and Wu, L and Real, R and Ryten, M and Hardy, J and De Pablo Fernandez, E and Warner, TT and Morris, HR and Lim, YM and Jaunmuktane, Z},
title = {Quantitative pathology and APOE genotype reveal dementia risk and progression in Lewy body disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag114},
pmid = {41889331},
issn = {1460-2156},
abstract = {Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, co-pathology including concomitant Alzheimer's disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies, and controls, integrating APOE genotype, clinical data and assessment of ischaemic pathology alongside large-scale digital pathology quantification. We established an image analysis pipeline utilising machine learning to enable automated, standardised measurement of α-synuclein, amyloid-β, and phosphorylated tau burden across multiple brain regions. Quantitative pathology strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE ε3 and ε4 carriers showed distinct dementia risk profiles. APOE ε3 carriers developed dementia at lower quantitative α-synuclein and amyloid-β thresholds than ε4 carriers, although overall dementia risk was dominated by ε4 genotype, consistent with ε4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in ε3 carriers with low Lewy and Alzheimer's proteinopathy burden, while male sex further modulated dementia risk for this subgroup. The Subtype and Stage Inference (SuStaIn) algorithm identified four trajectories of Lewy pathology progression. Two corresponded to recognised patterns, one brainstem-first and the other with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement, one with early cingulate cortex involvement together with brainstem pathology and the other starting in neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-β, phosphorylated tau, or α-synuclein, and showed that Lewy subtypes follow two propagation trajectories in opposite directions. Together, these findings demonstrate that integrating quantitative pathology with genotype and clinical data reveals distinct yet overlapping pathways to dementia in LBD, refining disease progression models and providing a basis for genotype- and pathology-informed patient stratification in therapeutic trials.},
}

@article {pmid41889579,
year = {2026},
author = {Vesnupriya, P and Karukuvelraja, R and Rehanaz, N and Shamna, ME and Saranya, N},
title = {Mind gut harmony: psychobiotics effects on the gut-brain axis and harnessing its effects for the mental health.},
journal = {Journal of food science and technology},
volume = {63},
number = {4},
pages = {613-634},
pmid = {41889579},
issn = {0022-1155},
abstract = {The microbiota-gut-brain axis is gaining attention as a potential therapeutic avenue for treating illnesses of the illnesses of the central nervous system. In recent years, there has been a notable increase in literature examining the connection between the gut microbiome and its impact on overall health and wellness. The microbiota-gut-brain axis is a promising therapeutic target for treating central nervous system diseases and reducing drug adverse effects. Probiotics have been shown in pre-clinical and clinical trials to improve health by modulating the microbiota in the gut-brain axis. Psychobiotics are probiotics that modulate the gut-brain axis (GBA) and regulate the central nervous system to improve gastrointestinal function, as well as have antidepressant and anxiolytic properties via neuronal, humoral, and metabolic mechanisms. Some psychobiotic strains have been shown to reduce inflammation and cortisol levels, thereby degenerative and neurodevelopmental illnesses such as Parkinson's disease, Alzheimer's disease, and autism spectrum disorder can be effectively treated with psychobiotics. Alleviating anxiety and depression symptoms. Neurodegenerative and neurodevelopmental illnesses such as Parkinson's disease, Alzheimer's disease, and autism spectrum disorder can be effectively treated with psychobiotics. This review summarizes the psychobiotic potential on the gut-brain axis for the mental health.},
}

@article {pmid41889760,
year = {2026},
author = {Saha, D and Sun, X and Yang, W and Luo, J and Zheng, W},
title = {Residue-Specific Modulation of Aggregation-Associated Interactions by Spermine in Tau, α‑Synuclein, and Aβ40.},
journal = {JACS Au},
volume = {6},
number = {3},
pages = {2040-2054},
pmid = {41889760},
issn = {2691-3704},
abstract = {Preventing neurodegenerative diseases associated with intrinsically disordered proteins (IDPs) remains a major challenge due to the lack of a detailed, sequence-level picture of disease-relevant structure formation and the influence of cellular factors that modulate these transitions. Here, we probe spermine (Spm), a +4 charged polyamine abundant in cells, to determine how it reshapes the conformational ensembles and fibril-associated contact propensities of three disease-linked IDPs: the K18 domain of Tau, α-synuclein (αS), and amyloid-β40 (Aβ40). Using long all-atom molecular dynamics simulations across a range of Spm concentrations, we quantify residue-level changes in intrachain contacts relative to native contacts observed in fibrils and corroborate computational predictions with ThT fluorescence assays for Tau constructs. Spm acts in a sequence- and region-specific manner, not simply through the overall net charge. In K18, Spm binds near the fourth microtubule-binding repeat, disrupting intrachain contacts associated with Alzheimer's fibril structures and thereby inhibiting aggregation. In αS, Spm binds mainly to acidic residues in the C-terminal half of the sequence and redistributes intramolecular contacts to enhance aggregation-prone interactions in the central region, providing a residue-level mechanistic basis for previously reported Spm-enhanced αS aggregation. For Aβ40, Spm neutralizes acidic residues near positions 22-24 and shifts intrachain interactions toward its aggregation-prone core, resulting in a net promotion of fibril-like conformations. These divergent effects show that net charge alone cannot predict the polyamine influence on IDPs. Instead, residue-specific binding hotspots and local reweighting of aggregation-linked contacts determine whether Spm promotes or suppresses fibril-like conformations. This combined simulation-experimental framework provides a mechanistic basis for how small molecules reprogram IDP conformational ensembles and suggests principles for designing ligands that exploit similar residue-level modulation.},
}

@article {pmid41889765,
year = {2026},
author = {Gabani, ZY and Singh, J and Hamlett, ED and Granholm, AC and Margittai, M},
title = {Cofactor-Free Serial Amplification of Tau Filaments from Alzheimer's Disease and Other Tauopathies Depends on the Conformational State of Tau Monomers.},
journal = {JACS Au},
volume = {6},
number = {3},
pages = {1789-1800},
pmid = {41889765},
issn = {2691-3704},
abstract = {Tau filaments are a defining characteristic of Alzheimer's disease (AD) and numerous other neurodegenerative disorders. The deposition of Tau protein into aggregates involves templated recruitment of Tau monomers onto the filament ends via their microtubule-binding repeats. This structural conversion is central to the propagation of Tau pathology, yet its molecular mechanisms are still poorly understood. Specifically, it is unclear whether cofactors are required for templated growth. To gain insights into this process, we probed the serial amplification of pathological Tau filaments from AD, Pick's disease (PiD), and progressive supranuclear palsy (PSP). These filaments are made from different compositions of three- and four-repeat (3R and 4R) Tau. We observe that AD Tau filaments recruit full-length 3R and 4R Tau in the absence of cofactors at low salt concentration but not at physiological salt concentration and that these filaments can be independently amplified over multiple generations. PiD Tau and PSP Tau filaments can be similarly amplified. The generated filaments retain the cross-seeding properties of the pathological seeds; PSP filaments recruit only 4R Tau, PiD filaments recruit only 3R Tau, and AD filaments recruit both. Regardless of the structural fidelity of the amplification process, we show that the Tau monomer ensemble serves as an entry point for templated growth and that the conformational state of this ensemble (expanded versus compact) determines whether propagation occurs.},
}

@article {pmid41889823,
year = {2026},
author = {Qureshi, YH and Williams, CA and Hajdu, I and Kannan, S and Govindarajan, A and Végh, B and Petsko, GA and Young, JE and Závodszky, P and Small, SA},
title = {RhoGEF12 regulates endosomal SORL1-retromer and its inhibition is therapeutic in human neuronal models of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.709427},
pmid = {41889823},
issn = {2692-8205},
abstract = {UNLABELLED: The interaction of the endosomal sorting protein SORL1 with the retromer complex at endosomal membranes controls a recycling pathway whose dysfunction is pathogenic in Alzheimer's disease (AD) and is linked to other neurodegenerative disorders. To search for novel therapeutic targets, we hypothesize that endosomal SORL1-retromer might be regulated by SORL1's cytoplasmic tail. We begin by completing an in vitro analysis of the tail and show that its phosphorylation by ROCK2 (Rho-associated kinase 2) reduces SORL1's affinity to retromer. Since RhoGEF12 (Rho guanine nucleotide exchange factor 12) is an upstream activator of ROCK2 that is upregulated in AD, we used a RhoGEF12 pharmacological inhibitor to mechanistically and therapeutically validate the findings in neuronal cultures. First, in mouse neurons we confirm that the inhibitor increases endosomal SORL1-retromer. Next, we turned to human iPSC-derived neurons to show that the inhibitor reduces Aβ40 and Aβ42, an indicator of pathway upregulation, in a SORL1-dependent manner. Finally, we validate its therapeutic potential by applying the RhoGEF12 inhibitor to human iPSC-derived neurons expressing AD-associated mutations in either APP or SORL1 . Collectively, our results identify a novel and therapeutically amenable mechanism that regulates endosomal SORL1-retromer and preclinically validate RhoGEF12 as a therapeutic target for AD and potentially other neurodegenerative disorders.

ONE SENTENCE SUMMARY: Pharmacological inhibition of RhoGEF12 increases endosomal SORL1-retromer recycling and reduces pathogenic amyloid secretion in human neuronal models, identifying a novel, targetable pathway for treating Alzheimer's disease.},
}

@article {pmid41889829,
year = {2026},
author = {Xia, Q and Wang, Q and Jia, D and Dong, D and Li, M and Sherman, E and Ao, J and Ren, Q and Bao, H and Jiang, L and Cheng, JX},
title = {IR-AMES uncovers structure and composition of Alzheimer's tau oligomers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711458},
pmid = {41889829},
issn = {2692-8205},
abstract = {Tau misfolding and aggregation are central to cognitive decline in Alzheimer's disease and related neurodegenerative disorders [1-3] . Although soluble tau oligomers are implicated as primary toxic species [4-6] , the structural and compositional determinants of their toxicity remain inaccessible at the single oligomer level. Here we introduce infrared absorbance-modulated evanescent scattering (IR-AMES), a label-free single-molecule spectroscopic imaging approach that photothermally encodes mid-infrared vibrational fingerprints into evanescent scattering from individual biomolecular assemblies under native aqueous conditions. Applying IR-AMES to recombinant human tau resolves random-coil-dominated monomers and captures the emergence of structurally heterogeneous oligomers. Analysis of tau oligomers from postmortem Alzheimer's disease brains uncovers enrichment of antiparallel β-sheet structures and RNA components, features that are largely obscured in ensemble-averaged measurements. Using lipid nanodiscs as a defined membrane mimic, we further show that pathological tau oligomers exhibit enhanced interactions with anionic membranes. Together, these findings establish a link between structure and neurotoxicity of tau oligomers, and position IR-AMES as a platform for uncovering structure-function relationships in complex biomolecular assemblies.},
}

@article {pmid41889831,
year = {2026},
author = {Benbow, SJ and Saxton, AD and Baum, M and Uhrich, RL and Stair, JG and Keene, K and Dahleen, C and Wordeman, L and Liachko, NF and Kow, RL and Kraemer, BC},
title = {Dominant α-tubulin mutations rescue tauopathy neurodegenerative phenotypes in C. elegans.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.18.712642},
pmid = {41889831},
issn = {2692-8205},
abstract = {Tau protein, the primary component in neurofibrillary tangles characteristic of Alzheimer's Disease and related dementia disorders, normally regulates microtubule growth and stability. While tau dysfunction contributes to the progression of tauopathies, the role of microtubules in disease has remained unclear. Through forward genetic screening in Caenorhabditis elegans tauopathy models, we found multiple tubulin gene mutations that rescue tau-mediated neurodegeneration. Whole animal behavioral and in vitro biochemical assays were employed to characterize mutation-driven effects on neuron function, neurodegeneration, and effects on tubulin and tau proteins as well as microtubule function. Mutant tubulin genes were found to confer different levels of suppression correlating with the level of mutant gene expression. Mutant tubulins did not drastically alter total tau protein levels, tau phosphorylation or aggregation, however tau-induced neurodegeneration was rescued. The suppression of tau toxicity by tubulin gene mutations cannot be explained by changes in tau or tubulin expression, tau phosphorylation, or tau aggregation state. Rather the tubulin mutations appear to act by influencing global microtubule properties. In vitro experiments using C. elegans tubulin in semi-isolated and isolated contexts have indicated changes to microtubule properties without observable changes to tau-tubulin affinity. This work suggests that manipulation of microtubules can rescue tauopathy even when pathological tau species persist, supporting the importance of understanding microtubule contributions to disease progression and investigation into microtubule targeted gene therapy or small molecule approaches for tauopathy intervention.},
}

@article {pmid41889854,
year = {2026},
author = {Fitz, NF and Alam, MS and Ostach, MA and Garg, S and Lefterov, I and Koldamova, R},
title = {A novel technique for monitoring Alzheimer's disease associated changes in brain-derived extracellular vesicle cargos in mouse models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.13.711599},
pmid = {41889854},
issn = {2692-8205},
abstract = {Extracellular vesicles (EVs) are critical mediators of intercellular communication, carrying molecular cargos such as small noncoding RNAs (ncRNAs) that reflect the physiological and pathological state of their cells of origin. However, studying brain-derived EVs has been challenging due to the blood-brain barrier. Here, we optimized and validated an open-flow microdialysis (OFM) protocol for sampling EVs directly from brain interstitial fluid (ISF) in wild-type and APP/PS1 transgenic mice. Ex-vivo validation using plasma EVs demonstrated that OFM effectively captures the full EV population. In-vivo cerebral OFM (cOFM) enabled successful collection of brain ISF EVs, which were characterized by nanoparticle tracking analysis (NTA), electron microscopy, and western blotting, confirming their similarity to EVs isolated directly from brain tissue and plasma. Identification of small ncRNA cargos revealed that EVs sampled from brain ISF by cOFM were enriched in brain-specific signatures, many of which are associated with neuronal cell populations and biological functions. Furthermore, we observed a unique small ncRNA signature from the brain ISF EVs in the Alzheimer's disease preclinical model compared to wild-type mice. These small ncRNAs were associated with genes considered important in biological functions associated with neurodegeneration. Our findings demonstrate that cOFM is a powerful tool for in-vivo sampling of brain EVs and highlight the unique molecular landscape of ISF EV small ncRNA cargos. This study offers new opportunities for biomarker discovery and mechanistic insights into neurodegenerative diseases, such as Alzheimer's disease.},
}

@article {pmid41889929,
year = {2026},
author = {Shi, Y and Rozen, SD and Swint, JT and McRoberts, WA and McCurry, SN and Salinas, R and Moffett, EG and Pollock, CM and Goldstein, LR and Katzev, SS and Carter, ME and Bloom, GS and Güler, AD},
title = {LiFE, a multimodal circadian intervention, improves sleep, glycemic control, and recognition memory.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711428},
pmid = {41889929},
issn = {2692-8205},
abstract = {In mammals, sleep is regulated by the central circadian system, which responds to environmental timing cues including light, exercise and availability of food. In this study, we developed a light-, food-, and exercise-based daily lifestyle intervention (LiFE) that combines the effects of multiple circadian entrainment cues on central clock function, ultimately strengthening central clock rhythms. In wild-type (WT) mice, LiFE consolidated nocturnal activity, enhanced suprachiasmatic nucleus rhythmicity, and increased sleep time. Despite comparable caloric intake to control conditions, LiFE lowered baseline blood glucose, reduced glycemic variability, and improved glucose tolerance. We found long-term LiFE treatment improved recognition memory in WT mice. Sleep and circadian disruption are commonly observed in patients with Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. We applied long-term LiFE treatment in two AD mouse models (5xFAD and 5xFAD/PS19). Alongside a subtle reduction in AD histopathology, LiFE produced near-significant trends toward improved motor performance and recognition memory. Together, these findings support multimodal circadian chronotherapy as a non-pharmacological approach in which integrated light, feeding, and exercise entrainment promotes sleep and metabolic health.},
}

@article {pmid41889933,
year = {2026},
author = {Ruff, DA and Sheets, DEG and Srinath, R and Diniz, GB and Griggs, DJ and Beckman, D and Ott, S and Schwartz, K and Erices, C and Muller, S and Kordower, JH and Morrison, JH and Cohen, MR},
title = {Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.18.712735},
pmid = {41889933},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) and related dementias (ADRD) are defined by molecular and cellular pathology and cognitive decline, but linking these levels requires understanding how pathology alters large-scale neuronal activity. We longitudinally tracked behavior, multi-area neuronal population activity, and fluid and histological biomarkers in a macaque model of early-stage ADRD. As pathology progressed, visually guided behavior became increasingly disorganized, reflected in less structured exploration despite preserved task performance. Guided by systems neuroscience principles linking neuronal population activity with organized goal-directed behavior, we found progressive reductions in coordinated neuronal population activity within and between visual and parietal cortices, even as single-neuron tuning and basic feature encoding remained stable. These changes emerged when tau pathology was largely confined to regions providing feedback to visual cortex. This disorganized state appears modifiable: proof-of-concept methylphenidate administration was associated with transient improvement in behavioral organization. Together, these findings identify disruption of neuronal population organization as a defining feature of early-stage ADRD and frame early dysfunction as a disorder of coordinated population activity.},
}

@article {pmid41889952,
year = {2026},
author = {Tsagkogianni, C and Trivisonno, M and Willner, JS and Garcia-Molinero, C and Tang, Y and Mattina, B and Latorre-Leal, M and Wang, W and Roussarie, JP and Rodriguez-Rodriguez, P},
title = {Optineurin is a gatekeeper of mitochondrial health and proteostasis in Alzheimer's disease vulnerable neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.15.711617},
pmid = {41889952},
issn = {2692-8205},
abstract = {Alterations in autophagy-related pathways and in mitochondrial function have long been associated with the pathology of several neurodegenerative disorders, including Alzheimer's disease (AD). However, the cascade of events that links these processes and how they contribute to the early degeneration of specific neuronal subpopulations remain to be understood. Here, we use a data-driven approach and identify Optn as a potential regulator of AD pathology that is highly enriched in vulnerable ECII neurons compared to neurons that degenerate later in the disease continuum. We show that Optineurin downregulation triggers early dysregulation of mitochondrial function, followed by alterations in AD-associated processes, including proteostasis, synaptic function, and neuroinflammation. This is accompanied by ECII neuron loss and astrocyte reactivity in EC neuron projecting areas in the hippocampus. Together our results suggest that Optineurin plays a central role in the maintenance of mitochondrial health and bioenergetics in AD vulnerable neurons and that pathological processes that impair this homeostasis may contribute to the early degeneration of vulnerable ECII neurons.},
}

@article {pmid41889956,
year = {2026},
author = {Marshall, CR and Moser, FA and Scott, CF and Ventura-Antunes, L and Romero-Fernandez, W and Migas, ŁG and Tideman, LEM and Colley, ME and Dufresne, M and Schrag, MS and Van de Plas, R and Spraggins, JM},
title = {Multimodal Molecular Mapping of the Vasculature in Human Cortex Reveals Lipid Markers of Cerebral Amyloid Angiopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.13.711741},
pmid = {41889956},
issn = {2692-8205},
abstract = {Cerebral amyloid angiopathy (CAA) commonly co-occurs with Alzheimer's disease (AD), yet the molecular changes that accompany vascular β-amyloid deposition in human tissue remain incompletely defined. Herein, we use a novel imaging approach that combines matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS) with immunofluorescence microscopy on the same sections of postmortem human frontal cortex to map the lipid microenvironment of leptomeningeal vasculature in cases with and without CAA. Autofluorescence-guided regions-of-interest were imaged by IMS in both negative and positive ion modes and registered to post-IMS-acquired microscopy images. Immunofluorescence microscopy using collagen IV, α-smooth muscle actin (αSMA), and thiazine red enabled automated segmentation of total, amyloidpositive, and amyloid-negative vasculature regions. A CAA index, the ratio of amyloid-positive area to total vasculature area in a region imaged by IMS, was used to define vasculature and classify each case into having CAA, or CAA-present and not having CAA, or CAA-absent. An interpretable machine learning approach (XGBoost models with Shapley additive explanations for interpretation) was trained on pixel-level spectra and identified lipid signatures of vascular identity shared across groups as well as class-specific marker candidates that distinguished CAA-present from CAA-absent vasculature. CAA-present vessels were enriched for gangliosides (e.g. , GM1), whereas CAA-absent vessels were characterized by higher contributions from phosphatidylserines (e.g. , long-chain polyunsaturated PS species). Univariate differences were inconsistent between the two groups, but multivariate models in negative mode yielded stable discriminatory features. These results define spatial lipid correlates of vascular amyloid pathology in the human brain and establish a multimodal framework for mechanistically linking lipid metabolism, vascular integrity, and CAA in AD.},
}

@article {pmid41890007,
year = {2026},
author = {Park, S and Maldonado, DM and Kadnar, ML and Andrade, M and Fomitchova, AP and Liebman, SW and Derkatch, IL},
title = {Interactions between non-prion and prion domains of Rnq1 direct formation of amyloid vs liquid-like aggregates and create transmission barriers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.01.14.633072},
pmid = {41890007},
issn = {2692-8205},
abstract = {UNLABELLED: Prions are self-propagating protein conformations usually existing as amyloid aggregates. [ PIN [+] ], a prion form of the Rnq1 protein occasionally found in wild and laboratory yeast strains, facilitates both the de novo formation and destabilization of other yeast prions, and affects aggregation and toxicity of human misfolding disease proteins expressed in yeast. Rnq1 contains a short N-terminus with no confirmed function (the non-prion domain, NPD) and a C-terminus that carries four QN-rich regions and is sufficient for [ PIN [+] ] formation and maintenance (prion domain, PD). In the current study, a genetic screen identified the NPD T27P mutation that blocks transmission of the [ PIN [+] ] prion state from wild type Rnq1 (Rnq1 WT) to mutant Rnq1 T27P . The mutation doesn't prevent Rnq1 T27P from switching to a prion state when overexpressed in vivo , or from forming amyloid fibers in vitro . Furthermore, like [ PIN [+] WT ], the newly formed [ PIN [+] T27P ]s promote the de novo appearance of the Sup35-based prion [ PSI [+] ]. We conclude that the NPD mutation creates a barrier for prion transmission from [ PIN [+] WT ] to Rnq1 T27P . Because fluorescence microscopy shows that Rnq1 T27P efficiently joins [ PIN [+] WT ] aggregates, the barrier is likely due to the inability of Rnq1 T27P to propagate the specific [ PIN [+] WT ] conformational variant. Indeed, the analysis of [ PIN [+] T27P ]s resulting from rare transmission events from [ PIN [+] WT ] indicates that these [ PIN [+] T27P ]s must undergo conformational adaptation to yield more stable prion variants. Deletion analysis revealed that T27P constrains prion conformations through the first two QN-rich regions within the PD. The finding that Rnq1 T27P -YFP readily forms non-amyloid liquid-like droplets, which Rnq1 WT -YFP does not form, supports the idea that the NPD affects aggregation properties of the PD. We propose that these aggregation properties are essential for Rnq1's functions, such as controlling aggregation of other proteins. This provides new insight into the role of heterologous proteins and transmission barriers in the origins of protein misfolding diseases.

AUTHOR SUMMARY: Proteins must fold into the right shapes to work properly. Sometimes they fold incorrectly and stick together, forming long fiber aggregates that damage cells. This kind of "protein misfolding" causes human diseases such as Alzheimer's. Certain yeast proteins behave similarly, making them useful to study this process. We investigate a yeast protein called Rnq1, which has a region that helps it misfold into fibers. These fibers can also cause other, unrelated proteins to misfold. We found that a mutation in a different part of Rnq1- outside the aggregation region - reduces the ability of non-mutant Rnq1 fibers to convert mutant Rnq1 into growing fiber aggregates. We also identified which section of the aggregation region is affected by this mutation. Interestingly, although the rarely converted mutant aggregates grow poorly at first, they can eventually "adapt" into a shape that grows better. The same mutation also pushes Rnq1 to form liquid-like droplets instead of fibers. Our findings show that the non-aggregating part of Rnq1 controls how Rnq1 aggregates, and, consequently, the appearance and elimination of aggregates formed by other proteins. Our work also helps explain how barriers to misfolded protein growth can be overcome, which is relevant to understanding human protein misfolding diseases.},
}

@article {pmid41890022,
year = {2026},
author = {Barbour, AJ and Hoag, K and Lee, VMY and Talos, DM and Jensen, FE},
title = {Seizures drive tau propagation in a tauopathy mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.14.711088},
pmid = {41890022},
issn = {2692-8205},
abstract = {A bidirectional relationship between seizures and neurodegenerative disease has been established with neurodegenerative pathology found in late-onset epilepsy patients, increased risk of seizures in tauopathies, and accelerated Alzheimer's disease progression in patients with epileptiform activity. Tau pathology spreads between interconnected neuronal networks, driving disease progression. We hypothesized that seizures would promote tau propagation throughout the brain in a tauopathy mouse model. To explore the brain-wide relationship between tau pathology and seizure activity, we crossed the T40PL-GFP mouse, which contains a pathogenic MAPT mutation tagged with GFP, with targeted recombination in active population (TRAP; T40PL-TRAP) mice to label all seizure activated neurons with tdTomato. We triggered tau propagation in these mice with intracerebral seeding of human AD brain-derived tau lysate and induced seizures with pentylenetetrazol (PTZ) kindling. With light sheet microscopy, we imaged and mapped tau-GFP and tdT levels throughout whole brain. We found that PTZ induced seizures worsened tau pathology in brain regions with increased tdT levels, including the hippocampus and cortex, and in the fiber tracts in T40PL-TRAP mice. We also found that seizure-activated (tdT+) neurons were more likely to develop somatic tau pathology compared to the surrounding (tdT-) populations. Overall, these data demonstrate that seizures can enhance tau pathology propagation.},
}

@article {pmid41890040,
year = {2026},
author = {Wei, X and Munechika, K and Sun, Y and Wan, Y and Xia, T and Hou, Y and Song, W and Yugandhar, K and Wang, Y and Lee, SI and Sha, Z and Zhou, Y and Feng, W and Zhu, J and Tang, Y and Luo, W and Cheng, F and Gan, L and Yu, H},
title = {Interactome mapping in human excitatory neurons reveals novel risk genes and pathways in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.14.711835},
pmid = {41890040},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2's function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology.},
}

@article {pmid41890046,
year = {2026},
author = {Hu, H and Lin, PB and Zeng, C and Sharma, P and Li, Y and Jiang, H and Nulman, J and Ohara, RA and Wu, T and Li, S and Yokoyama, WM and Artyomov, MN and Murphy, KM and Ulrich, JD and Holtzman, DM},
title = {CD8 [+] T cells are primed by cDC1 and exacerbate tau-mediated neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.26.708260},
pmid = {41890046},
issn = {2692-8205},
abstract = {There are changes in adaptive immunity in Alzheimer's disease (AD) and increases in activated CD8 [+] T cells in brain correlate with tau pathology [1-3] . However, which cells mediate T cell priming in tau-mediated neurodegeneration remains unclear. In different conditions such as cancer, viral infections, and autoimmune diseases outside the CNS, conventional type-1 dendritic cells (cDC1) perform antigen cross-presentation to prime CD8 [+] T cells [4,5] . We demonstrate that tauopathy mice deficient in cDC1 are markedly protected against tau-mediated neurodegeneration and display a selective decrease in brain CD8 [+] T cell infiltration and glial reactivity. The remaining CD8 [+] T cells showed an antigen inexperienced status with less clonal expansion, indicating suboptimal T cell priming. We confirm that brain derived antigens are presented in secondary lymphoid tissues to prime CD8 [+] T cells. Our study identifies cDC1 cells as critical for CD8 [+] T cell priming outside the CNS. This priming is required for a large increase of activated CD8 [+] T cells in the brain which promotes tau-mediated neurodegeneration.},
}

@article {pmid41890066,
year = {2026},
author = {Sadleir, KR and Gomez, KP and Chandra, S and Ley, ML and Khatri, AW and Guo, J and Xue, Y and Cepko, CL and Vassar, R},
title = {Neuronal overexpression of Nrf2 reduces dystrophic neurites in 5XFAD Alzheimer's disease model mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.16.711596},
pmid = {41890066},
issn = {2692-8205},
abstract = {BACKGROUND: The hallmark lesions of the Alzheimer's disease (AD) brain are amyloid plaques consisting of the β-amyloid protein and neurofibrillary tangles comprised of hyperphosphorylated, aggregated tau protein, which both cause neuronal dysfunction and loss. One goal of neuroprotective therapies is to maintain normal neuronal function and survival in the presence of toxic pathologies such as plaques and tangles. A potential neuroprotective target is nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which regulates the expression of many antioxidant and detoxification genes. Nrf2 mRNA is decreased in AD brains, and deletion of the Nrf2 gene causes increased BACE1 and Aβ production and worsened cognitive deficits in amyloid pathology mouse models. Overexpression of Nrf2 in astrocytes has been shown to be protective against neurodegeneration, but the role of Nrf2 is neurons is unclear.

METHODS: We overexpressed Nrf2 from birth in neurons of 5XFAD amyloid pathology model mice using AAV8, hypothesizing that neuronal Nrf2 overexpression decreases cortical neuron loss and reduces plaque load by decreasing BACE1 levels. We quantified protein levels by immunoblot and neuropathology by immunofluorescent staining, using two-way ANOVA to measure differences between genotypes and AAV treatments. To assess genetic changes, we performed bulk mRNA seq.

RESULTS: While neuronal overexpression of Nrf2 in 5XFAD mice did not prevent neuronal loss as measured by NeuN labeling, decrease neuroinflammation by Iba1 or GFAP labeling, or reduce amyloid load by Aβ antibody or methoxy-XO4 staining, we show that increased Nrf2 expression reduces BACE1 protein levels, especially in swollen axonal dystrophic neurites around amyloid plaques. Other proteins that accumulate in dystrophic neurites were also reduced, indicating decreased dystrophic neurites overall. Immunoblot analysis suggested increased autophagy was unlikely to play a role, while bulk mRNA sequencing indicated changes in lipid metabolism and microtubule stability may have contributed to reduced dystrophic neurite formation.

CONCLUSIONS: Dystrophic neurites impair action potential conductance and contribute to tau seeding and spreading. Their reduction by neuronal Nrf2 overexpression may protect neurons against these pathologic changes. Further study of the mechanisms by which Nrf2 reduces dystrophic neurites may lead to therapeutic strategies that can limit neuritic damage caused by cerebral amyloid accumulation.},
}

@article {pmid41890077,
year = {2026},
author = {Lemon, NL and Canepa, E and Vázquez-Torres, R and Parodi-Rullán, R and Hirt, T and Petersohn, LM and Rifat, T and Abyaneh, MH and Ilies, MA and Fossati, S},
title = {Mitochondrial carbonic anhydrase-VB inhibition rescues brain endothelial stress and memory in Alzheimer's disease models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.16.711716},
pmid = {41890077},
issn = {2692-8205},
abstract = {Alzheimer's Disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated Amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CA) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial CA isoform CA-VB by pharmacological and genetic manipulation, in human cerebral microvascular endothelial cells (hCMEC) and we confirm the protective effects of the CA-V inhibitor in AD mice. CA-V inhibition and CA-VB KO prevent Aβ induced mitochondria-mediated endothelial apoptosis, loss of barrier resistance, and hCMEC inflammatory activation. Strikingly, CA-V inhibition also mitigates caspase activation and endothelial cell activation in the brains of 3xTg AD mice, resulting in preserved memory function. Our results demonstrate that selective CA-V inhibition is an effective and promising strategy against AD-mediated cerebrovascular pathology, neuroinflammation and cognitive impairment.},
}

@article {pmid41890089,
year = {2026},
author = {Blackhurst, BM and Bhatt, A and Kretchmer, E and Tucker, AE and Kurtz, B and Reagin, KL and Funk, KE},
title = {CD8[+] T cells induce interstrand crosslinking-associated DNA damage in neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.14.711737},
pmid = {41890089},
issn = {2692-8205},
abstract = {UNLABELLED: Viral pathogens cause neurologic sequelae during acute and post-acute phases of infection. CD8 [+] T cells are hypothesized to contribute to these effects, but the mechanisms through which they act are poorly understood. We posited that viral infections and/or antiviral immune responses induce DNA damage, which may underlie neuronal dysfunction. Using a model of neurotropic flavivirus infection, we found that genes associated with interstrand crosslinking (ICL) DNA damage were upregulated post-infection, temporally congruent with T cell infiltration. Using an in vitro co-culture system, our results demonstrate that CD8 [+] T cells induced ICL-like damage in primary neurons, independent of antigen-specific interactions or direct contact. Human transcriptomic data also showed overexpression of genes associated with ICL damage in the brains of people with Parkinson's disease, Alzheimer's disease, and multiple sclerosis, which are neurologic diseases characterized by neuroinflammation. Together, these data indicate that CD8 [+] T cells cause genotoxic DNA damage in neurons, which may underlie the neurologic dysfunction seen in neurodegenerative conditions.

SUMMARY: Results indicate that CD8 [+] T cells induce interstrand crosslinking-like DNA damage in neurons independent of antigen-specificity in a mouse model of viral infection, in vitro primary cell culture system, and human neurologic diseases. These findings provide insight on the mechanistic connection between neuroinflammation and neurologic dysfunction.},
}

@article {pmid41890202,
year = {2026},
author = {Zhu, T and Cai, L and Hu, L and Yang, D and Li, M and Quan, F and Lu, C and Liu, S and Cui, J},
title = {Cognitive improvement by non-pharmacological electrical stimulation modalities in mild cognitive impairment: a protocol for systematic review and network meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1752516},
pmid = {41890202},
issn = {1663-4365},
abstract = {OBJECTIVE: Mild cognitive impairment, characterized by progressive cognitive decline, represents a prevalent transitional state among the global aging population and demonstrates high conversion rates to Alzheimer's disease, establishing itself as a critical window for preventive interventions against AD. Although growing evidence supports the efficacy of various non-pharmacological therapies in enhancing cognitive function, their comparative effectiveness remains insufficiently elucidated. This study aims to analyze the efficacy and safety of different electrical stimulation modalities in treating MCI patients, quantitatively compare the therapeutic benefits across multiple interventions, and provide evidence-based recommendations to facilitate informed clinical decision-making.

METHODS: We will systematically search 13 databases. All relevant studies published from inception until November 1, 2025, will be retrieved. Two reviewers will independently assess the risk of bias for all included studies using the revised Cochrane Risk of Bias tool (RoB 2). The primary outcome will be the Montreal Cognitive Assessment score to evaluate changes in cognitive function. Secondary outcomes will include neuropsychological assessments related to cognition, such as the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), as well as the modified Barthel Index for activities of daily living and the patient-reported Pittsburgh Sleep Quality Index. Data synthesis will be performed using Stata software, employing a random-effects network meta-analysis model to compare the efficacy and safety of non-pharmacological electrical stimulation therapies. The surface under the cumulative ranking curve (SUCRA) will be used to estimate the probability of intervention hierarchies. The strength of evidence will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations framework.

CONCLUSION: This study will synthesize evidence from multiple studies on various electrical stimulation therapies for improving cognitive function in patients with mild cognitive impairment, thereby providing a diverse body of evidence to support clinical decision-making by physicians and optimization of treatment strategies for patients.

STUDY PROTOCOLS REGISTRATION: [https://www.crd.york.ac.uk/prospero/], identifier [CRD420251184505].},
}

@article {pmid41890204,
year = {2026},
author = {Yan, P and Du, X and Yang, S},
title = {Distinguishing early from late mild cognitive impairment: a multi-level analysis of regional morphometry and KLS-derived network topology.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1730305},
pmid = {41890204},
issn = {1663-4365},
abstract = {INTRODUCTION: Distinguishing between early Mild Cognitive Impairment (EMCI) and late mild cognitive impairment (LMCI) is crucial for clinical trials, but objective biomarkers are lacking. We therefore examined regional morphometry and network topology across cognitively normal (CN), EMCI, and LMCI groups to address this gap. We also evaluated whether combining these features could effectively classify mild cognitive impairment (MCI) subtypes.

METHODS: We analyzed T1-weighted magnetic resonance imaging (MRI) data from 208 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (67 CN, 83 EMCI, 58 LMCI). We used both voxel- and surface-based morphometry to measure local atrophy and combined this with graph analysis of individual structural covariance networks (SCNs). We also performed correlation and machine learning analyses.

RESULTS: We found that cortical thickness (CT) in EMCI was not significantly different from CN, but it was significantly reduced in the LMCI group. The right hippocampus and the left thalamus, however, showed a significant difference between CN and EMCI. In the Kullback-Leibler (KL) divergence-based similarity (KLS) network analysis, the EMCI group showed a greater randomization when compared to the LMCI group, while LMCI was accompanied by elevated nodal centrality in the left hippocampus and orbital frontal region. Correlation analysis confirmed this was a maladaptive phenomenon, as higher centrality was linked to poorer cognitive performance. Finally, a classifier combining these structural and network features successfully differentiated the MCI subtypes.

CONCLUSION: Our findings suggest that differences in Gray matter volume (GMV) may be more easily observed in the EMCI group. We identified a corresponding non-linear pattern of network topology, characterized by randomization in the EMCI group than in the LMCI. These multi-faceted biomarkers enabled the accurate machine-learning-based differentiation of MCI subtypes, offering a powerful framework for improving patient stratification in clinical trials.},
}

@article {pmid41890356,
year = {2026},
author = {Sun, P and Peng, W and Li, LY and Wang, Y and Pohl, KM},
title = {Evaluation of 3D Counterfactual Brain MRI Generation.},
journal = {Deep generative models : 5th MICCAI workshop, DGM4MICCAI 2025, held in conjunction with MICCAI 2025, Daejeon, South Korea, September 23, 2025, Proceedings. DGM4MICCAI (Workshop) (5th : 2025 : Taejon-si, Korea)},
volume = {16128},
number = {},
pages = {46-56},
pmid = {41890356},
abstract = {Counterfactual generation offers a principled framework for simulating hypothetical changes in medical imaging, with potential applications in understanding disease mechanisms and generating physiologically plausible data. However, generating realistic structural 3D brain MRIs that respect anatomical and causal constraints remains challenging due to data scarcity, structural complexity, and the lack of standardized evaluation protocols. In this work, we convert six generative models into 3D counterfactual approaches by incorporating an anatomy-guided framework based on a causal graph, in which regional brain volumes serve as direct conditioning inputs. Each model is evaluated with respect to composition, reversibility, realism, effectiveness and minimality on T1-weighted brain MRIs (T1w MRIs) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In addition, we test the generalizability of each model with respect to T1w MRIs of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). Our results indicate that anatomically grounded conditioning successfully modifies the targeted anatomical regions; however, it exhibits limitations in preserving non-targeted structures. Beyond laying the groundwork for more interpretable and clinically relevant generative modeling of brain MRIs, this benchmark highlights the need for novel architectures that more accurately capture anatomical interdependencies. Code: https://github.com/pengwei2000/counterfactual_3DMRI.},
}

@article {pmid41890380,
year = {2026},
author = {Devi, MD and Padmavathi, P},
title = {Effectiveness of Nursing Strategies on Memory and Sleep Quality among Patients with Alzheimer's Disease in a Selected Centers at Coimbatore.},
journal = {Journal of pharmacy & bioallied sciences},
volume = {18},
number = {1},
pages = {65-67},
pmid = {41890380},
issn = {0976-4879},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a decline in memory, cognition, sleep quality, and activities of daily living. Non-pharmacological, nursing strategies are increasingly emphasized to improve the quality of life among patients with AD.

AIM: To evaluate the effectiveness of nursing strategies on memory and sleep quality among patients with AD.

METHODS: A quantitative, true experimental pretest-posttest control group design was adopted. The pilot study was conducted among 44 patients with AD (22 experimental and 22 control) selected through simple random sampling from a selected centers at Coimbatore. The experimental group received nursing strategies comprising visual images, mnemonic training, dyadic sleep intervention, and pumpkin seed supplementation for 3 months, while the control group received routine care. Memory was assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Activity of Daily Living (ADL) inventory and sleep quality using the Pittsburgh Sleep Quality Index (PSQI). Descriptive and inferential statistics were used for analysis.

RESULTS: Postintervention, the experimental group demonstrated significant improvement in memory (t = 10.962, P < 0.001) and sleep quality (t = 14.329, P < 0.001) compared to the control group, which showed no significant changes.

CONCLUSION: Nursing strategies were effective in improving memory and sleep quality among patients with AD. These findings support the incorporation of structured nursing interventions into routine Alzheimer's care.},
}

@article {pmid41890415,
year = {2025},
author = {Pinzon, MM and Garcia, DM and Perales-Puchalt, J},
title = {Policy and Organizational Factors that Affect the Utilization of Health Services for Alzheimer's Disease Among the Latino Community - The Primary Care Provider Perspective.},
journal = {Journal of the National Hispanic Medical Association},
volume = {3},
number = {2},
pages = {54-66},
pmid = {41890415},
issn = {2693-8960},
abstract = {BACKGROUND: Latino individuals bear a disproportionate burden of Alzheimer's disease and related dementias (ADRD), with higher risk, underdiagnosis, and limited access to quality care. Primary care providers (PCPs) are crucial for early detection and management. However, organizational and policy factors significantly impact their ability to provide culturally competent and equitable ADRD care for this community. This study explores PCP perspectives on these organizational and policy factors to inform the development of accessible models that improve early diagnosis, preventive care, and quality of life for Latino individuals with ADRD.

METHODS: We used thematic analysis to analyze qualitative interviews with 23 diverse PCPs across the United States. We recruited our sample using snowball sampling. We strengthened the validity of our findings by using rigorous data reduction techniques.

RESULTS: Key themes emerged, highlighting the interplay of organizational and policy factors: 1) Insurance eligibility and care options for those uninsured were foremost, with mandated language services facing access and quality challenges that affected the ability of clinicians to perform an accurate diagnosis. 2) Staffing and available resources dictated the type of care offered, leading to inconsistent protocols and options. Providers reported that workup was influenced by their level of training, time availability, and comfort. 3) While recognized as crucial, comprehensive assessments that include evaluation of their home and social environment were limited by appointment constraints and lack of follow-up resources.

CONCLUSION: Economic and organizational factors, including insurance, costs, staffing models, and resource navigation, shape PCPs' ability to deliver culturally competent and equitable ADRD care. Future interventions should address these barriers by training PCPs in dementia-related diagnostic procedures in Latino communities and developing accessible service models and culturally appropriate diagnostic tools.},
}

@article {pmid41890452,
year = {2026},
author = {Arriaga, P and Vianna, K and Montez, C and Panariello, B and Tran, S and Rodrigues, D and Porto Barboza, E},
title = {Association of Periodontal Pathogens and Their Inflammatory Mediators With Alzheimer's Disease Neurodegeneration: A Systematic Review.},
journal = {Cureus},
volume = {18},
number = {2},
pages = {e104127},
pmid = {41890452},
issn = {2168-8184},
abstract = {Periodontitis is implicated in a range of systemic conditions, including cardiovascular disease, diabetes, and respiratory disorders. Emerging evidence suggests a link between periodontal infection, inflammation, and the neurodegenerative process of Alzheimer's disease (AD). This paper aimed to systematically review observational studies examining the association of periodontal pathogens and their inflammatory products with AD neurodegeneration. The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO - No. CRD42020150043). Methods followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search (PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Web of Science, Scopus, Cochrane Library, grey literature) was conducted until September 2025 with no language or date restrictions. Two independent reviewers screened and extracted data. The risk of bias was assessed via the Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS‑E) tool. Of 1,421 identified citations, eight studies met the inclusion criteria. Participant numbers ranged from 349 to 2,191, and ages ranged from 40 to 90 years old. Meta‑analysis was not feasible due to methodological heterogeneity. Risk of bias was moderate in five studies and serious in three. Findings indicated that higher serum IgG antibodies to periodontal pathogens and elevated inflammatory mediators, notably tumor necrosis factor-alpha (TNF‑α), correlated with greater cognitive decline and markers of AD neurodegeneration, including MRI outcomes and APOE ε4 status. In conclusion, the current body of evidence suggests a potential association between periodontitis‑related inflammatory mediators, particularly TNF‑α, and elevated antibody responses to periodontal pathogens with AD progression. However, causality remains unestablished. Future prospective cohort and interventional studies are warranted to clarify the role of periodontal infection and inflammation in AD and to guide clinical strategies that may improve outcomes in AD populations.},
}

@article {pmid41890557,
year = {2026},
author = {Aguero, C and Klein, CZ and Haase, G},
title = {Why it should be "Alzheimer disease" rather than "Alzheimer's disease".},
journal = {Free neuropathology},
volume = {7},
number = {},
pages = {7},
pmid = {41890557},
issn = {2699-4445},
abstract = {The terms "Alzheimer's disease" and "Alzheimer disease" are often used interchangeably in the biomedical literature. Yet this seemingly minor grammatical difference carries implications that extend beyond style: the possessive form, marked by the 's eponym, may imply ownership of a disease by an individual, a notion discouraged by several authoritative medical style guides and international health organizations [1]. In this article, we examine the historical emergence of the term "Alzheimer's disease", analyze the trajectories of the possessive and non-possessive eponyms in PubMed-indexed article titles from 1950 to 2025, and assess how the choice of terminology influences literature retrieval. Our analysis indicates that the possessive form has overwhelmingly dominated the literature for decades. However, searches using "Alzheimer's disease" or "Alzheimer disease" retrieve non-identical, only partially overlapping sets of records in PubMed. We argue that adopting the non-possessive form "Alzheimer disease" would improve conceptual clarity, terminological consistency, and the completeness of literature retrieval, particularly in systematic reviews and meta-analyses.},
}

@article {pmid41890613,
year = {2026},
author = {Vazquez-Palomo, A and Betegón, C and Weickenmeier, J and Martínez-Pañeda, E},
title = {A computational framework to predict the spreading of Alzheimer's disease.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41890613},
issn = {2331-8422},
abstract = {Alzheimer's disease is characterised by the spreading of misfolded proteins and progressive structural changes in the brain. Despite significant clinical research, understanding how microscopic protein dynamics translate into macroscopic tissue degeneration remains a major challenge. In this work, we present a three-dimensional, finite element-based computational framework to model disease progression by combining multi-protein transport and brain tissue deformation within anatomically realistic geometries. The propagation of toxic tau and amyloid-beta proteins is described using reaction-diffusion equations of the Fisher-Kolmogorov type, incorporating prion-like growth mechanisms and anisotropic transport along white matter fibre tracts. Brain atrophy is represented through a hyperelastic constitutive model driven by protein-dependent volume loss. Subject-specific simulations are achieved through an automated preprocessing pipeline that generates finite element meshes and reconstructs axonal orientation fields from medical imaging data. The model reproduces key morphological patterns observed in Alzheimer's disease and shows good quantitative agreement with longitudinal imaging measurements. Overall, the proposed framework offers an extensible computational platform for studying Alzheimer's disease progression across subject-specific brain geometries. The models developed, including the image processing framework (BrainImage2Mesh) and the coupled bio-chemo-mechanical COMSOL finite element implementation, are made freely available to download at https://mechmat.web.ox.ac.uk/codes.},
}

@article {pmid41890703,
year = {2026},
author = {Li, X and Liu, F and Zhu, Y and Shi, H},
title = {Gut Microbiota, Insulin Resistance, and Alzheimer's Disease: A Narrative Review of Mechanistic Links and Therapeutic Perspectives.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {593664},
pmid = {41890703},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD) is increasingly regarded as a "neurometabolic syndrome" wherein systemic insulin resistance exacerbates cerebral glucose hypometabolism, tau hyperphosphorylation, and neuroinflammation. We hypothesize that gut microbiota dysbiosis produces metabolites that are associated with peripheral insulin sensitivity, potentially contributing to disruptions in cerebral insulin signaling and an increased risk of AD. We conducted integrated search of PubMed, Web of Science, and Scopus to synthesize evidence showing: (i) consistent taxonomic shifts in AD, highlighting reduced Firmicutes and increased Proteobacteria and Bacteroidetes, depletion of Ruminococcaceae and enrichment of Blautia and Bilophila; (ii) functional consequences of dysbiosis, leading to lower short-chain fatty acids, altered secondary bile‑acid signaling, elevated lipopolysaccharide and trimethylamine‑N‑oxide, and perturbed tryptophan catabolism; (iii) these microbial metabolites compromising gut and blood-brain barrier integrity, thereby triggering chronic inflammation, potentially modulating the PI3K‑Akt‑GSK‑3β pathway, and linking peripheral insulin resistance to cerebral dysfunction; and (iv) a translational discussion of therapeutic strategies that target both microbiota and insulin pathways, including dietary modulation, probiotics and prebiotics, fecal microbiota transplantation, intranasal insulin, metformin, and metabolite-based agents, show promise. This review uniquely integrates taxonomic, functional, and therapeutic literature to propose a mechanistic microbiota-insulin resistance-AD axis and highlights the need for longitudinal and interventional trials.},
}

@article {pmid41890752,
year = {2026},
author = {Wu, Z and Zhang, Y and Wang, L and Yi, Y and Dai, B and Chen, H and Yang, F},
title = {Periodontitis and systemic diseases: insights into the correlation, mechanisms, and clinical implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1777955},
pmid = {41890752},
issn = {1664-3224},
mesh = {Humans ; *Periodontitis/immunology/epidemiology ; Cardiovascular Diseases ; Animals ; Oxidative Stress ; Arthritis, Rheumatoid ; Helicobacter Infections ; Alzheimer Disease ; Diabetes Mellitus/epidemiology ; Renal Insufficiency, Chronic ; Inflammation ; },
abstract = {Periodontitis is a chronic oral infectious inflammatory disease caused by dental plaque, affecting approximately 35% - 50% of adults globally. Far from a localized oral condition, it exerts systemic pathogenic effects through multiple biological conduits. This review synthesizes current evidence on the bidirectional associations between periodontitis and a broad spectrum of systemic disorders, including cardiovascular disease (CVD), diabetes mellitus (DM), respiratory diseases, preterm birth, Alzheimer's disease (AD), chronic kidney disease (CKD), rheumatoid arthritis (RA), and Helicobacter pylori (H. pylori) infection. Furthermore, the review delves into the potential pathophysiological mechanisms underpinning these associations, with emphasis on bacterial translocation, systemic inflammation, immune dysregulation, and oxidative stress pathways. The concluding remarks underscore the critical importance of preserving optimal periodontal health as a cornerstone of systemic wellbeing.},
}

Humans
*Periodontitis/immunology/epidemiology
Cardiovascular Diseases
Animals
Oxidative Stress
Arthritis, Rheumatoid
Helicobacter Infections
Alzheimer Disease
Diabetes Mellitus/epidemiology
Renal Insufficiency, Chronic
Inflammation

@article {pmid41890831,
year = {2026},
author = {Haapasalo, K and Heiland, L and Kumar, DKV and Uvarov, P and Moir, A and Maaser-Hecker, A and Wang, X and Juselius, E and Syed, S and Tuhkala, A and Kajander, T and Lappalainen, M and Hytönen, J and Varjosalo, M and Kim, DY and Kamm, R and Meri, T and Choi, SH and Tanzi, R},
title = {Innate Immune Evasion of Lyme Disease Pathogen Drives Alzheimer-Like Pathology.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8804079/v1},
pmid = {41890831},
issn = {2693-5015},
abstract = {The amyloid β (Aβ) peptide is the main component of amyloid plaques in Alzheimer's disease (AD). Growing evidence has pointed to a role for Aβ as an antimicrobial peptide (AMP). However, the interactions of Aβ with neurotropic pathogens and host evasion strategies have remained largely unexplored. Using quantitative proteomic analysis of patient cerebrospinal fluid (CSF), advanced biochemical methods, and four different 3D brain models, ranging from blood-brain barrier (BBB) microfluidic systems to 3D neurovascular networks, we show that Lyme neuroborreliosis (LNB) Borrelia spp. induce molecular and immunological alterations in the central nervous system (CNS) that resemble key pathological features of AD. These include upregulation of the complement cascade and a decrease in CSF Aβ levels. By assessing the antimicrobial action of Aβ against Borrelia spp., we demonstrate that Aβ acts as a pre-opsonin by promoting complement activation on microbial surfaces. We also show that LNB Borrelia spp. exhibit unique survival strategies that reduce Aβ binding and block oligomerization, while halting complement attack by recruiting complement regulator factor H. This facilitates bacterial adhesion to the BBB, and modulation of glial and cytokine responses, fostering CNS invasion. Our findings reveal a previously unrecognized mechanism of bacterial immune escape spanning the entire invasion pathway from the BBB to neuronal compartments, demonstrating that LNB Borrelia spp. evade Aβ-mediated antimicrobial action by interfering with opsonization and oligomerization of the peptide. Collectively, these findings provide a direct mechanistic link between pathogen immune evasion, Aβ dynamics, and neuroinflammatory cascades, advancing our understanding of infection-induced neuropathology, offering insights into novel potential therapeutic targets for AD and neuroborreliosis.},
}

@article {pmid41890852,
year = {2026},
author = {Ramirez, G and Hernandez, D and Teal, A and Chellaganapathy, L and Pianeta, R and Segvich, DM and Wallace, JM and Plotkin, LI},
title = {Moderate Effects of the Arginine to Histidine R47H Variant of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) on Bone Structure in Male and Female Mice: Insights from the Four Core Genotypes mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9076483/v1},
pmid = {41890852},
issn = {2693-5015},
abstract = {Background The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) gene is expressed in cells of the hematopoietic lineage, like microglia and osteoclasts. A TREM2 gene variant known as TREM2-R47H is associated with an increased risk of developing Alzheimer's disease (AD). Previous studies have shown sex-dimorphic bone and muscle consequences that are associated with the TREM2 variant. Sex chromosomes have also been shown to play a key contributor to skeletal mass and bone strength. Due to the sex-dimorphic bone and skeletal muscle phenotype exhibited by mice expressing the TREM2 gene variant, we investigated the role of chromosomal (XX vs XY) or gonadal (ovaries vs testes) sex. Methods Four Core Genotypes (FCG) C57Bl/6J mice expressing the TREM2-R47H variant were mated to obtain TREM2 wildtype (TREM2 [+/+] , WT) and TREM2 [R47H/+] FCG mice. Four to 5.5-month-old gonadal male (XXT and XYT) and female (XXO and XYT) mice were analyzed. Body weight and bone mineral density were initially measured at baseline and endpoint (5.5 months of age) by DXA/Piximus. Micro-computed tomography, dynamic histomorphometry, 3-point bending test (mechanical properties), and bone turnover markers were measured at the endpoint. Two-way ANOVA analyses were performed through Prism 10 to identify the contributions of chromosome sex, the presence of the TREM2-R47H variant, and their interaction, separately for each gonadal sex. Results Gonadal males: chromosome sex (XX/XY) effects are found for several bone structural parameters in femur and lumbar vertebra 5, whereas there was an interaction between gonadal sex and chromosome sex for other structural measurements in both bones by µCT. Overall, values are higher for TREM2 [R47H/+] than WT for XYT, but not XXT mice, suggesting that the TREM2 genotype effects depend on the presence of the Y chromosome. Mechanical testing shows chromosome sex effects, with higher overall values for XXT mice. Bone formation on the femur cortex and serum formation/resorption markers were unchanged, suggesting that structural changes result from bone modeling/remodeling at an earlier age. Gonadal females: Chromosome sex affects body weight gain (higher in XYO than XXO mice), but no bone mineral density accrual. Chromosome sex affects total lean mass (XYO > XXO) with chromosome sex x TREM2 genotype interaction and differences in total/%fat mass (TREM2 [R47H/+] WT) only for XYO mice. Chromosome sex affects distal femur volumetric bone mass (XYO > XXO), but the TREM2 genotype influences lumbar vertebra trabecular number and separation, which trended higher in TREM2 [R47H/+] vs WT mice for sex complement. Chromosome sex influences femur cortical bone, with overall higher values in XXO mice, independent of TREM2 genotype. Mechanical testing parameters also were XXO > XYO mice. Femur cortical bone formation is higher on the endocortical but lower on the periosteal surface in XXO vs XYO (chromosome sex effect). The opposite effects on the bone surfaces might explain the unchanged serum bone formation marker, Procollagen Type 1 N-terminal propeptide (P1NP). Yet, chromosome sex affects the levels of the resorption marker, C-terminal telopeptide of type 1 collagen (CTX-1), which were lower in XXO mice. Conclusion Our findings suggest that chromosome sex partially affects the consequences of expression of the TREM2-R47H variant on bone structure, whereas the outcomes of the gene variant depend on the mouse gonadal sex.},
}

@article {pmid41890856,
year = {2026},
author = {Rodríguez-Baz, Í and Vaqué-Alcázar, L and Maure-Blesa, L and Pertierra, L and Martinez, JA and Molina-Porcel, L and Aldecoa, I and Ferreira, N and Paradela, R and Videla, L and Barroeta, I and Carmona-Iragui, M and Sánchez-Saudinós, MB and Selma-González, J and Dols-Icardo, O and Aranha, MR and Dolcet, SS and Abdelnour, C and Illán-Gala, I and Alcolea, D and Lleo, A and Suemoto, C and Fortea, J},
title = {Amyloid-linked versus age-driven copathologies in Alzheimer's dementia: differential associations with APOE ε4.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9044264/v1},
pmid = {41890856},
issn = {2693-5015},
abstract = {The mechanisms by which apolipoprotein E (APOE) drives copathologies in established Alzheimer's disease (AD) dementia via amyloid-dependent versus age-driven pathways remain unresolved. Analyzing data from 11,897 autopsied individuals from the National Alzheimer's Coordinating Center, with copathology analyses restricted to amyloid-positive AD dementia, we show that APOE effects followed two distinct trajectories. Cerebral amyloid angiopathy exhibited a striking ε4 dose-response (OR = 5.76, 95% CI: 4.20-7.96, p < 0.001; for ε4/ε4 compared to ε3/ε3), whereas arteriolosclerosis and atherosclerosis risk increased with age, independent of APOE haplotype. Lewy body pathology showed modest APOE associations restricted to limbic/amygdalar-predominant forms and was related to dementia duration, suggesting AD-mediated secondary synucleinopathy. TDP-43 pathology was associated with chronological age, demonstrating regional progression with minimal APOE dependence. These findings suggests that in amyloid-positive AD dementia, APOE ε4 selectively amplifies amyloid-related pathology, particularly cerebral amyloid angiopathy, while other copathologies accumulate through age-driven, APOE haplotype-independent processes.},
}

@article {pmid41891004,
year = {2026},
author = {Roberts, KF and Abrams, ZB and Cappelletti, L and Moqri, M and Heugel, N and Caufield, JH and Bourdenx, M and Li, Y and Banerjee, J and Foschini, L and Galeano, D and Harris, NL and Li, M and Ying, K and Melendez, JA and Barthélemy, NR and Bollinger, JG and He, Y and Ovod, V and Benzinger, TLS and Flores, S and Gordon, BA and Ojewole, AA and Phatak, M and Elbert, DL and Biber, S and Landsness, EC and Mungall, CJ and Bateman, RJ and Reese, JT},
title = {OpenScientist: evaluating an open agentic AI co-scientist to accelerate biomedical discovery.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.15.26348338},
pmid = {41891004},
abstract = {BACKGROUND: Advances in medicine depend on analyzing large and complex data sources, but discovery is partly constrained by the limited time and domain expertise of human researchers. Agentic artificial intelligence (agentic AI) can accelerate discovery by automating components of the scientific workflow, including information retrieval, data analysis, and knowledge synthesis.

AIM: OpenScientist, an open-source agentic AI co-scientist, aims to accelerate biomedical discovery by semi-autonomously investigating scientist-defined queries and generating clinically relevant, verifiable scientific insights.

METHODS: Domain experts evaluated OpenScientist for novel discoveries in four clinical case studies: (1) a prespecified analysis in a community-based Alzheimer's disease biomarker cohort, (2) unsupervised modeling for plasma proteomic survival prediction, (3) hypothesis investigation in single-cell transcriptomic data from neurons with neurofibrillary tangles, and (4) hypothesis generation with validation in a multiple myeloma dataset with a randomized negative control.

RESULTS: OpenScientist completed analyses in minutes that otherwise would take weeks to months of human time and expertise. It identified %ptau217 as the best predictor of amyloid PET status, generated a plasma proteomic survival model with performance comparable to published models, proposed a mechanism linking tau pathology to altered lysosomal acidification, and generated multiple myeloma hypotheses that were validated in an external cohort while distinguishing true signal from randomized controls.

CONCLUSION: OpenScientist demonstrates that open, auditable, agentic AI can support real-world clinical research by generating hypotheses, executing analyses, and discovering insights from complex datasets.},
}

@article {pmid41891033,
year = {2026},
author = {Gong, J and Bloomberg, M and Scholes, S and Hao, X and Salih, DA and Zaninotto, P and Steptoe, A},
title = {Proteomics signatures associated with cognitive trajectories: evidence from the English Longitudinal Study of Ageing.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.19.26348791},
pmid = {41891033},
abstract = {Alzheimer's disease and related dementias (ADRD) pose a growing global health challenge, with early detection critical to slowing cognitive decline and prevent ADRD. We analyzed high-throughput plasma proteomics in 2,460 cognitively healthy adults from the English Longitudinal Study of Ageing (ELSA) to identify proteins linked to 15-year cognitive trajectories, including verbal fluency, episodic memory, and orientation. Mixed-effect linear models revealed 34 proteins associated with faster orientation decline and 18 with accelerated episodic memory decline. Enrichment analyses implicate extracellular matrix remodeling, immune signaling, apoptosis, and lysosomal-autophagic pathways in cognitive deterioration. Subgroup analyses showed sex-specific effects, highlighting heterogeneity in proteomics signatures in cognitive aging. Notably, ten identified proteins are targets of drugs under clinical investigation, suggesting opportunities for therapeutic repurposing. These findings define a plasma proteomic signature associated with decline in domain-specific cognitive functions, offering promising biomarkers and druggable targets to prevent or slow age-related cognitive decline.},
}

@article {pmid41891046,
year = {2026},
author = {Kohli, M and Castro Leal, G and Wyllie, D and Oxtoby, N and Leech, R and Weston, P and Cole, J and , },
title = {AutoML-Multiverse: An Instability-Aware Framework for Quantifying Analytic Variability in Alzheimer's Disease Machine-Learning Studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.13.26347938},
pmid = {41891046},
abstract = {UNLABELLED: Machine-learning (ML) models for Alzheimer's disease (AD) frequently yield divergent conclusions, raising concerns about robustness, reproducibility, and interpretability. This instability is partially driven by researcher biases and analytic variability. Coupled with the clinical heterogeneity, mixed pathologies, and cohort differences in AD research, these issues limit the reliability and validity of conclusions from individual models. We introduce AutoML-Multiverse, an instability-aware framework characterising how analytic choices influence ML-based conclusions. The AutoML-Multiverse explores a large space of ∼20,000 analysispipelines and by retaining the full distribution of pipelines, enables direct examination of analytic variability. We evaluate this framework across 20 classification tasks in two independent cohorts studying Alzheimer's disease progression (ADNI, N≤1,930; NACC, N≤1,057), using multiple data modalities: neuroimaging, clinical/cognitive and fluid biomarkers. AutoML-Multiverse performance was equal to or better than non-automated models across all tasks. For example, stable versus progressive mild cognitive impairment (MCI) classification accuracy was 0.68±0.06 (ADNI) and 0.63±0.08 (NACC), while AD versus cognitively normal (CN) classification reached 0.97±0.01 (ADNI). Crucially, each modality's utility was task- and cohort-dependent: clinical measures dominated diagnostic tasks, whereas imaging better predicted progression, with modality preferences often switching between cohorts, highlighting limited generalisability of single-cohort results. Using the AutoML-Multiverse, we obtained strong classification performance without pre-specifying key model design choices. By reducing analysis-driven variability and explicitly characterising uncertainty, instability-aware evaluation can support the development of more robust and clinically applicable prediction models in AD research.

HIGHLIGHTS: AutoML-Multiverse systematically quantifies analytic instability in clinical ML.Analysis of ∼20,000 pipelines across ADNI and NACC cohorts.Pipeline choices substantially alter model rankings and biomarker importance.Cross-cohort variability highlights risks of single-dataset studies.Instability-aware evaluation improves robustness of AI-driven research.},
}

@article {pmid41891120,
year = {2026},
author = {Grande, I and Schmidt, SN and Reines, E and Christensen, MC},
title = {Vortioxetine in Subgroups of Patients with Major Depressive Disorder and Early-Stage Dementia: Further Results from the MEMORY Study.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {549106},
pmid = {41891120},
issn = {1176-6328},
abstract = {BACKGROUND: Depression and dementia are common in older adults; however, many antidepressants have limited effectiveness in patients with major depressive disorder (MDD) comorbid with dementia. In the MEMORY study (NCT04294654), significant improvements in depressive symptom severity, cognitive performance, overall functioning, and health-related quality of life were seen in patients with MDD and early-stage dementia during treatment with vortioxetine. This subgroup analysis was undertaken to further explore the effectiveness of vortioxetine in this patient population.

METHODS: MEMORY was a multinational, open-label, Phase IV study. Patients (n = 82) aged 55-85 years with MDD and early-stage dementia were treated with vortioxetine (5-20 mg/day) for 12 weeks. This was a post-hoc analysis for four key subgroups of patients in this study: (i) those with Alzheimer's disease (n = 35), (ii) those with mixed-type dementia (n = 22), (iii) those receiving concomitant drugs for dementia (n = 34), and (iv) those with severe depression (Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≥30) at baseline (n = 42).

RESULTS: Significant improvement in depressive symptom severity was seen in all patient subgroups from week 1 onwards (P < 0.05). At week 12, the mean change from baseline ranged from approximately -12 to -14 for MADRS total score (P < 0.0001), -6 to -8 for MADRS anhedonia subscore (P < 0.0001), and +3 to +6 for Digit Symbol Substitution Test score (P < 0.05). Improvements in verbal memory, ability to perform activities of daily living, health-related quality of life, and overall disease severity were also observed in all patient subgroups.

CONCLUSION: Our findings provide further support for the effectiveness and tolerability of vortioxetine in patients with MDD and early-stage dementia. Clinically significant improvement in depressive symptoms, cognitive performance, and health-related quality of life during treatment with vortioxetine was observed in patients with Alzheimer's disease, those with mixed-type dementia, patients receiving concomitant treatment with drugs for dementia, and those with severe depression.},
}

@article {pmid41891254,
year = {2026},
author = {Harrison, EM and Maki, PM and Chang, Y and Wu, M and Kamboh, MI and Aizenstein, H and Thurston, RC},
title = {Associations of anxiety and worry symptoms with cognitive performance among midlife women: importance of APOE4 genotype status.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13803395.2026.2647965},
pmid = {41891254},
issn = {1744-411X},
abstract = {INTRODUCTION: Anxiety symptoms and disorders are the most common psychiatric conditions among women and can have implications for cognitive performance. Anxiety may be notably prevalent during the menopause transition, a midlife transition experienced by most women. There is limited understanding about the relationship of anxiety to women's cognitive performance at midlife. Further, little research has considered how the relationship between anxiety and cognition may vary by apolipoprotein E4 (APOE4) genotype status, a known risk factor for Alzheimer's disease.

METHODS: Two hundred and sixty-one women underwent study procedures, including assessments of anxiety and worry symptoms, a comprehensive neuropsychological battery, and phlebotomy. Factor analysis was used to derive cognitive factors. Associations of anxiety and worry with cognitive factors were tested with linear regression. Interactions by APOE4 were tested.

RESULTS: Associations of trait anxiety and worry symptoms with cognitive factors significantly varied by APOE4 status (interaction p's < 0.05). Among APOE4 carriers, higher trait anxiety was associated with poorer cognitive performance, including poorer verbal learning/memory (b[SE] = -0.361[0.143], p = 0.037), attention/working memory (b[SE] = -0.272[0.121], p = 0.048), and verbal fluency (b[SE] = -0.412[0.117], p = 0.005). Similar patterns were observed for worry.

CONCLUSIONS: Findings underscore the importance of anxiety and worry for women's cognitive performance at midlife among APOE4 carriers. They suggest the potential value of treating anxiety symptoms in APOE4 carriers to support women's cognition at midlife and beyond.},
}

@article {pmid41891380,
year = {2026},
author = {Zeng, X and Li, Y and Hua, L and Lu, R and Franco, LL and Kochunov, P and Chen, S and Detre, JA and Wang, Z and , },
title = {Spatially and temporally progressive hypoperfusion in Alzheimer's disease revealed by normative modeling.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71203},
doi = {10.1002/alz.71203},
pmid = {41891380},
issn = {1552-5279},
support = {R01AG081693/AG/NIA NIH HHS/United States ; R01AG070227/AG/NIA NIH HHS/United States ; R33AG080518/AG/NIA NIH HHS/United States ; R01 EB031080/EB/NIBIB NIH HHS/United States ; //the University of Maryland Baltimore/ ; 1UL1TR003098//Institute for Clinical and Translational Research, University of Maryland, Baltimore/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology/pathology ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology ; *Cerebrovascular Circulation/physiology ; *Brain/diagnostic imaging/pathology/blood supply ; Disease Progression ; Aged, 80 and over ; Spin Labels ; Middle Aged ; },
abstract = {INTRODUCTION: Cerebral perfusion is implicated in Alzheimer's disease (AD), but its development in AD and mild cognitive impairment (MCI) is not well characterized.

METHODS: We constructed a normative model using > 12,000 arterial spin labeling MRI scans and applied generalized additive models for location, scale, and shape (GAMLSS). Individual deviation z scores were derived by normative model, and outlier regions (z ≤ 2.3) were quantified as the total negative proportion (TNP) of extreme hypoperfusion. These metrics were then related to other AD biomarkers through linear modeling.

RESULTS: Compared to cognitively normal controls, AD showed higher TNP and greater longitudinal increases (p = 0.003), indicating progressive hypoperfusion. Progressive MCI exhibited greater perfusion decline than stable MCI (p = 0.01). Perfusion changes correlated with cognition, brain volume, amyloid, and apolipoprotein E status (all p < 0.05).

DISCUSSION: Normative modeling revealed inter-individual heterogeneity in cerebral perfusion trajectories, underscoring its potential relevance for AD development.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology/pathology
Male
Female
Aged
Magnetic Resonance Imaging
*Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology
*Cerebrovascular Circulation/physiology
*Brain/diagnostic imaging/pathology/blood supply
Disease Progression
Aged, 80 and over
Spin Labels
Middle Aged

@article {pmid41891882,
year = {2026},
author = {Yokoyama, M and Kobayashi, H and Kaneko, N and Naito, H and Ota, K and Sekiya, S and Ikemura, K and Opoku, G and Hirohata, S and Iwamoto, S and Tanaka, K and Tomita, T},
title = {Identification of ADAMTS5 as APP-Cleaving Enzyme at the APP669 Site.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {7},
pages = {e71701},
doi = {10.1096/fj.202600043},
pmid = {41891882},
issn = {1530-6860},
support = {19H01015//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23H00394//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 17H04313//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 20H00548//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22J14778//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 25KJ1052//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP20dm0207073//Japan Agency for Medical Research and Development (AMED)/ ; JPMJMS2024//MEXT | JST | Moonshot Research and Development Program (Moonshot)/ ; JPMJSP2108//MEXT | JST | Support for Pioneering Research Initiated by the Next Generation (SPRING)/ ; //Japan Science and Technology Agency/ ; },
mesh = {*ADAMTS5 Protein/metabolism/genetics ; Humans ; Animals ; *Amyloid beta-Protein Precursor/metabolism ; Mice ; Alzheimer Disease/metabolism ; ADAMTS4 Protein/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Peptide Fragments/metabolism ; },
abstract = {Cerebral amyloid-β (Aβ) deposition is a pathological hallmark of the earliest phases of Alzheimer disease (AD). We previously reported APP669-711 as a novel Aβ-related peptide detectable in human plasma and developed a composite biomarker that combines APP669-711/Aβ1-42 and Aβ1-40/Aβ1-42 ratios to serve as a plasma surrogate of cerebral Aβ burden. We also identified ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 4) as an APP669-cleaving enzyme that catalyzes the rate-limiting step of APP669-711 production. However, ADAMTS4 accounts for approximately 40% of APP669-site cleavage, leaving the enzymes responsible for the remaining 60% unknown. Here, we identify ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 5) as a protease with stronger APP669-site cleavage activity in vitro. We further show that the difference in APP669-site cleavage activity between ADAMTS4 and ADAMTS5 is explained by the regulation through the spacer (Sp) domain. Nonetheless, in vivo experiments did not confirm a role for ADAMTS5 in plasma APP669-711 production under healthy conditions. Because ADAMTS5 expression increases in certain pathological states, our results suggest that ADAMTS5 may contribute to plasma APP669-711 production in AD patients with comorbid conditions.},
}

*ADAMTS5 Protein/metabolism/genetics
Humans
Animals
*Amyloid beta-Protein Precursor/metabolism
Mice
Alzheimer Disease/metabolism
ADAMTS4 Protein/metabolism/genetics
*Amyloid beta-Peptides/metabolism
*Peptide Fragments/metabolism

@article {pmid41891938,
year = {2026},
author = {Sessiz Menekşe, EB and Bayraktar, DZ and Çevik, MU and Menekşe, V and Elmas, N},
title = {Nutritional status, Mediterranean diet adherence, and quality of life in older adults with dementia: A cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261434990},
doi = {10.1177/13872877261434990},
pmid = {41891938},
issn = {1875-8908},
abstract = {BackgroundNutritional problems are common among individuals living with dementia and may adversely affect quality of life. While the Mediterranean diet has been widely studied in dementia prevention, evidence regarding its role after dementia diagnosis remains limited.ObjectiveThis study aimed to evaluate the relationship between nutritional status, adherence to the Mediterranean diet, and quality of life among older adults with dementia.MethodsThis cross-sectional study was conducted with 150 older adults diagnosed with dementia. Data were collected using the Mini Nutritional Assessment (MNA), the Mediterranean Diet Adherence Screener (MEDAS), and the WHOQOL-OLD Quality of Life Questionnaire.ResultsParticipants generally demonstrated moderate adherence to the Mediterranean diet (mean MEDAS 9.4 ± 2.4). Mediterranean diet adherence was not significantly associated with nutritional status or quality of life. In contrast, nutritional status showed a significant and independent positive association with quality of life after adjustment for potential confounders. In multiple linear regression analysis, MNA score remained a significant predictor of quality of life (β = 0.28, p = 0.002).ConclusionsIn older adults with dementia, nutritional status is independently associated with quality of life, whereas adherence to the Mediterranean diet shows no significant relationship with nutritional status or quality of life in this cross-sectional sample. These findings highlight the importance of routine nutritional assessment and individualized nutritional support in dementia care.},
}

@article {pmid41891939,
year = {2026},
author = {Huang, X and Li, R and Ning, J and For The Alzheimer's Disease Neuroimaging Initiative, },
title = {Addressing nonignorable missing data and heterogeneity in prognostic biomarker assessment.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261432996},
doi = {10.1177/09622802261432996},
pmid = {41891939},
issn = {1477-0334},
abstract = {Covariate-specific and time-dependent area-under-curve (AUC) is often used to evaluate the discriminative performance of biomarkers with time-to-event outcomes, particularly when certain covariates influence biomarkers' accuracy. In biomarker research, despite extensive efforts, missing data remain unavoidable, with nonignorable missingness posing significant challenges. This article focuses on estimating the impact of covariates on time-dependent AUC in the presence of nonignorable missing biomarkers. Assuming a parametric model on the missing probability, we leverage instrumental variables to address the identifiable issue and estimate the unknown parameters. We integrate the inverse probability weighting approach into the score equation of a pseudo partial likelihood for estimation and inference. Additionally, we establish the asymptotic properties of the proposed estimators. Through simulation studies, we evaluate finite sample performance of the proposed estimators, and apply the method to data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.},
}

@article {pmid41892053,
year = {2026},
author = {Feng, Y and Chen, C},
title = {Progress in Machine Learning-Assisted Biosensors for Alzheimer's Disease.},
journal = {Biosensors},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/bios16030161},
pmid = {41892053},
issn = {2079-6374},
support = {252102240080//Science and Technology Development Program of Henan Province/ ; },
mesh = {*Alzheimer Disease/diagnosis ; *Biosensing Techniques ; *Machine Learning ; Humans ; Biomarkers ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, affecting 55 million people worldwide. Its characteristics include the accumulation of senile plaques and neurofibrillary tangles. This disease is associated with changes in the concentration of AD biomarkers, such as microRNAs, amyloid peptides, Tau protein, and neurofilament light chains. Due to the fact that neuropathological processes begin decades before the onset of cognitive symptoms, accurate detection of AD biomarkers is crucial for its early diagnosis. The combination of analytical techniques and machine learning methods plays a crucial role in medical innovation. Recently, efforts have been made to develop machine learning-assisted biosensors for AD diagnosis. This article provides an overview of the progress in machine learning-assisted sensing of AD biomarkers in bodily fluids. It mainly includes three parts: machine learning algorithms, machine learning-assisted electrochemical and optical biosensors, and challenges and future perspectives. We believe that this work will contribute to the development of innovative analytical devices based on artificial intelligence for monitoring and managing neurodegenerative diseases.},
}

*Alzheimer Disease/diagnosis
*Biosensing Techniques
*Machine Learning
Humans
Biomarkers

@article {pmid41892131,
year = {2026},
author = {Kasabov, NK and Yang, A and Wang, Z and Abouhassan, I and Kassabova, A and Lappas, T},
title = {eXCube2: Explainable Brain-Inspired Spiking Neural Network Framework for Emotion Recognition from Audio, Visual and Multimodal Audio-Visual Data.},
journal = {Biomimetics (Basel, Switzerland)},
volume = {11},
number = {3},
pages = {},
doi = {10.3390/biomimetics11030208},
pmid = {41892131},
issn = {2313-7673},
abstract = {This paper introduces a biomimetic framework and novel brain-inspired AI (BIAI) models based on spiking neural networks (SNNs) for emotional state recognition from audio (speech), visual (face), and integrated multimodal audio-visual data. The developed framework, named eXCube2, uses a three-dimensional SNN architecture NeuCube that is spatially structured according to a human brain template. The BIAI models developed in eXCube2 are trainable on spatio- and spectro-temporal data using brain-inspired learning rules. Such models are explainable in terms of revealing patterns in data and are adaptable to new data. The eXCube2 models are implemented as software systems and tested on speech and video data of subjects expressing emotional states. The use of a brain template for the SNN structure enables brain-inspired tonotopic and stereo mapping of audio inputs, topographic mapping of visual data, and the combined use of both modalities. This novel approach brings AI-based emotional state recognition closer to human perception, provides a better explainability and adaptability than existing AI systems. It also results in a higher or competitive accuracy, even though this was not the main goal here. This is demonstrated through experiments on benchmark datasets, achieving classification accuracy above 80% on single-modality data and 88.9% when multimodal audio-visual data are used, and a "don't know" output is introduced. The paper further discusses possible applications of the proposed eXCube2 framework to other audio, visual, and audio-visual data for solving challenging problems, such as recognizing emotional states of people from different origins; brain state diagnosis (e.g., Parkinson's disease, Alzheimer's disease, ADHD, dementia); measuring response to treatment over time; evaluating satisfaction responses from online clients; cognitive robotics; human-robot interaction; chatbots; and interactive computer games. The SNN-based implementation of BIAI also enables the use of neuromorphic chips and platforms, leading to reduced power consumption, smaller device size, higher performance accuracy, and improved adaptability and explainability. This research shows a step toward building brain-inspired AI systems.},
}

@article {pmid41892298,
year = {2026},
author = {Prud'homme, GJ and Wang, Q},
title = {Antiaging Properties of the Klotho Protein.},
journal = {Cells},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/cells15060507},
pmid = {41892298},
issn = {2073-4409},
support = {2-SRA-2018-497-A-B//Juvenile Diabetes Research Foundation International/ ; OG-3-13-4066//Diabetes Canada/ ; 81570518, 81630020, 82370814//National Science Foundation of China/ ; N/A//St. Michael's Hospital Foundation, Toronto, Canada/ ; N/A//Keenan Research Centre for Biomedical Science, Toronto, Canada/ ; },
mesh = {*Klotho Proteins/metabolism ; Humans ; *Aging/metabolism/genetics ; Animals ; *Glucuronidase/metabolism ; Inflammation/metabolism ; Cellular Senescence ; },
abstract = {Mice genetically deficient in α-Klotho (henceforth Klotho) display accelerated aging. The mechanisms are only partially understood. Here, we examine how these relate to the 12 hallmarks of aging consisting of chronic inflammation (inflammaging), as well as damaging changes to the genome (DNA damage), telomeres, epigenetic regulation, proteostasis, nutrient sensing, mitochondria, stem cells, intercellular communication, macroautophagy, microbiome and cell replication (senescence). Inflammation aggravates the other hallmarks. We report that Klotho counters the majority of these hallmarks. It ameliorates mitochondrial function and reduces reactive oxygen species (ROS), telomere attrition and cellular senescence. It protects against inflammation by inhibiting NF-κB and the NLRP3 inflammasome. This applies to inflammaging, several chronic inflammatory diseases, atherosclerosis, diabetes, and Alzheimer's disease. Klotho also counters some aging factors outside of these hallmarks. Low Klotho (often due to kidney disease) produces hyperphosphatemia, which injures cells (especially endothelial cells) and promotes aging. Another key action of Klotho is the mitigation of fibrosis in major organs (kidneys, heart, lungs and other), mainly through the inhibition of TGF-β and Wnt. Klotho also protects against muscle atrophy (sarcopenia)-a common feature of aging-and exhibits anti-cancer activity. We describe several factors that increase Klotho, and are potentially amenable to clinical therapy.},
}

*Klotho Proteins/metabolism
Humans
*Aging/metabolism/genetics
Animals
*Glucuronidase/metabolism
Inflammation/metabolism
Cellular Senescence

@article {pmid41892301,
year = {2026},
author = {Gonçalves, FQ and Silva, HB and Tomé, ÂR and Agostinho, P and Cunha, RA and Lopes, JP},
title = {Neurophysiological In Vitro Model of Amyloid-β-Induced Deficits of Hippocampal LTP Involving Neuronal Adenosine A2A Receptor Dysfunction Through CD73.},
journal = {Cells},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/cells15060510},
pmid = {41892301},
issn = {2073-4409},
support = {2023.13319.PEX//FCT - Foundation for Science and Technology, I.P./ ; },
mesh = {Animals ; *Receptor, Adenosine A2A/metabolism ; *Long-Term Potentiation/drug effects ; *Hippocampus/metabolism/drug effects/physiopathology ; *Amyloid beta-Peptides/metabolism ; Mice ; *5'-Nucleotidase/metabolism ; *Neurons/metabolism/drug effects ; Adenosine/metabolism ; Male ; Mice, Inbred C57BL ; Neuronal Plasticity/drug effects ; Alzheimer Disease/metabolism ; },
abstract = {Amyloid-β peptides (Aβ) are considered a main culprit of Alzheimer's disease (AD), leading to synaptic dysfunction and memory deficits. Although studies in animal models of AD converge to show alterations of synaptic plasticity, namely of long-term potentiation (LTP), the mechanisms through which Aβ affects synaptic function remain to be unveiled. In this study, we established experimental conditions showing that the acute exposure of mouse hippocampal slices to optimized concentrations of Aβ impaired short-term (PPF-paired-pulse facilitation) and long-term (LTP-long-term potentiation) plasticity without altering basal synaptic transmission. We observed that the elimination of extracellular adenosine with adenosine deaminase abrogated the impact of Aβ on synaptic plasticity, showing a mandatory involvement of extracellular adenosine in the neurophysiological effects of Aβ. Additionally, inhibiting adenosine receptor function with caffeine, as well as selectively blocking adenosine A1 receptors (A1R) with DPCPX, or adenosine A2A receptor (A2AR) with either an antagonist SCH58261 or through knocking out A2AR, demonstrated that acute Aβ modified mouse hippocampal PPF via A1R and LTP through A2AR. Furthermore, the use of slices from mice bearing forebrain-neuron A2AR deletion, along with the application of α,β-methylene ADP, a CD73 inhibitor, confirmed that the neurophysiological actions of Aβ on hippocampal LTP occur selectively through the overfunction of neuronal A2AR via CD73-mediated formation of extracellular adenosine. Overall, the exploitation of a neurophysiological model of early AD, based on the acute administration of Aβ to hippocampal slices, confirmed the critical involvement of adenosine signaling in the impact of Aβ on synaptic plasticity.},
}

Animals
*Receptor, Adenosine A2A/metabolism
*Long-Term Potentiation/drug effects
*Hippocampus/metabolism/drug effects/physiopathology
*Amyloid beta-Peptides/metabolism
Mice
*5'-Nucleotidase/metabolism
*Neurons/metabolism/drug effects
Adenosine/metabolism
Male
Mice, Inbred C57BL
Neuronal Plasticity/drug effects
Alzheimer Disease/metabolism

@article {pmid41892302,
year = {2026},
author = {Milward, AE and Hood, RJ and Lin, CA and Bettencourt, C and Acquah, E and Brooks, J and Collingwood, JF and Kagawa, Y and Richardson, SJ and Wu, Y and Lu, Y and Dottori, M and Johnstone, DM},
title = {Paradoxes in the Ontological Classification of Glia-Evidence for an Important New Class of Brain Cells with Primary Functions in Iron Regulation.},
journal = {Cells},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/cells15060511},
pmid = {41892302},
issn = {2073-4409},
mesh = {Humans ; *Iron/metabolism ; *Neuroglia/metabolism/classification/cytology ; *Brain/cytology/metabolism ; Animals ; Oligodendroglia/metabolism ; Neurons/metabolism ; },
abstract = {The ontological categorization of the cellular elements of the brain was proposed over a century ago by Santiago Ramón y Cajal (neurons, astroglia) and Pío del Río-Hortega (oligodendroglia, microglia). It combines histochemical observations of morphology with allied inferences about the specialized functions and origins (ectoderm or mesoderm) of each cellular element. This ontology shapes modern neuroscience, with the main non-neuronal cells-astroglia, oligodendroglia and microglia-viewed as having distinct primary roles relating respectively to the metabolic support, myelination and immunoprotection of neurons, the information signaling cells. Yet contemporary techniques, ranging from electrophysiology to single-cell transcriptomics and ultrahigh resolution spectroscopy, are revealing intersecting molecular profiles and functional capacities of these cell groups, for example metabolic support, neuroimmune and signaling functions in oligodendroglia. Here we identify discrepancies in current glial paradigms, from empirical, evolutionary and pragmatic perspectives. We suggest a subset of small, iron-rich glial cells, usually with few processes, often viewed as oligodendroglia with myelin-related primary functions, instead have iron-related primary functions that are central to all aspects of brain activity. We call these 'ferriglia'. We discuss implications for pathogenesis across the spectrum of neuropsychiatric and neurological disorders, including neurodegenerative conditions such as Alzheimer's disease and other less common cognitive, movement and neurobehavioral disorders, stroke and cerebrovascular disease, glioblastoma and other brain cancers and neuroimmune conditions. We also briefly address the question of where ferriglia may reside within existing glial compartments and lineages, implications for the ontological classification of other glial cells, and research challenges that must be overcome going forward.},
}

Humans
*Iron/metabolism
*Neuroglia/metabolism/classification/cytology
*Brain/cytology/metabolism
Animals
Oligodendroglia/metabolism
Neurons/metabolism

@article {pmid41892340,
year = {2026},
author = {Cohen, BM and Koh, E and Levental, KR and Levental, I and Sonntag, KC},
title = {Inherent Lipid Composition Abnormalities in Astrocytes Associated with Late-Onset Alzheimer's Disease (LOAD).},
journal = {Cells},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/cells15060549},
pmid = {41892340},
issn = {2073-4409},
support = {N/A//Steele Fund SUNDRY/ ; R35GM134949/GM/NIGMS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; Lipidomics ; Fatty Acids/metabolism ; *Lipid Metabolism ; Mitochondria/metabolism ; *Lipids/chemistry ; Aged ; Male ; Cholesterol Esters/metabolism ; },
abstract = {Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived brain cells. These cells lack markers associated with aging and environmental exposures. The iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Astrocytes are crucial to neural activity and health, and altered astrocyte functions are associated with LOAD pathology. Lipidomics analyses were performed on whole-cell and mitochondria-enriched fractions. Large reductions in cholesterol esters (CEs) and imbalances in fatty acids (FAs) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. The findings identify abnormalities in CEs, as well as in FAs, as inherent abnormalities and likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Astrocytes/metabolism/pathology
Induced Pluripotent Stem Cells/metabolism
Lipidomics
Fatty Acids/metabolism
*Lipid Metabolism
Mitochondria/metabolism
*Lipids/chemistry
Aged
Male
Cholesterol Esters/metabolism

@article {pmid41892599,
year = {2026},
author = {Li, J and Kong, W and Wang, S},
title = {A Two-Stage Framework for Early Detection and Subtype Identification of Alzheimer's Disease Through Multimodal Biomarker Extraction and Improved GCN.},
journal = {Brain sciences},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/brainsci16030255},
pmid = {41892599},
issn = {2076-3425},
abstract = {BACKGROUND: Imaging-transcriptomic analysis, through the integration of multimodal magnetic resonance imaging (MRI) and transcriptomic data, provides complementary structural, functional, and molecular information that is crucial for the early detection and mechanistic exploration of Alzheimer's disease (AD). However, effectively extracting features from heterogeneous multimodal data and capturing the associations between microscopic molecular variations and macroscopic brain alterations remain key challenges. Recent advances in deep learning and multimodal integration have enhanced the ability to model nonlinear cross-modal relationships, enabling more accurate identification of imaging-transcriptomic biomarkers and subtypes. Developing robust multimodal frameworks is therefore essential for early AD detection, subtype identification, and advancing precision medicine in neurodegenerative diseases.

METHODS: In this study, a two-stage method of multimodal Feature Extraction based on Association Analysis and Graph Convolutional Network with Self-Attention and Self-Expression framework (MFEAA-GCNSASE) for early diagnosis of AD and effective identification of subtypes of MCI with different progression to AD is proposed. In the first stage, the MFEAA model is applied to integrate multiple association analysis methods on sMRI, PET, and transcriptomic data to identify key multimodal biomarkers for AD and mild cognitive impairment (MCI). In the second stage, the GCNSASE model enhances classification accuracy between AD and MCI patients through self-attention and self-expression layers. Additionally, unsupervised clustering was performed on MCI samples using top multimodal biomarkers to explore subtype heterogeneity and conversion risk. Reliable MCI subtypes were also identified through a consensus clustering approach.

RESULTS: The proposed algorithm integrates sMRI, PET, and transcriptomic data, identifying robust biomarkers including the Left Hippocampus, Left Angular Gyrus, and key genes such as SLC25A5 and GABARAP. To ensure statistical robustness given the extreme class imbalance, we employed a rigorous repeated stratified cross-validation (RSCV) framework. GCNSASE achieved state-of-the-art discrimination performance with mean AUC values ranging from 0.946 to 0.961 across feature subsets (10-50%), significantly outperforming MOGONET (mean AUC: 0.844-0.875, p < 0.001) and conventional machine learning models with tighter 95% confidence intervals, indicating superior stability despite the limited AD sample size. Clustering analysis revealed two distinct MCI subtypes with divergent molecular landscapes: Subtype A was enriched in energy metabolism and cellular maintenance pathways, whereas Subtype B was enriched in neuroinflammatory and aberrant signaling pathways. Notably, the majority of MCI patients who subsequently converted to AD were concentrated in the immune-inflammatory Subtype B. These findings highlight that neuroinflammation coupled with bioenergetic failure constitutes a critical mechanism driving the conversion from MCI to AD.

CONCLUSIONS: The proposed methods not only provide the key multimodal biomarkers and enhance the accuracy of the classification model for early AD diagnosis but also identify biologically and clinically meaningful MCI subtypes with distinct molecular signatures and conversion risks. Exploring these associated multimodal biomarkers and MCI subtypes is of great significance, as they help elucidate the heterogeneous mechanisms underlying AD onset and progression, enable the identification of high-risk individuals likely to convert to AD, and provide a foundation for targeted therapeutic strategies and individualized clinical management. These findings have important implications for understanding disease heterogeneity, discovering potential intervention targets, and advancing precision medicine in neurodegenerative diseases.},
}

@article {pmid41892608,
year = {2026},
author = {Zhang, T and Sun, F and Stang, A and Ayoub, G},
title = {Peripheral Sensory Stimulation for Long-Term Improvement in Mild Cognitive Decline: A Prospective Interventional Study.},
journal = {Brain sciences},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/brainsci16030265},
pmid = {41892608},
issn = {2076-3425},
support = {grant in aid//Nova Palm Foundation/ ; },
abstract = {BACKGROUND: Despite recent breakthroughs in pharmacological treatment for Alzheimer's disease, high costs and the complex procedure to monitor safety have limited access for many patients. Less invasive and more accessible non-pharmacological therapies that support neuroplasticity and slow cognitive decline are needed. Processing Inner Strength Toward Actualization (PISTA) stimulation applies structured tactile input to promote cortical-subcortical activation. This study evaluated the long-term effects of PISTA on cognition and pain in older adults with mild cognitive impairment or early dementia.

METHODS: This single-arm, prospective trial enrolled 100 outpatients aged 47-70 years at outset (50 women, 50 men) with no control group. Participants received clinician-supervised PISTA stimulation three times weekly for 48 months. Each 30 min session delivered rhythmic tactile input calibrated to individual sensory thresholds. Cognitive performance was assessed monthly using the Mini-Mental State Examination (MMSE). Perceived pain was measured monthly with the Numeric Pain Rating Scale. Outcomes were analyzed using ANCOVA, adjusting for age, sex, and baseline cognitive status.

RESULTS: Cognitive scores improved significantly across all age strata, with a mean annual MMSE increase of 0.75 points (95% CI: 0.26-1.21; p < 0.0025). Pain intensity decreased in parallel (mean reduction: 0.56 points; 95% CI: 0.34-0.78; p < 0.001). Improvements in cognition and pain were moderately correlated (r = 0.38). The greatest combined benefits occurred in participants aged 55-62 years. No serious adverse events were observed during the 48-month trial.

CONCLUSIONS: PISTA stimulation produced sustained improvement in cognition and reduced perceived pain, supporting its promising role as a safe, non-invasive adjunct for neurodegenerative cognitive decline. These findings suggest peripheral sensory activation as a promising driver of functional neuroplasticity and warrant verification in randomized, controlled trials.},
}

@article {pmid41892638,
year = {2026},
author = {Kochhann, R and da Silva, PF and van Duinkerken, E and Holz, MR and Chaves, MLF and Borelli, WV and Fonseca, RP},
title = {Performance-Based Functional Status Predicts Diffuse Cortical Atrophy in Alzheimer's Disease.},
journal = {Brain sciences},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/brainsci16030295},
pmid = {41892638},
issn = {2076-3425},
support = {471514/2014-4//National Council for Scientific and Technological Development/ ; },
abstract = {Objectives: We aimed to compare performance-based functional ability and cognitive screening performance to determine the cortical thickness relationship in cognitively unimpaired (CN) elders, mild cognitive impairment (MCI) and dementia patients, as well as to compare performance-based and proxy-evaluated functional ability and to determine its cerebral white and gray matter correlates. Methods: In total, 22 CN, 32 MCI, and 21 dementia patients were included in this study. They underwent clinical, cognitive, and Magnetic Resonance Imaging (MRI) assessment. Individuals were evaluated with the Mini-Mental State Examination (MMSE), the Rey Auditory Verbal Learning test (RAVLT), the Activities of Daily Living Questionnaire (ADL-Q) and the Direct Assessment of Functional Status-Revised (DAFS-R). Results: Higher ADL-Q scores were significantly associated with lower cortical thickness (bilateral temporoparietal regions, including the inferior temporal lobes and precuneus), p < 0.05. The DAFS-R scale showed a relationship with greater cortical thickness across extensive regions of the bilateral frontal, parietal, and temporal cortices (p < 0.05). MMSE presented a more focal association, primarily in canonical memory-related areas, including the medial and lateral temporal lobes and inferior parietal regions (p < 0.05). Conclusions: Functional independence measured by ADL-Q was associated with frontal and parietal cortical thickness, while DAFS-R scores demonstrated a more diffuse evaluation of cortical atrophy. Additionally, performance-based functional abilities according to the DAFS-R appear to be a stronger marker of cortical thickness than ADL-Q and MMSE.},
}

@article {pmid41892660,
year = {2026},
author = {Stojanoski, S and Karher, K and Kozić, D and Babović, SS and Vuković, M and Koprivšek, K},
title = {Frontal Lobe and Subregional Volumetric Alterations Across Alzheimer's Disease, Amnestic Mild Cognitive Impairment, and Vascular Dementia: An MRI Volumetry Study.},
journal = {Brain sciences},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/brainsci16030317},
pmid = {41892660},
issn = {2076-3425},
support = {003873711 2025 09418 003 000 000 001//Provincial Secretariat for Science and Higher Education, Novi Sad Serbia/ ; },
abstract = {BACKGROUND: Frontal lobe involvement represents an important but heterogeneously expressed feature across neurodegenerative and vascular cognitive disorders. While frontal atrophy has been described in Alzheimer's disease (AD), detailed volumetric assessment of frontal subregions across Alzheimer's disease, amnestic mild cognitive impairment (aMCI), and vascular dementia (VaD) remains insufficiently characterized. The aim of this study was to evaluate frontal lobe and frontal subregional volumetric alterations across these diagnostic groups using automated MRI-based volumetry.

METHODS: This cross-sectional study included 120 participants divided into four groups: AD, VaD, aMCI, and cognitively healthy controls (n = 30 per group). All participants underwent standardized neuropsychological assessment and 3T brain MRI. Automated volumetric analysis of the frontal lobe and its subregions was performed using the Vol2Brain pipeline. Group differences in total intracranial volume-adjusted frontal volumes were assessed using analysis of covariance, controlling for age and sex, followed by Bonferroni-corrected post hoc comparisons. False discovery rate (FDR) correction was applied across subregional comparisons.

RESULTS: A significant main effect of diagnostic group was observed for total frontal lobe volume, with lower adjusted volumes in patients with AD compared with aMCI and cognitively healthy controls. After correction for multiple comparisons, only total frontal lobe volume remained statistically significant. At the nominal level, group differences were observed in several frontal subregions, predominantly involving prefrontal and orbitofrontal areas. However, these findings did not survive FDR correction and should be interpreted as exploratory. No consistent frontal volumetric pattern was observed in VaD. Receiver operating characteristic analysis demonstrated moderate discriminatory ability of total frontal lobe volume for distinguishing AD from cognitively healthy controls.

CONCLUSIONS: Automated MRI-based volumetry revealed global frontal lobe reduction in Alzheimer's disease, whereas subregional findings were exploratory after correction for multiple testing. Frontal volumetric measures did not demonstrate a characteristic pattern in VaD. Global frontal volume may provide complementary structural information within clinically define cognitive disorders.},
}

@article {pmid41892676,
year = {2026},
author = {Shim, JH and Baek, HM},
title = {Alzheimer's Disease Classification Using Population-Referenced Brain Volumetric Percentiles.},
journal = {Brain sciences},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/brainsci16030334},
pmid = {41892676},
issn = {2076-3425},
support = {2021R1A6C101A432//Korea Basic Science Institute/ ; },
abstract = {Background/Objectives: Translating brain volumetric biomarkers to individual-level Alzheimer's disease (AD) diagnosis remains challenging due to difficulty interpreting raw volumes without longitudinal monitoring or matched controls. We tested a classification model using population-referenced volumetric percentiles to distinguish AD from cognitively normal (CN) subjects and evaluated its generalization across independent cohorts. Methods: Brain volumes from 95 regions were extracted using an automated segmentation pipeline and converted to age and sex adjusted percentiles using a reference population (N = 1833). A logistic regression classifier was trained on ADNI subjects (N = 873; AD = 183, CN = 690) split into training (60%), validation (20%), and test (20%) sets. The model was evaluated on two independent validation datasets: the held-out ADNI validation set and an external Korean cohort (N = 72; AD = 36, CN = 36) acquired with different scanner protocols and demographic characteristics. Results: The model achieved excellent discrimination across all evaluation sets: ADNI validation (AUC = 0.963, accuracy = 90.3%), ADNI test (AUC = 0.960, accuracy = 89.7%), and Korean external validation (AUC = 0.981, accuracy = 87.5%). The minimal validation gap (0.018) demonstrated robust generalization. Positive coefficients for ventricular regions reflected AD-associated atrophy patterns, while negative coefficients for medial temporal structures indicated their contribution within multivariate patterns distinguishing AD from normal aging. Conclusions: Population-referenced brain volumetric percentiles enable accurate AD classification with robust generalization across populations and scanner protocols. By contextualizing individual brain structure relative to normative populations while accounting for age and sex, this approach demonstrates potential for clinical translation as an accessible neuroimaging-based diagnostic tool.},
}

@article {pmid41892684,
year = {2026},
author = {Bardopoulou, M and Chryssanthopoulos, C and Cherouveim, ED and Tzeravini, E and Stanitsa, E and Koustimpi, M and Chatzinikita, E and Patsaki, I and Poulos, S and Papatriantafyllou, J and Vassilakopoulos, T and Maridaki, M and Consoulas, C and Papageorgiou, SG and Koutsilieris, M and Philippou, A},
title = {Acute Effects of High-Velocity Interval Cycling Versus Continuous Moderate-Intensity Cycling on Cognitive Function in Patients with Mild Cognitive Impairment.},
journal = {Brain sciences},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/brainsci16030342},
pmid = {41892684},
issn = {2076-3425},
support = {Enhancing Human Resources Potential by undertaking a Doctoral Research" Sub-action 2: IKY Scholarship Program for PhD candidates in the Greek Universities.//Greece and the European Union (European Social Fund - ESF) through the Operational Programme "Human Resources Development, Education and Lifelong Learning" 2014-2020/ ; },
abstract = {Background/Objectives: Physical exercise has emerged as a promising non-pharmacological intervention for cognitive dysfunction; however, the most effective mode of exercise remains unclear. This study aimed to investigate the acute effects of two cycling exercise protocols, (a) continuous aerobic/moderate-intensity (CA) and (b) high-velocity/low-resistance (high-cadence) interval (HVI), on cognitive and executive performance in patients with mild cognitive impairment (MCI). Methods: Seventeen patients (10 females and 7 males, age: 65.5 ± 8.85 years) diagnosed with MCI or early-stage Alzheimer's disease (13 MCI and 4 eAD) participated in a random order in three different conditions: CA, HVI, and control/no exercise (CON). Cognitive parameters were assessed acutely before and after the completion of each condition. Results: Significant condition × time interactions were observed for both Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB) (p < 0.01). Higher scores (p < 0.01) for MoCA and FAB post-intervention were found compared to baseline in both exercise bouts, whereas no changes occurred in CON. Interestingly, when post-intervention scores were compared between conditions, cognitive performance was improved only in HVΙ compared to CON in MoCA (p < 0.01) and FAB (p < 0.001), revealing a stronger acute effect of HVI. Conclusions: A single bout of high-velocity, low-resistance (high-cadence) interval cycling acutely enhanced global cognition and executive function in individuals with MCI, exerting greater improvement compared to continuous aerobic exercise or control condition. These findings emphasize the potential utilization of HVI as an effective non-pharmacological intervention to acutely enhance cognitive performance in older adults with MCI.},
}

@article {pmid41892900,
year = {2026},
author = {Hasan, ME and Fuad, MTH and Sharif, O and Wagler, A},
title = {Hybrid Vision Transformer-CNN Framework for Alzheimer's Disease Cell Type Classification: A Comparative Study with Vision-Language Models.},
journal = {Journal of imaging},
volume = {12},
number = {3},
pages = {},
doi = {10.3390/jimaging12030098},
pmid = {41892900},
issn = {2313-433X},
abstract = {Accurate identification of Alzheimer's disease (AD)-related cellular characteristics from microscopy images is essential for understanding neurodegenerative mechanisms at the cellular level. While most computational approaches focus on macroscopic neuroimaging modalities, cell type classification from microscopy remains relatively underexplored. In this study, we propose a hybrid vision transformer-convolutional neural network (ViT-CNN) framework that integrates DeiT-Small and EfficientNet-B7 to classify three AD-related cell types-astrocytes, cortical neurons, and SH-SY5Y neuroblastoma cells-from phase-contrast microscopy images. We perform a comparative evaluation against conventional CNN architectures (DenseNet, ResNet, InceptionNet, and MobileNet) and prompt-based multimodal vision-language models (GPT-5, GPT-4o, and Gemini 2.5-Flash) using zero-shot, few-shot, and chain-of-thought prompting. Experiments conducted with stratified fivefold cross-validation show that the proposed hybrid model achieves a test accuracy of 61.03% and a macro F1 score of 61.85, outperforming standalone CNN baselines and prompt-only LLM approaches under data-limited conditions. These results suggest that combining convolutional inductive biases with transformer-based global context modeling can improve generalization for cellular microscopy classification. While constrained by dataset size and scope, this work serves as a proof of concept and highlights promising directions for future research in domain-specific pretraining, multimodal data integration, and explainable AI for AD-related cellular analysis.},
}

@article {pmid41892906,
year = {2026},
author = {Sijilmassi, O},
title = {The Retina as a Proxy for Brain Neurodegeneration: A Narrative Review on OCT-Based Retinal Imaging in the Early Detection of Alzheimer's and Parkinson's Disease.},
journal = {Journal of imaging},
volume = {12},
number = {3},
pages = {},
doi = {10.3390/jimaging12030104},
pmid = {41892906},
issn = {2313-433X},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are major causes of cognitive and motor decline, yet early diagnosis remains challenging due to asymptomatic phases and limited non-invasive biomarkers. This narrative review systematically synthesized studies on retinal imaging in AD and PD. Published studies were identified through searches of PubMed, MEDLINE, Google Scholar, and reference lists, focusing on Optical Coherence Tomography (OCT), OCT Angiography (OCTA), and Spectral-Domain OCT (SD-OCT) assessing retinal structural and vascular changes. Data were extracted on retinal layer thickness, vascular parameters, and diagnostic metrics. Findings indicate that both diseases consistently exhibit thinning of inner retinal layers, particularly the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL). In AD, studies reported progressive inner retinal thinning across disease stages, sometimes accompanied by outer retinal and retinal pigment epithelium changes. In PD, thinning was observed predominantly in RNFL and GCIPL, correlating with disease duration and motor severity. Microvascular alterations were described in both disorders, with disease-specific spatial patterns reported across studies. Overall, retinal imaging emerges as a non-invasive, high-resolution, and cost-effective tool for early detection, differential assessment, and longitudinal monitoring of neurodegenerative diseases. These findings support the translation of retinal biomarkers into clinical practice for improved disease management.},
}

@article {pmid41893025,
year = {2026},
author = {Kwak, YT and Yang, Y},
title = {A Multi-Axis Framework for Late-Life Alzheimer's Disease Interpretation.},
journal = {Journal of personalized medicine},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/jpm16030157},
pmid = {41893025},
issn = {2075-4426},
abstract = {Late-life Alzheimer's disease (AD) is increasingly defined by biomarkers, yet in adults aged ≥65 years the relationship between amyloid positivity and near-term cognitive decline is often discordant. Amyloid PET robustly detects fibrillar plaque burden, but it incompletely captures dynamic and potentially neurotoxic amyloid processes, particularly soluble assemblies and oligomer-related "activity." This review rethinks the late-life AD spectrum by integrating four clinical lenses that frequently drive real-world interpretive uncertainty: (1) amyloid PET positivity as a measure of fibrillar plaque presence and magnitude; (2) plasma amyloid-β oligomerization tendency measured by the multimer detection system (MDS-OAβ) as an activity-oriented (i.e., a dynamic readout hypothesized to reflect ongoing processes rather than cumulative lesion burden), process-linked readout that may decouple from plaque burden; (3) postoperative delirium (POD) as a time-anchored stress-test phenotype revealing vulnerability and reduced resilience under systemic insults; and (4) drug-linked biomarker trajectories, contrasting rapid plaque removal by anti-amyloid monoclonal antibodies with observational signals raising the hypothesis that Ginkgo biloba may be associated with oligomer-related biology and, in some contexts, differences in longitudinal amyloid accumulation trajectories in the absence of observed immediate plaque reduction. We propose a pragmatic multi-axis framework-plaque burden, amyloid activity, downstream engagement, and vulnerability/resilience-to contextualize late-life discordances such as PET positivity without decline, PET negativity with elevated MDS-OAβ, delirium-associated decompensation, and clinical change without rapid PET decline. This synthesis highlights testable predictions and prioritizes longitudinal, multi-marker studies to determine whether activity-oriented biomarkers and stress phenotypes can refine late-life risk stratification beyond plaque-centered models.},
}

@article {pmid41893050,
year = {2026},
author = {Duranti, E and Villa, C},
title = {Misfolded Proteins and Cognitive Decline: Mechanistic Insights into Neurodegenerative Disorders.},
journal = {Neurology international},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/neurolint18030048},
pmid = {41893050},
issn = {2035-8385},
abstract = {Cognitive decline represents one of the most common clinical manifestations of neurodegenerative diseases (NDs), substantially affecting the quality of life of both patients and their families. Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are major NDs characterized by a progressive degeneration of the central nervous system, with functional impairments extending beyond motor symptoms to multiple cognitive domains, including memory, attention, language, and executive functions. Increasing evidence highlights misfolded protein accumulation as a key driver of neuronal dysfunction and cognitive deterioration. This narrative review examines the major cognitive deficits associated with these disorders, focusing on the underlying molecular mechanisms, particularly protein aggregation, as well as clinical manifestations and their effects on daily life. Furthermore, current diagnostic tools and emerging therapeutic options for mitigating cognitive decline will be further discussed.},
}

@article {pmid41893052,
year = {2026},
author = {Burdman, G and Akkaoui, J and Colon, N and Perez, A and Lakshmana, MK},
title = {Genetic Architecture of Cognitive Resilience in Alzheimer's Disease: Mechanisms, Pathways, and Therapeutic Implications.},
journal = {Neurology international},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/neurolint18030050},
pmid = {41893052},
issn = {2035-8385},
support = {5R01DA052271, 1R21DA060111, 1R61AG086971//National Institute of Health (NIH) USA/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is defined by amyloid-β plaques and tau neurofibrillary tangles and is typically associated with progressive cognitive decline. However, a substantial subset of individuals remains cognitively intact despite intermediate-to-high AD pathology, a phenomenon termed cognitive resilience. This review aims to synthesize genetic variants and biological pathways associated with preserved cognition in the presence of AD neuropathology. Methods: We performed a narrative thematic synthesis of human genetic studies (GWAS, sequencing, biomarker-informed cohorts) and extreme resilience case reports. Variants were prioritized by replication, mechanistic plausibility, and relevance to clinicopathologic dissociation, and were organized by shared biological pathways. When applicable, cognitive resilience was operationalized using residual-based approaches modeling cognitive performance after adjustment for neuropathological burden, age, sex, and education or cognitive reserve proxies reported by each cohort. Results: Recurrent resilience-associated variants include APOE ε2, APOE3-Christchurch, RELN-COLBOS, ATP8B1, RAB10, PLCG2, PICALM, CLU, FN1, and synapse-linked markers such as NPTX2. These variants converge on lipid metabolism, synaptic function and neuroplasticity, tau regulation and proteostasis, immune and inflammatory signaling, vascular/BBB resilience, and RNA regulation. Conclusions: Genetic determinants of cognitive resilience highlight mechanisms that preserve neural integrity independent of pathological load. Targeting resilience pathways may enable precision therapies designed to maintain cognitive function in AD.},
}

@article {pmid41893324,
year = {2026},
author = {Bientinesi, E and Vignoli, A and Ristori, S and Salobehaj, M and Bertoni, G and Monti, D and Tenori, L},
title = {An NMR-Based Protocol for Profiling the Endo- and Exo-Metabolomes in Aβ1-42 Treated Human Astrocytes from Healthy and Alzheimer's Disease Donors.},
journal = {Metabolites},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/metabo16030173},
pmid = {41893324},
issn = {2218-1989},
support = {M4C2 Investment 1.3 - Research Program PE8 Project Age-It: "Ageing Well in an Ageing Society" (CUP B83C22004800006)//Ministero dell'università e della ricerca/ ; },
abstract = {Background/Objectives: Astrocytes play a critical role in maintaining brain homeostasis and are increasingly recognized as active contributors to neurodegenerative processes. Metabolic dysfunction in astrocytes has been implicated in the onset and progression of Alzheimer's disease (AD), yet the underlying metabolic alterations remain poorly characterized. Methods: We used an optimized protocol for untargeted metabolomic profiling of both intracellular and extracellular compartments of primary human astrocytes derived from AD patients and healthy subjects (HS) using [1]H nuclear magnetic resonance (NMR) spectroscopy. Cells were treated with oligomeric Aβ1-42 to model pathological conditions. Results: Aβ1-42 treatment induced intracellular metabolic alterations in both AD and HS astrocytes, including a consistent reduction in phosphocreatine, potentially indicating impaired energy-buffering capacity. Notably, a decrease in β-alanine was observed only in AD astrocytes, suggesting alterations in carnosine-related antioxidant defence. Analysis of conditioned media revealed differential responses between groups: AD astrocytes showed increased extracellular levels of 2-oxoglutarate, citrate, and glycine, whereas HS astrocytes exhibited reduced extracellular levels of leucine and isoleucine, suggesting distinct adaptive metabolic responses to Aβ-induced stress. However, none of these differences remained statistically significant after correction for multiple testing. Conclusions: These findings suggest that NMR-based metabolomics can detect subtle metabolic shifts in human astrocyte models of AD and HS exposed to amiloidogenic challenge. Given the limited sample size and the exploratory design adopted, the results should be interpreted as preliminary and require validation in larger, better-matched cohorts. Nevertheless, this study provides a methodological framework and generates biologically plausible hypotheses regarding astrocyte metabolic responses relevant to AD pathophysiology.},
}

@article {pmid41893338,
year = {2026},
author = {Kiriyama, Y and Nakatsuma, A and Tokumaru, H and Sadamoto, H and Nochi, H},
title = {Physiological Functions of Side-Chain-Retaining Sterols in the Brain and Their Roles in Neurodegenerative Diseases.},
journal = {Metabolites},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/metabo16030189},
pmid = {41893338},
issn = {2218-1989},
abstract = {Although the brain comprises only 2% of total body weight, it contains approximately 23% of the total cholesterol of the body. In the brain, cholesterol plays a critical role as a structural component of cell membranes and myelin sheaths. However, the blood-brain barrier restricts cholesterol influx from the systemic circulation into the brain. As a result, the brain synthesizes cholesterol de novo and regulates its metabolism independently. Desmosterol, a cholesterol precursor produced during cholesterol biosynthesis, and cholesterol metabolites, 24S-hydroxycholesterol and chenodeoxycholic acid, are sterols with structurally retained side chains. These side-chain-retaining sterols have traditionally been regarded as intermediates in the cholesterol synthesis process or as metabolites for cholesterol excretion, but accumulating evidence indicates that they also function as physiologically active signaling molecules that influence brain function via nuclear receptors, such as liver X receptors, and membrane receptors, such as NMDA receptors. Through nuclear receptors, these side-chain-retaining sterols regulate the transcription of genes involved in lipid transport, inflammation control, and amyloid clearance, while their membrane receptor action enables rapid synaptic effects. These side-chain-retaining sterols mediate metabolic crosstalk between neurons and glial cells and contribute to maintaining cholesterol balance in the developing brain. Furthermore, these side-chain-retaining sterols have been shown to affect amyloid-β clearance, α-synuclein aggregation, neuroinflammation, mitochondrial function, and remyelination. Dysregulation of these side-chain-retaining sterols is associated with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Overall, side-chain-retaining sterols are important regulators of brain physiology. This review focuses on the current knowledge regarding the physiological functions of side-chain-retaining sterols in the brain and their roles in neurodegenerative diseases.},
}

@article {pmid41893345,
year = {2026},
author = {Yang, D and Guo, W and Guo, L},
title = {Exercise Reprograms the Spatial Function of Phosphoglycerate Dehydrogenase of a Pathogenic Nuclear Transcription Factor (PHGDH): A Narrative Review.},
journal = {Metabolites},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/metabo16030196},
pmid = {41893345},
issn = {2218-1989},
abstract = {Background: Alzheimer's disease (AD) represents a significant therapeutic challenge, largely attributed to the complex interplay of genetic and non-genetic mechanisms. Among the latter, metabolic dysregulation has emerged as a critical factor influencing disease progression. This study proposes a paradigm shift in our understanding of the role of phosphoglycerate dehydrogenase (PHGDH), a key metabolic enzyme, which, under pathological conditions associated with AD, transitions from a protective role to a pathogenic influence through alterations in its cellular localization and function. Methods: To elucidate the impact of exercise on PHGDH dynamics, a narrative review methodology was employed. We conducted comprehensive searches across bibliographic databases, including PubMed, Scopus, and Web of Science, focusing on peer-reviewed articles that detail the relationship between exercise, PHGDH activity, and AD-related neuroinflammation. The review was structured around specific inclusion criteria, which prioritized studies elucidating the mechanisms underlying PHGDH's dual role in AD pathology and the influence of exercise on this process. Results: Our findings reveal that under AD-associated stress, PHGDH translocates to the nucleus, facilitating the activation of pro-inflammatory genes such as IKKα and HMGB1, while simultaneously suppressing autophagy and enhancing amyloid beta (Aβ) deposition. However, exercise induces the release of the myokine irisin, which inhibits PHGDH nuclear translocation through AMPK/PGC-1α signaling pathways. Additionally, peripheral effects of exercise are observed in hepatic Kupffer cells, where exercise attenuates PHGDH activity, leading to reduced systemic IL-1β release and neuroinflammation. Conclusions: This study underscores the potential of exercise as a precision intervention in AD management, highlighting its capacity to modulate PHGDH activity and mitigate neuroinflammatory processes. The therapeutic implications of these findings are profound, paving the way for novel diagnostic tools, such as PET probes for assessing PHGDH compartmentalization, and promoting a synergistic approach to "exercise-pharmacotherapy" in the treatment of Alzheimer's disease. Future research should aim to further delineate the mechanisms by which exercise influences metabolic pathways in the context of neurodegeneration.},
}

@article {pmid41893618,
year = {2026},
author = {Keesee, E and Fabius, CD and Kim, J and Stevenson, D and Keohane, LM},
title = {Medicaid Home and Community-Based Services Initiation and Acute Services Use.},
journal = {JAMA health forum},
volume = {7},
number = {3},
pages = {e260206},
doi = {10.1001/jamahealthforum.2026.0206},
pmid = {41893618},
issn = {2689-0186},
mesh = {Humans ; United States ; *Medicaid/statistics & numerical data ; Aged ; Female ; Male ; *Home Care Services/statistics & numerical data ; Cohort Studies ; *Community Health Services/statistics & numerical data ; Aged, 80 and over ; Emergency Service, Hospital/statistics & numerical data ; Medicare/statistics & numerical data ; Southeastern United States ; },
abstract = {IMPORTANCE: For more than a decade, Medicaid has funded the majority of long-term services and supports through home and community-based services (HCBS). Whether access to Medicaid HCBS may affect dual-eligible beneficiaries' use of Medicare-covered medical services is not well understood.

OBJECTIVE: To determine whether Medicaid HCBS initiation is associated with changes in acute services use and medication fills.

This cohort study used Southern Community Cohort Study data linked to Medicare and Medicaid claims to identify a cohort of older adults residing across 11 southeastern states, largely recruited from community health centers between 2002 and 2009. The sample included older adults with 12 months of continuous traditional Medicare or Medicare Advantage enrollment centered on first month of Medicaid HCBS initiation. All analyses were conducted from spring 2023 to fall 2025.

EXPOSURE: Initiation of Medicaid HCBS between 2006 and 2018. HCBS was identified by presence of a Medicaid personal care claim or 1915(c) waiver enrollment or claim.

MAIN OUTCOMES AND MEASURES: Inpatient discharges, emergency department (ED) use, and unique prescription drugs filled estimated using linear regressions with an event study structure. Event study models with person and year fixed-effects estimated changes in person-month probability of ED use and inpatient discharge and unique drugs filled in the 6 months before and after initiation of HCBS. Subanalyses estimated differences by pre-HCBS Medicaid enrollment status, Medicaid waiver vs state plan HCBS use, Alzheimer disease and related dementia, and diabetes diagnosis.

RESULTS: In a sample of 1218 new HCBS users (75% female, 77% Black; mean [SD] age, 70.5 [7.5] years), Medicaid HCBS initiation was associated with a decrease in probability of ED use (-2.70 percentage points; 95% CI, -4.18 to -1.22 percentage points) and a decrease in probability of inpatient discharge (-2.63 percentage points; 95% CI, -3.75 to -1.51 percentage points). These differences represent a 24% decrease in the within-person probability of any ED use and a 32% decrease in inpatient discharge down from adjusted pre-HCBS probabilities of 11.4% and 8.1%. Event-month trends demonstrated discontinuity at HCBS initiation and reduced the probability of acute services use that was maintained 6 months thereafter. The number of unique drugs filled steadily increased before and after HCBS, with no discontinuity observed at HCBS initiation.

CONCLUSIONS AND RELEVANCE: In this study among a large cohort of older adults with low income across the southeastern US, Medicaid HCBS was associated with a persistent decrease in acute services use. Future research should explore additional outcomes to better inform policies that can improve HCBS outcomes and an understanding of its tradeoffs with acute services use.},
}

Humans
United States
*Medicaid/statistics & numerical data
Aged
Female
Male
*Home Care Services/statistics & numerical data
Cohort Studies
*Community Health Services/statistics & numerical data
Aged, 80 and over
Emergency Service, Hospital/statistics & numerical data
Medicare/statistics & numerical data
Southeastern United States

@article {pmid41893715,
year = {2026},
author = {Dondi, M and Bianchi, E and Borghetti, P and Di Lecce, R and Gnudi, G and Guarnieri, C and Buffagni, V and Ravanetti, F and Saleri, R and Corradi, A},
title = {Canine Cognitive Dysfunction and Alzheimer's Disease: Pathophysiological Relationships and the Impact of Glymphatic System Impairment on Neurodegeneration.},
journal = {Veterinary sciences},
volume = {13},
number = {3},
pages = {},
doi = {10.3390/vetsci13030298},
pmid = {41893715},
issn = {2306-7381},
abstract = {Canine cognitive dysfunction (CCD) is a common age-related neurodegenerative disorder in dogs that shares several pathological and clinical features with human Alzheimer's disease (AD). In both species, β-amyloid (Aβ) accumulates within the brain parenchyma and cerebral vessel walls and is associated with synaptic loss, oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, ultimately leading to progressive cognitive decline. Increasing evidence indicates that impairment of brain clearance mechanisms, particularly the glymphatic system, represents a central pathogenic mechanism in both CCD and AD. The glymphatic system is a glia-dependent perivascular network involved in the clearance of Aβ and other metabolic waste products from the brain. Its function declines with aging, vascular disease, and astrocytic alterations, including changes in aquaporin-4 distribution. Reduced glymphatic and periarterial drainage promotes the retention and aggregation of Aβ and tau proteins. Compared with AD, tau pathology in CCD is generally less extensive, supporting the interpretation of CCD as an Aβ-predominant condition and a partial pathological analog of Alzheimer's disease. Clinically, CCD is characterized by a constellation of behavioral changes including, disorientation, altered social interactions, sleep-wake cycle disturbances, a loss of housetraining, changes in activity levels, and increased anxiety, commonly summarized by the DISHAA acronym. Overall, CCD represents a valuable spontaneous large-animal model for investigating neurodegenerative mechanisms and clearance-related therapeutic targets relevant to both veterinary and human medicine.},
}

@article {pmid41893744,
year = {2026},
author = {Rzymski, P},
title = {Potential Non-Specific Benefits of Seasonal Influenza Vaccination: Evidence, Knowledge Gaps, and Future Directions.},
journal = {Vaccines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/vaccines14030207},
pmid = {41893744},
issn = {2076-393X},
abstract = {Seasonal influenza vaccination is a cornerstone of public health, providing well-established protection against infection, hospitalization, and mortality. In recent years, increasing attention has been directed toward the possibility that influenza vaccination may be associated with health effects extending beyond prevention of influenza itself. This narrative review synthesizes current evidence on these potential effects, integrating epidemiological findings with emerging mechanistic insights. The most consistent evidence relates to cardiovascular outcomes, with a number of studies, i.e., clinical trials, observational studies, and meta-analyses, reporting associations between influenza vaccination and a reduced risk of major adverse cardiovascular events. Influenza vaccination has also been associated with reduced antibiotic use at the population level, largely through prevention of influenza and its complications, thereby potentially contributing to efforts to mitigate antimicrobial resistance. Emerging epidemiological evidence further suggests an association between influenza vaccination and a lower risk of neurodegenerative disorders, including Alzheimer's disease. Associations have also been reported between influenza vaccination and lower risk of selected malignancies; however, the generalizability of these findings remains uncertain. At the mechanistic level, experimental and immunological studies indicate that influenza vaccination can modulate innate and adaptive immune responses, including features consistent with trained immunity and heterologous protection, thereby providing biological plausibility for some epidemiological observations. Importantly, though, for most non-influenza outcomes, causal relationships have not been established, and residual confounding and healthy-vaccinee effects cannot be excluded. Future research integrating epidemiology, immunology, and systems biology, particularly based on well-designed randomized clinical trials and mechanistic human studies, is needed to clarify the contexts, populations, and vaccine characteristics in which such effects may occur. Overall, while seasonal influenza vaccination remains a highly effective intervention for influenza prevention, its potential broader health implications warrant continued rigorous investigation.},
}

@article {pmid41893846,
year = {2026},
author = {Lin, Z and Sun, R and Ross, JS and Lau, K and Stumpf, S and Chen, X},
title = {Racial and Ethnic Reporting and Representation in US Alzheimer Clinical Trials: A Systematic Review.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e262427},
doi = {10.1001/jamanetworkopen.2026.2427},
pmid = {41893846},
issn = {2574-3805},
mesh = {Humans ; *Alzheimer Disease/drug therapy/ethnology ; United States ; *Ethnicity/statistics & numerical data ; *Racial Groups/statistics & numerical data ; *Clinical Trials, Phase III as Topic/statistics & numerical data ; Clinical Trials as Topic ; },
abstract = {IMPORTANCE: Alzheimer disease (AD) disproportionately affects racial and ethnic populations underrepresented in US clinical research, raising concerns about the generalizability of AD trial findings and the evaluation of treatment safety and efficacy for populations most affected by AD.

OBJECTIVE: To examine patterns and trends in the reporting and representation of patient race and ethnicity in US-based phase 3 AD clinical trials.

EVIDENCE REVIEW: This systematic review examined US-based phase 3 AD drug trials identified through the Trialtrove trial database between 1997 and 2023. Trials were cross-referenced with peer-reviewed publications, ClinicalTrials.gov, pharmaceutical company reports, and conference abstracts. Completed trials were eligible for inclusion if they were designated as phase 3 drug trials targeting AD and recruited patients exclusively in the US. Primary outcomes included reporting of race and ethnicity, the number of racial and ethnic groups reported, and their representation among trial populations. Secondary outcomes included terminology used, reporting of safety or efficacy differences by race and ethnicity, and discussion of racial and ethnic representation in trial reports. Temporal trends in reporting and representation were assessed. Methodologic quality was evaluated using the Quality Rating Scheme for Studies and Other Evidence. Data collection was completed May 2024.

FINDINGS: Among 88 US-based phase 3 AD clinical trials conducted between 1997 and 2023, 71 (80.7%) had publicly available results, including 52 (59.1%) published in peer-reviewed journals. Nearly half of published trials (35 [49.3%]) did not report patient race or ethnicity. Among published trials, reporting was inconsistent and focused predominantly on White (36 [50.7%]) patients, with substantially fewer trials reporting data on Asian or Pacific Islander (11 [15.5%]), Black (20 [28.2%]), Hispanic (13 [18.3%]), or Native American (2 [2.8%]) patients. Median (IQR) enrollment of White patients was 91.3% (87.3%-93.6%), whereas enrollment of underrepresented patient populations was markedly lower, with median (IQR) enrollment of 0.9% (0.6%-1.6%) for Asian or Pacific Islander, 4.5% (3.6%-6.6%) for Black (ethnicity unspecified), 7.2% (3.7%-9.1%) for Black (non-Hispanic), 5.2% (3.1%-6.6%) for Hispanic, and 0.4% (0%-0.8%) for Native American patients. Few trials (3 of 71 [4.2%]) conducted subgroup analyses by race or ethnicity, and none reported detailed subgroup characteristics or safety or efficacy outcomes by patient race and ethnicity. Reporting practices and representation showed little improvement over time.

CONCLUSIONS AND RELEVANCE: US-based phase 3 AD trials showed substantial gaps in racial and ethnic reporting and representation from 1997 to 2023, limiting the evaluation of treatment safety and efficacy across diverse populations. These findings suggest that stronger reporting standards and more inclusive trial design and recruitment strategies are needed to improve the equity and generalizability of AD trials.},
}

Humans
*Alzheimer Disease/drug therapy/ethnology
United States
*Ethnicity/statistics & numerical data
*Racial Groups/statistics & numerical data
*Clinical Trials, Phase III as Topic/statistics & numerical data
Clinical Trials as Topic

@article {pmid41893852,
year = {2026},
author = {Bubu, OM},
title = {Aligning Alzheimer Trials With Disease Demographics-From Rhetoric to Reality.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e262373},
doi = {10.1001/jamanetworkopen.2026.2373},
pmid = {41893852},
issn = {2574-3805},
}

@article {pmid41894064,
year = {2026},
author = {Chaki, J and Deshpande, G},
title = {The Deep Learning Revolution in Neuroimaging: Insights from a Bibliometric Analysis (2014-2024).},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {41894064},
issn = {1559-0089},
mesh = {*Deep Learning/trends ; *Bibliometrics ; *Neuroimaging/trends/methods ; Humans ; *Brain/diagnostic imaging ; },
abstract = {This paper presents a bibliometric analysis of the fast-growing area of deep learning in neuroimaging. Using data from the Scopus database, we analyzed 12564 peer-reviewed publications originating from 102 countries, published in 2259 sources over the period from 2014 to 2024. The field demonstrated a compound average annual growth rate of 51.7%. We found that China emerged as the most productive contributor, accounting for 22.9% of the total publications and 18% of total citations. The Chinese Academy of Sciences was identified as the most productive research institution with 149 publications and 1557 citations, while Lecture Notes in Computer Science was noted as the most highly cited source in this domain. High usage of deep learning, brain, and magnetic resonance imaging identified the most prominent research themes. Also, our analysis noted strong research emphasis on the application of various deep learning architectures for the diagnosis and study of important neurological disorders like Parkinson's Disease, Alzheimer's Disease, and Mild Cognitive Impairment. The article would be useful in understanding the current state-of-the-art deep learning for neuroimaging by identifying key research trends, influential institutions, and prominent research themes. In this way, it will contribute to helping future researchers go further in this fast-growing field.},
}

*Deep Learning/trends
*Bibliometrics
*Neuroimaging/trends/methods
Humans
*Brain/diagnostic imaging

@article {pmid41894147,
year = {2026},
author = {Dorfsman, D and Prough, MB and Gulyayev, A and Caywood, LJ and Clouse, JE and Herington, SD and Slifer, SH and Adams, LD and Laux, RA and Song, YE and Lynn, A and Fuzzell, SL and Hochstetler, SD and Miskimen, K and Main, LR and Wang, P and Liu, Y and Moore, N and Ogrocki, P and Lerner, AJ and Vance, JM and Cuccaro, ML and Haines, JL and Pericak-Vance, MA and Scott, WK},
title = {WDR12 and HIVEP3 are contributors to cognitive preservation in Amish SuperAgers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71293},
doi = {10.1002/alz.71293},
pmid = {41894147},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; AG058066/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; Aged, 80 and over ; Alzheimer Disease/genetics ; *Amish/genetics ; Genetic Linkage ; *Cognition/physiology ; Aged ; Pedigree ; Polymorphism, Single Nucleotide/genetics ; Memory, Episodic ; },
abstract = {INTRODUCTION: Cognitive SuperAgers (SAs) are individuals aged 80+ with exceptional episodic memory performance for their age, exceeding middle-aged adult norms. This study integrates family- and association-based methods to identify genetic variants associated with SAs in the Midwestern Amish population.

METHODS: Eighty-three Amish SAs were grouped into 16 pedigrees for parametric and non-parametric linkage analysis. Variants in linked regions (heterogeneity logarithm of the odds [HLOD] or Kong and Cox logarithm of the odds [LOD*] ≥ 3) were tested for association with SAs using two contrasts: SA versus Alzheimer's disease (AD; n = 40) and SA versus cognitively unimpaired (CU), age-matched non-SA individuals (CU80+; n = 157).

RESULTS: Evidence of linkage for SAs was observed on chromosomes 1, 2, 7, 16, and 20, with the strongest signal around the AD-associated locus WDR12 on chromosome 2. Association analysis for SA versus AD identified eight variants in HIVEP3 (chromosome 1) that were nominally significant when comparing SA versus CU80+.

DISCUSSION: WDR12 and HIVEP3 are potential candidate genes contributing to SAs in the Amish population.},
}

Humans
Male
Female
Aged, 80 and over
Alzheimer Disease/genetics
*Amish/genetics
Genetic Linkage
*Cognition/physiology
Aged
Pedigree
Polymorphism, Single Nucleotide/genetics
Memory, Episodic

@article {pmid41894159,
year = {2026},
author = {Suemoto, CK and Custodio, N and Aguilar, D and Avila-Funes, JA and Baez, S and Bagnati, PM and Barnes, LL and Brucki, SMD and Calandri, IL and Caramelli, P and Cornejo-Olivas, M and Derio, CD and Ferreira, ST and García, AM and Grinberg, LT and Ibanez, AM and Isasi, R and Josephy-Hernández, SE and Porras, ML and Llibre-Guerra, JJ and Llibre-Rodriguez, JJ and Lourenco, MV and Meza, BMM and Migeot, J and Miranda, JJ and Miranda-Castillo, C and Mummery, CJ and Parodi, JF and Castro, NP and Contreras, RMS and Santamaría-García, H and Slachevsky, A and Souza-Talarico, JN and Surace, EI and Takada, LT and Tsoy, E and Pilalumbo, MU and Zimmer, ER and Fontana, IC and Mahinrad, S and Snyder, HM and Carrillo, MC},
title = {The landscape of dementia research, diagnosis, treatment, and care in Latin America.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71309},
doi = {10.1002/alz.71309},
pmid = {41894159},
issn = {1552-5279},
support = {//Global Brain Health Institute/ ; //ANID/FONDEF/ ; //ANID/Fondecyt/ ; //ANID/Fondap/ ; //NIH D43 Fogarty/ ; //ANID Millennium Science Initiative Program/ ; //National Institute for Health and Care Research/ ; //ANID/PIA/ANILLOS/ ; //Multi-partner Consortium to Expand Dementia Research in Latin America (ReDLat)/ ; //DICYT-USACH/ ; //Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; //National Institute for Translational Neuroscience (INNT-Brazil)/ ; //Agencia Nacional de Investigación y Desarrollo/ ; //Consejo Nacional de Desarrollo Científico y Tecnológico/ ; //Pilot Awards for Global Brain Health Leaders (Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society)/ ; /NH/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Agencia Nacional de Promoción Científica y Tecnológica/ ; //Takeda/ ; //National Institutes of Aging/ ; },
mesh = {Humans ; *Dementia/diagnosis/therapy/epidemiology ; Latin America/epidemiology ; *Biomedical Research ; Congresses as Topic ; },
abstract = {Latin America is undergoing rapid population aging alongside a rising burden of dementia. While the region holds substantial potential for dementia risk reduction, challenges remain, such as delayed diagnoses, limited access to specialized care and biomarker testing, persistent stigma, and deep-rooted structural inequities. To address these gaps and foster regionally informed solutions, the Alzheimer's Association convened the 2025 Alzheimer's Association International Conference (AAIC) Satellite Symposium in Lima, Peru, on May 14-15, in collaboration with the Global Brain Health Institute (GBHI) and the Atlantic Fellows for Equity in Brain Health. The meeting aimed to bring core elements of the global AAIC meeting to regional Latin American settings, recognizing that national and cultural contexts demand tailored approaches to dementia prevention, risk reduction, treatment and care all aimed at promoting brain health in the region. This manuscript synthesizes the symposium's key discussions, scientific advances, and opportunities for collaboration across the region.},
}

Humans
*Dementia/diagnosis/therapy/epidemiology
Latin America/epidemiology
*Biomedical Research
Congresses as Topic

@article {pmid41894477,
year = {2026},
author = {Park, Y and Jeong, H and Kim, EJ and Park, S and Lee, M and Jakovljevic, M},
title = {Global burden of disease due to young-onset dementia and the forecast for 2050: update from global burden of disease study 2021.},
journal = {Journal of medical economics},
volume = {29},
number = {1},
pages = {1012-1026},
doi = {10.1080/13696998.2026.2646088},
pmid = {41894477},
issn = {1941-837X},
mesh = {Humans ; Female ; Male ; Middle Aged ; *Global Burden of Disease/trends ; *Dementia/epidemiology ; Risk Factors ; Adult ; Sex Factors ; Disability-Adjusted Life Years ; Age of Onset ; Aged ; Bayes Theorem ; Body Mass Index ; Forecasting ; Age Factors ; Quality-Adjusted Life Years ; Blood Glucose/analysis ; Prevalence ; Young Adult ; Aged, 80 and over ; },
abstract = {OBJECTIVE: The prevalence of young-onset dementia (YOD) is increasing worldwide, leading to greater economic and social burden, necessitating strategic management and prevention.

MATERIALS AND METHODS: Using GBD 2021 data, disability-adjusted life years (DALYs) rates were analyzed by age, sex, and risk factors across five age groups. ARIMA and Bayesian models were applied to predict disease burden through 2050.

RESULTS: From 1990 to 2021, disease burden increased in both sexes aged ≥55 years, with the greatest rise in the 55-59 group. DALYs rates were consistently higher in females, peaking in the 60-64 group. High fasting plasma glucose was the leading risk factor. Model performance varied by sex and age; applying the best-fitting models indicated a continued increase in burden, particularly among females.

CONCLUSIONS: YOD burden has risen over time and is associated with modifiable factors such as high blood glucose and body mass index. The increasing trend is expected to persist, highlighting the need for effective management strategies to reduce future socioeconomic impact.},
}

Humans
Female
Male
Middle Aged
*Global Burden of Disease/trends
*Dementia/epidemiology
Risk Factors
Adult
Sex Factors
Disability-Adjusted Life Years
Age of Onset
Aged
Bayes Theorem
Body Mass Index
Forecasting
Age Factors
Quality-Adjusted Life Years
Blood Glucose/analysis
Prevalence
Young Adult
Aged, 80 and over

@article {pmid41894504,
year = {2026},
author = {Zhou, J and Liu, J and Liu, X and Ren, L and Yu, Z and Zheng, Z and Li, G},
title = {Clinically relevant stereochemistry reprograms amyloid proteome for aggregation cross-talk-conferred neuroprotection.},
journal = {Science advances},
volume = {12},
number = {13},
pages = {eaeb2729},
doi = {10.1126/sciadv.aeb2729},
pmid = {41894504},
issn = {2375-2548},
mesh = {Humans ; *Amyloid beta-Peptides/chemistry/metabolism ; Stereoisomerism ; *Proteome/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Neuroprotection ; *Protein Aggregates ; *Peptide Fragments/chemistry/metabolism ; *Protein Aggregation, Pathological/metabolism ; Neuroprotective Agents/pharmacology ; Brain/metabolism/pathology ; },
abstract = {The stereochemical diversity of Aβ42 in the brains of patients with Alzheimer's disease (AD) is a clinically recognized but poorly understood phenomenon. A critical gap in our knowledge is how the complex mixture of these stereoisomers collectively influences the aggregation pathway and neurotoxicity of Aβ42 at the molecular level. Drawing from stereoproteome data from AD patient brain tissues and previous studies, we engineered a panel of stereoisomers to more simply simulate the stereochemical diversity of the AD marker Aβ42. We found that the coexistence of L-Aβ42 with specific D-isomers initiates a potent antagonistic effect, suppressing the formation of toxic fibrils. This stereochemically driven antagonism conferred notable neuroprotection, suggesting an endogenous protective mechanism. This proof-of-concept work elucidates at the molecular level that by regulating the stereochemical composition of Aβ, its inherent cellular protective antagonistic effect can be activated, providing unprecedented molecular basis for understanding the disease mechanism and subsequent possible clinical research.},
}

Humans
*Amyloid beta-Peptides/chemistry/metabolism
Stereoisomerism
*Proteome/metabolism
*Alzheimer Disease/metabolism/pathology
*Neuroprotection
*Protein Aggregates
*Peptide Fragments/chemistry/metabolism
*Protein Aggregation, Pathological/metabolism
Neuroprotective Agents/pharmacology
Brain/metabolism/pathology

@article {pmid41894693,
year = {2026},
author = {Maadadi, R and Boukentoucha, C and Bazine, I and Menacer, R and Bensouici, C and Pevzner, L and Petrov, M and Stepakov, A and Abou Dib, A and Harakat, D},
title = {In situ hemisynthesis of new meso-substituted dipyrromethanes using natural aldehydes: in vitro anticholinesterase activity and in silico study.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14786419.2026.2648132},
pmid = {41894693},
issn = {1478-6427},
abstract = {This study reports the in situ hemisynthesis of two novel dipyrromethanes (DPM-1 and DPM-2) from ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate and natural aldehydes: perillaldehyde from Ammodaucus leucotrichus and cuminaldehyde from cumin seed essential oil. The compounds were synthesized via a double Friedel-Crafts reaction under two catalytic systems: (i) water/ethanol (1:1 v/v) with 0.18 M HCl, and (ii) iodine-catalyzed chloroform. Structural elucidation was achieved using [1]H NMR,[13]C NMR, HSQC, HMBC, and HR-MS. Both derivatives showed significant inhibitory activity against AChE and BChE. DPM-2 was more active against AChE (IC50 = 22.6 ± 0.06 μM) than DPM-1 (IC50 = 51 ± 1.74 μM), and comparable to Galantamine (IC50 = 21.81 ± 1.15 μM). Regarding BChE, DPM-2 (IC50 = 115 ± 1.91 μM) exhibited greater inhibitory potency than DPM-1 (IC50 = 230.41 ± 0.75 μM), and remained close to Galantamine (IC50 = 120.93 ± 1.99 μM). In silico analysis supported their potential as anti-Alzheimer's agents.},
}

@article {pmid41894824,
year = {2026},
author = {Wang, T and Wang, M and Yuan, Y},
title = {Closed-loop transcranial ultrasound stimulation based on NREM and REM sleep for bidirectional modulation of sleep neural oscillation and memory.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae584a},
pmid = {41894824},
issn = {1741-2552},
abstract = {Sleep plays an important role in memory integration. Closed-loop physical stimulation during rapid eye movement (REM) or non-rapid eye movement (NREM) sleep can modulate neural oscillations and associated memory functions. However, the impact of closed-loop transcranial ultrasound stimulation (CLTUS), a non-invasive technique with high spatial resolution and deep penetration, on sleep-specific oscillations and memory remains unclear. Approach: In this study, we developed a CLTUS system using deep learning to target NREM and REM sleep oscillations and evaluated sleep neural oscillations and memory ability. Main results: Our findings revealed that CLTUS of the slow oscillation up-state during NREM sleep reduced NREM-specific neural activity and significantly weakened spatial and fear memory abilities. These changes were positively correlated with the induced neural dynamics. Conversely, during REM sleep, CLTUS delivered at the theta peak enhanced REM-specific neural activity in both healthy and Alzheimer's disease model mice. Consequently, spatial memory was significantly improved in both groups, and this improvement was closely related to ultrasound-induced neural activity. Significance: CLTUS based on NREM and REM sleep exerts a bidirectional modulation effect on sleep neural oscillations and memory ability, providing important guidance for selecting and optimizing stimulation protocols for modulating sleep and memory.},
}

@article {pmid41894949,
year = {2026},
author = {Brem, AK and Khan, Z and Radermacher, J and Georgiadis, K and Lazarou, I and Grammatikopoulou, M and Pickering, E and Mitterreiter, J and Aakre, JA and Ashton, NJ and Baquero, M and Beser-Robles, M and Braboszcz, C and Brandt, S and Brown, J and Cacciamani, F and Campill, S and Collins, C and Deshpande, P and Diaz, A and Durrleman, S and Engelborghs, S and Ferré-González, L and Frisoni, GB and Gjestsen, MT and Gove, D and Honigberg, L and Huang, B and Hudak, A and Kaushik, S and Letoha, T and Marquardt, G and Mendes, AJ and Müllenborn, M and Paletta, L and de Barros, NP and Pszeida, M and Vik-Mo, AO and Rostamipour, H and Perneczky, R and Rauchmann, BS and Russegger, S and Schirmer, T and Shadmaan, A and Solana, AB and Soria-Frisch, A and Tegethoff, P and Ribbens, A and De Witte, S and van der Giezen, M and Nikolopoulos, S and Corbett, A and Fröhlich, H and Aarsland, D and , },
title = {Screening for Alzheimer's disease in the community using an AI-driven screening platform: design of the PREDICTOM study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100545},
doi = {10.1016/j.tjpad.2026.100545},
pmid = {41894949},
issn = {2426-0266},
abstract = {BACKGROUND: Recent developments in physiological, imaging and digital biomarkers combined with the approval of new disease-modifying drugs against Alzheimer's disease (AD) and diagnostic blood tests provide an opportunity to shift the first diagnostic steps to the home-setting. While these novel biomarkers enable scalable screening and earlier detection and treatment of AD, they require an evaluation of their accuracy, feasibility, and safety in primary care and the community setting.

OBJECTIVES: The aim of PREDICTOM is to develop and test the accuracy of an artificial intelligence (AI) driven screening platform for the risk assessment and early detection of AD to extend the clinical pathway to home-based screening using established and novel biomarkers.

DESIGN/SETTING: PREDICTOM is a European (Norway, UK, Belgium, France, Switzerland, Germany, Spain) observational, prospective cohort study using a cloud-based platform that stores a digitalised journey for each participant and provides a collection of artificial-intelligence (AI) algorithms and tools for risk assessment and early diagnosis and prognosis.

PARTICIPANTS: Cohort 1 consists of 4000 adults aged 50 years or older at risk of developing AD. Cohort 2 consists of 615 participants selected from Cohort 1 based on estimates indicating high (N = 415) or low (N = 200) risk of AD. Data from existing cohorts will guide the analytic strategy of the study.

MEASUREMENTS: Cohort 1 will undergo home-based assessments (Level 1), Cohort 2 will undergo in-clinic assessments (Levels 2 and 3). Level 1 includes at-home screening, collecting digital and physiological data (questionnaires, cognition, hearing, eye-tracking) and biofluids (capillary blood via finger-stick and saliva) for biomarker analysis. Level 2 comprises a more complex biomarker collection, most of which can be completed in primary care, including EEG, MRI, venous blood, microbiome from stool, cognition, hearing, and eye-tracking. Level 3 includes a diagnostic evaluation to confirm or rule out AD pathology using established biomarkers (cerebrospinal fluid, or amyloid PET).

CONCLUSIONS: PREDICTOM will develop AI-driven algorithms for the early detection of AD using biomarkers that can be collected at home or in the community care setting, and evaluate their integration into a well-defined and comprehensive clinical pathway.},
}

@article {pmid41895180,
year = {2026},
author = {Chen, Z and Wang, Y and Jiang, F and Liu, T and Liu, Z and Wang, X and Li, Y and Fang, K and Ao, JP},
title = {Steric hindrance effect synergizing hole-trapping technique: High-Stability and high-accuracy Si/CdS n-n heterojunction photoelectrochemical biosensing of amyloid-β42.},
journal = {Talanta},
volume = {306},
number = {},
pages = {129703},
doi = {10.1016/j.talanta.2026.129703},
pmid = {41895180},
issn = {1873-3573},
abstract = {Due to rapid carrier recombination and photodegradation, cadmium sulfide (CdS), an n-type semiconductor photosensitive material, has a low utilization efficiency that restricts its use in biosensing. A synergistic hole-trapping approach utilizing steric hindrance effects is proposed in this paper. First, chemical bath deposition (CBD) is used to create a Si/CdS n-n heterojunction on the n-type silicon (n-Si) substrate surface. Through interface engineering, this heterojunction reduces rapid carrier recombination by optimizing carrier transport paths. In order to capture photogenerated holes building up in the CdS valence band, ascorbic acid (AA), which is strongly electron-donating and oxidizable, is added concurrently. This dual approach improves sensor stability and successfully reduces CdS self-oxidation faults. The resultant photoelectrochemical (PEC) sensor detects amyloid-β42 (Aβ42), a crucial biomarker for early diagnosis of Alzheimer's disease (AD), with great precision. The following is how the central mechanism functions: Upon the specific binding of Aβ42 to the sensor surface aptamer, the induced steric hindrance prevents AA from diffusing to the electrode surface. This lessens AA's capacity to absorb photogenerated holes by reducing oxidation processes. As a result, the photocurrent drops, and the suppression magnitude (ΔI) shows a positive association with the concentration of Aβ42. The sensor has a linear range of 10[-17]‒10[-12] g/mL under ideal conditions, and its limit of detection (LOD) is as low as 3.1 × 10[-18] g/mL (S/N = 3). This cutting-edge detection technology has great application potential in the realm of accurate biomarker identification and provides a fresh approach for early clinical diagnosis of AD.},
}

@article {pmid41895266,
year = {2026},
author = {Delivanoglou, N and Todd, KT and Almeida, F and Rego, S and Changavi, A and Spajer, M and Ayuso, VE and Pinho-Correia, LM and Sanchez, G and das Neves, SP and Barber, MJ and Schrader, R and Sacilotto, P and Martens, YA and Heckman, MG and Bu, G and Tanzi, RE and Thomas, JL and Fryer, JD and Oliveira, TG and Shekhar, K and Da Mesquita, S},
title = {Sex-specific APOE4-dependent innate immunity regulates meningeal lymphatics, brain lipids, neuroinflammation, and cognition.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.02.030},
pmid = {41895266},
issn = {1097-4199},
abstract = {Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer's disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the meningeal dura of humanized female and male mice expressing two alleles of APOE4 (E4/E4), when compared with their respective sex-matched E3/E3 controls. We also describe distinct effects of APOE4 on brain lipid composition and inflammation in females and males that were partially reverted upon colony-stimulating factor 1 receptor (CSF1R) inhibition. Suppressing innate immunity reduced neuroinflammation and restored cognitive function in E4/E4 females, while exacerbating neuroinflammation and accelerating cognitive decline in E4/E4 males. Finally, in line with the E4/E4 humanized mouse model data, we show that APOE4 expression is linked to sexually dimorphic leukocyte activation profiles in the human brain. This study highlights the need for personalized therapies when targeting APOE, brain immunity, and meningeal lymphatics to promote cognitive resilience in both females and males.},
}

@article {pmid41895269,
year = {2026},
author = {Etxeberria, A and Lee, SH and Kuhn, JA and Callow, M and Novikova, G and Fortin, JP and Choy, MK and Xie, L and Imperio, J and Vito, S and Tsai, MC and Lock, J and Taraborrelli, L and Haag, SM and Chen, H and Ge, M and Ngu, H and Foreman, O and Stark, K and Friedman, BA and Haley, B and Hansen, DV and Meilandt, WJ and Easton, A and Martin, S and Murthy, A and Costa, M and Bohlen, CJ},
title = {Microglia-mediated protection against Alzheimer's disease pathology and detrimental effects in white matter revealed by Ptpn6 deletion.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.02.023},
pmid = {41895269},
issn = {1097-4199},
abstract = {Genetic variants affecting microglia can cause early-onset neurodegeneration or elevate Alzheimer's disease risk. To nominate regulators of relevant signaling pathways, we developed a genome-wide CRISPR screen in primary macrophages focused on survival. We identified Ptpn6, which encodes the inhibitory phosphatase SHP-1, as a crucial regulator for macrophage survival under reduced CSF1R signaling conditions in vitro. Deletion of Ptpn6 from adult microglia in vivo enhanced survival and decreased neuritic dystrophy around amyloid plaques in the TauPS2APP model of Alzheimer's disease. However, deletion also dysregulated homeostasis in normal white matter and exacerbated neurodegeneration in disease. Heterozygous deletion revealed a differential gene-dosage sensitivity for beneficial and detrimental effects, exhibiting reduced neuritic damage near plaques without white-matter harm. Single-cell RNA sequencing uncovered multiple disease-associated microglia (DAM)-like transcriptional states, with Lgals3[+] microglia emerging alongside neurodegeneration after Ptpn6 deletion. In all, these findings reveal both the protective and latent degenerative potential of microglia held in check by Ptpn6.},
}

@article {pmid41895273,
year = {2026},
author = {Kim, D and Kondo, T and Inoue, H},
title = {Dissecting microglial contributions to neurodegenerative disease pathophysiology using human pluripotent stem cells.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102866},
doi = {10.1016/j.stemcr.2026.102866},
pmid = {41895273},
issn = {2213-6711},
abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss. Microglia, the brain's resident macrophages, are key contributors to disease pathogenesis, with many genetic risk variants enriched in microglia-specific genes. While rodent models have provided valuable insights, human induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) technologies now enable the generation of human microglia-like cells, offering a physiologically relevant platform to study human microglial biology. This review discusses the developmental origins and functions of microglia, current differentiation approaches, and how these models help elucidate disease-relevant phenotypes and molecular mechanisms in neurodegeneration.},
}

@article {pmid41895286,
year = {2026},
author = {Abd Alla, J and Perhal, A and Fu, X and Langer, A and Faramawy, YE and Quitterer, U},
title = {Analysis of GRK2 aggregation in the pathology of Alzheimer disease in animal models.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102707},
doi = {10.1016/j.xcrm.2026.102707},
pmid = {41895286},
issn = {2666-3791},
abstract = {The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L. Aggregated phospho-S670-GRK2 triggers aggregation of TOMM6 (translocase of outer mitochondrial membrane 6), promotes mitochondrial dysfunction, and enhances beta-amyloid. Transgenic expression of inactive GRK2-K220R or a GRK-inhibitory peptide proves that neuropathological features are caused by GRK2 inactivation. Restoration of TOMM6 by neuron-specific TOMM6 expression reduces beta-amyloid plaques but enhances soluble beta-amyloid and increases mortality. In contrast, reconstitution of monomeric GRK2 and proteasomal phospho-S670-GRK2 degradation by small molecules counteracts neuropathological AD features, prevents neuronal loss, and improves survival. Thus, targeting of pathological GRK2 aggregation slows aging-induced neurodegeneration.},
}

@article {pmid41895394,
year = {2026},
author = {Xia, X and Yi, F and Zhang, R and Wu, R and Zhang, X and Zhang, Y and Liu, J and Qin, H and He, B and Duan, Y and Xu, Y and Huang, XF and Yu, Y and Hu, M},
title = {Senolytic therapy ameliorates high-fat diet-induced hippocampal senescence and cognitive decline in mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115745},
doi = {10.1016/j.expneurol.2026.115745},
pmid = {41895394},
issn = {1090-2430},
abstract = {Obesity is a recognized risk factor for cognitive decline and neurodegenerative diseases, including Alzheimer's disease (AD). Obese individuals typically consume high-fat diet (HFD), particularly those rich in palmitate. However, the potential for HFD to induce neurodegeneration and their underlying mechanisms remain poorly understood. In this study, we demonstrate that HFD exposure induced significant deficits in hippocampal-dependent behaviors in mice and decreased synaptic protein expression. Transcriptomic analysis revealed differentially expressed genes in the hippocampus of HFD-fed mice, with enrichment predominantly in senescence-associated pathways. Furthermore, HFD-fed mice exhibited elevated hippocampal senescence markers, including increased SA-β-gal-positive cells, upregulated p16/p21 expression, elevated SASP factors and reduced Lamin B1. Remarkably, a palmitate-enriched diet recapitulated the hippocampal senescence phenotype and cognitive deficits induced by HFD, indicating that palmitate-the principal saturated fatty acid in HFD-served as a key mediator of cellular senescence. Finally, treatment with the senolytic cocktail dasatinib plus quercetin significantly reduced senescent cell burden, suppressed p16 protein expression, and normalized SASP factor levels. This intervention effectively restored cognitive function and synaptic protein expression. This work uncovers a novel HFD-induced cognitive impairment mechanism and suggests potential therapeutic strategies for mitigating obesity-associated neurodegeneration.},
}

@article {pmid41895620,
year = {2026},
author = {Pradhan, R and Sakib, MS and Kaurani, L and Krüger, DM and Pena, T and Burkhardt, S and Schütz, AL and Kronenberg-Versteeg, D and Delalle, I and Sananbenesi, F and Fischer, A},
title = {lncRNA 3222401L13Rik/ENSG00000272070 modulates microglial inflammatory programs in association with PU.1.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107366},
doi = {10.1016/j.nbd.2026.107366},
pmid = {41895620},
issn = {1095-953X},
abstract = {Long non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA Glelr as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog GLELR. We found that Glelr/GLELR is expressed in both astrocytes and microglia and increases with age. Knockdown of Glelr in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNFα, and increased phagocytic activity. RNA-sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog GLELR showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, Glelr interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, GLELR expression was significantly reduced in postmortem Alzheimer's disease (AD) brains, and AD-associated genes were enriched among Glelr-regulated targets. Together, our results identify Glelr/GLELR as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests GLELR as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases.},
}

@article {pmid41895668,
year = {2026},
author = {Jung, H and Hyun, G and Kim, S and Jeon, Y and Han, KA and Lee, KJ and Ko, J and Um, JW},
title = {Somatostatin-induced modulation of microglial activity contributes to mitigating Alzheimer's disease pathology.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106563},
doi = {10.1016/j.bbi.2026.106563},
pmid = {41895668},
issn = {1090-2139},
abstract = {Somatostatin (SST) is a neuropeptide widely expressed in the central nervous system, known to exert inhibitory effects through activation of G protein-coupled somatostatin receptors (SSTRs). Although its synaptic and network-level functions have been implicated in various neurological disorders, the direct peptidergic actions of SST-particularly on microglia-remain poorly understood. Given that SST levels are reduced in Alzheimer's disease (AD) and microglia predominantly express SSTR2, we hypothesized that SST modulates microglial function both in physiological and AD-related contexts. In this study, we demonstrate that SST treatment enhances phagocytic capacity and suppresses pro-inflammatory cytokine release in cultured microglia. Furthermore, SST overexpression in an AD mouse model reduced microglial density and amyloid-β plaque burden and improved hippocampus-dependent cognitive performance, indicating a protective effect mediated through microglial modulation. Our findings suggest a previously unrecognized role of SST in regulating microglial behavior and highlight the therapeutic potential of targeting the SST-SSTR signaling axis in neuroinflammatory and neurodegenerative diseases.},
}

@article {pmid41895681,
year = {2026},
author = {Iwao, T and Takata, F and Tanaka, Y and Aridome, H and Mizoguchi, J and Dohgu, S},
title = {Docosahexaenoic and eicosapentaenoic acids differentially enhance the blood-brain barrier function via distinct PPAR-dependent upregulation of tight junction proteins in brain endothelial cells.},
journal = {Microvascular research},
volume = {},
number = {},
pages = {104948},
doi = {10.1016/j.mvr.2026.104948},
pmid = {41895681},
issn = {1095-9319},
abstract = {Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are unsaturated omega-3 fatty acids that reduce the risk of Alzheimer's disease and dementia by protecting blood-brain barrier (BBB) function. However, the mechanisms through which DHA and EPA regulate BBB function remain unclear. DHA and EPA act as ligands for the peroxisome proliferator-activated receptor (PPAR), which is a nuclear receptor superfamily member, with three isoforms: α, β, and γ. Tight junctions (TJs) formed between brain endothelial cells play a central role in restricting the paracellular passage of substances across the BBB. In this study, we aimed to investigate whether DHA and EPA regulate TJ protein expression via PPARs. Primary cultured rat brain endothelial cells (RBECs) isolated from Wistar rats were used for in vitro analysis. TJ protein (ZO-1, occludin, and claudin5) and PPARα, β, and γ expression levels in RBECs were measured using western blot analysis. Additionally, to verify PPAR involvement in TJ protein expression regulation, RBECs were treated with DHA or EPA in combination with PPARα, β, or γ inhibitors. The DHA-induced ZO-1 upregulation was suppressed by PPARβ inhibition. Either PPARβ or PPARγ inhibition suppressed the DHA-induced occludin increase, whereas both PPAR inhibitors suppressed the DHA-induced claudin-5 increase. In contrast, the EPA-induced increase in claudin-5 expression was suppressed via PPARγ inhibition. Conclusively, DHA and EPA regulate TJ protein expression via different PPARs in brain endothelial cells, revealing potential targets for the prevention or treatment of neurodegenerative diseases.},
}

@article {pmid41895857,
year = {2026},
author = {Davis, MN and Bullock, M and Jhaldiyal, A and Holifield, N and Mikhail, K and Voskobiynyk, Y and Vollmer, RM and Prendergast, GC and Lauderdale, K and Palop, JJ and Gamble, KL and Roberson, ED},
title = {Parvalbumin Neuron-Targeted Loss of Alzheimer's Disease Risk Gene BIN1 Is Insufficient to Drive Cognitive or Network Excitability Changes.},
journal = {eNeuro},
volume = {13},
number = {3},
pages = {},
doi = {10.1523/ENEURO.0304-25.2026},
pmid = {41895857},
issn = {2373-2822},
mesh = {Animals ; *Parvalbumins/metabolism ; *Alzheimer Disease/genetics/metabolism/physiopathology ; Male ; Female ; *Neurons/metabolism ; Mice, Knockout ; *Adaptor Proteins, Signal Transducing/genetics/metabolism/deficiency ; *Tumor Suppressor Proteins/genetics/metabolism ; Mice ; Electroencephalography ; *Nerve Tissue Proteins/genetics/metabolism ; Disease Models, Animal ; *Cognitive Dysfunction/genetics/physiopathology/metabolism ; *Nuclear Proteins/genetics ; *Cognition/physiology ; Mice, Inbred C57BL ; },
abstract = {Bridging integrator 1 (BIN1) is one of the strongest genetic risk factors for Alzheimer's disease (AD), yet its function in the brain and role in AD remain unclear. Neuronal BIN1 isoform levels are decreased in AD, and recent data show an important role of BIN1 in inhibitory neurons. Inhibitory neurons are key regulators of cognition and network excitability, with parvalbumin-expressing (PV) neurons as the most abundant subtype. We tested the hypothesis that loss of BIN1 from PV neurons contributes to AD-related cognitive dysfunction and network hyperexcitability. We generated a cell type-specific conditional knock-out mouse line, Bin1-pvKO, and examined mice of both sexes. These mice showed few behavioral differences when assessed with traditional or machine learning-based behavioral tests, with only a slight reduction in exploratory behavior in aged cohorts. Bin1-pvKO mice showed no significant differences in network excitability on measures of induced seizure susceptibility and spiking on cortical electroencephalographic recordings. Finally, Bin1-pvKO mice exhibited no major differences in power spectral analysis of cortical electroencephalographic recordings, with only a modest reduction in delta power at high activity levels. These findings suggest that BIN1 loss in PV neurons alone is insufficient to drive the cognitive and network dysfunction observed in AD models. While these results do not exclude a role of BIN1 in PV neurons in AD models, if combined with a "second hit" or alterations in other cell types, they indicate that BIN1 loss in PV neurons alone does not recapitulate key AD-related phenotypes.},
}

Animals
*Parvalbumins/metabolism
*Alzheimer Disease/genetics/metabolism/physiopathology
Male
Female
*Neurons/metabolism
Mice, Knockout
*Adaptor Proteins, Signal Transducing/genetics/metabolism/deficiency
*Tumor Suppressor Proteins/genetics/metabolism
Mice
Electroencephalography
*Nerve Tissue Proteins/genetics/metabolism
Disease Models, Animal
*Cognitive Dysfunction/genetics/physiopathology/metabolism
*Nuclear Proteins/genetics
*Cognition/physiology
Mice, Inbred C57BL

@article {pmid41895957,
year = {2026},
author = {Ma, W and Wang, S and Yang, X and Chen, YB and Li, Y and Cui, YL},
title = {Gastrodin and gastrodigenin: advancing neurogenesis in neurological disease management.},
journal = {Food research international (Ottawa, Ont.)},
volume = {232},
number = {},
pages = {118882},
doi = {10.1016/j.foodres.2026.118882},
pmid = {41895957},
issn = {1873-7145},
mesh = {*Benzyl Alcohols/pharmacology/therapeutic use ; *Neurogenesis/drug effects ; *Glucosides/pharmacology/therapeutic use ; Humans ; Animals ; Gastrodia/chemistry ; *Nervous System Diseases/drug therapy ; Neural Stem Cells/drug effects ; },
abstract = {Neurogenesis, the creation of new neurons from neural stem cells (NSCs) in the brain, plays a crucial role in neurological diseases when disrupted. Herbal medicine components, especially those with dual applications in disease treatment and food, like those from Gastrodia elata Blume, have gained attention for their ability to influence neurogenesis. Notably, gastrodin and gastrodigenin from this herb influence neurogenesis and affect conditions like Alzheimer's, depression, stroke, and amnesia. Understanding these processes and mechanisms is essential for addressing neurological disorders. We also discuss gastrodin's potential in aiding peripheral nerve regeneration and its therapeutic effects on neurological diseases through neurogenesis regulation. This review offers insights into gastrodin's therapeutic potential, encouraging further research to boost its efficacy in neurological diseases.},
}

*Benzyl Alcohols/pharmacology/therapeutic use
*Neurogenesis/drug effects
*Glucosides/pharmacology/therapeutic use
Humans
Animals
Gastrodia/chemistry
*Nervous System Diseases/drug therapy
Neural Stem Cells/drug effects

@article {pmid41896008,
year = {2026},
author = {Grinberg, LT},
title = {The brainstem in neurodegenerative diseases.},
journal = {Handbook of clinical neurology},
volume = {216},
number = {},
pages = {201-212},
doi = {10.1016/B978-0-443-15736-3.00017-2},
pmid = {41896008},
issn = {0072-9752},
mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Brain Stem/pathology ; Disease Progression ; },
abstract = {The brainstem, despite its modest size relative to the cerebral cortex, is critically involved in the pathology and clinical manifestations of numerous neurodegenerative diseases (NDDs). Historically, research on NDDs such as Alzheimer disease, Lewy body disease, and frontotemporal lobar degeneration predominantly adopted a cortico-centric perspective. However, emerging neuropathologic evidence underscores the brainstem's essential role, with early pathologic changes often predating cortical involvement. This chapter highlights salient points regarding the pathology and clinicopathologic correlations of brainstem involvement across major NDDs, emphasizing the chronology of disease progression. Key mechanisms, including protein misfolding and aggregation, selective neuronal vulnerability, and neurotransmitter dysfunction, are explored. Clinical correlations illustrate how early brainstem pathology significantly contributes to prodromal symptoms and helps define distinct clinical phenotypes, such as autonomic dysfunction, sleep disturbances, and mood disorders. Recognizing the chronologic order and specific nuclei affected in the brainstem broadens our understanding of disease progression, highlighting opportunities for targeted interventions at earlier disease stages.},
}

Humans
*Neurodegenerative Diseases/pathology
*Brain Stem/pathology
Disease Progression

@article {pmid41896041,
year = {2026},
author = {Das, S and Mdawar, B and Diaconescu, A and Hill, AT and Desarkar, P and Ma, C and Zrenner, C and De Luca, V and Zomorrodi, R and Rajji, TK},
title = {Electroencephalogram microstates in Alzheimer's dementia and mild cognitive impairment: A systematic review and meta-analysis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {},
number = {},
pages = {2111856},
doi = {10.1016/j.clinph.2026.2111856},
pmid = {41896041},
issn = {1872-8952},
abstract = {OBJECTIVE: Electroencephalography (EEG) microstate analysis has emerged as a tool for investigating the spatial organization and temporal dynamics of large-scale cortical networks. Its potential role in identifying risk and progression of Alzheimer's dementia (AD) remains unclear. We conducted a systematic review and meta-analysis of EEG microstate parameters in AD and mild cognitive impairment (MCI).

METHODS: PubMed, PsychINFO, EMBASE, and MEDLINE were searched, identifying 30 eligible studies (16 included in meta-analysis). Random-effects models were used to pool effect sizes and 95% confidence intervals comparing microstate parameters between AD, MCI, and healthy controls.

RESULTS: Sixteen studies were included in the meta-analysis. In AD vs controls, microstate A duration (g = 0.41, 95% CI [0.10, 0.72]) and microstate B duration (g = 0.48, 95% CI [0.23, 0.73]) were significantly increased. In MCI vs controls, microstate D duration was significantly decreased (g = -0.26, 95% CI [-0.48, -0.04]) and microstate A occurrence rate was increased (g = 0.40, 95% CI [0.07, 0.74]), while microstate A and B duration were not significantly different. Heterogeneity was substantial for several outcomes.

CONCLUSION: Pooled evidence suggests prolonged microstate A/B duration as the most reproducible alteration in AD, with reduced microstate D duration emerging as a modest finding in MCI. However, substantial heterogeneity and possible small-study effects indicate that current evidence is best interpreted as hypothesis-generating pending standardized, longitudinal, and multimodal studies.

SIGNIFICANCE: EEG microstate analysis may provide complementary information about large-scale network dysfunction in MCI and AD, but methodological limitations currently constrain clinical biomarker interpretation.},
}

@article {pmid41896046,
year = {2026},
author = {Fisher, DW and Mehta, R and Morrow, CB and Kerr, KF and Jayadev, S and Domoto-Reilly, K and Schrift, MJ and Darvas, M},
title = {Clinical Associations and Possible Risk Factors for Affective Neuropsychiatric Symptoms in Older Adults With and Without Cognitive Impairment.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.02.015},
pmid = {41896046},
issn = {1545-7214},
abstract = {OBJECTIVE: Affective neuropsychiatric symptoms (NPS)-depression, anxiety, and apathy-are frequent in older adults. Understanding which clinical characteristics might be associated with which affective NPS may guide future treatment and prevention strategies.

DESIGN: The National Alzheimer's Coordinating Center dataset, a large case series of more than 170,000 clinical visits.

SETTING: Multiple Alzheimer's Disease Research Centers throughout the United States.

PARTICIPANTS: Adults 60 years and older with and without cognitive impairment.

MEASUREMENTS: The authors associated the odds of depression, anxiety, and apathy with clinical variables, including common and cardiovascular comorbidities, vital signs, medication classes, APOE status, race and ethnicity, and marital status across three cognitive groups: Cognitively Normal, Mild Cognitive Impairment, and Dementia.

RESULTS: Hearing loss and sleep abnormalities were robustly associated with all affective NPS at all cognitive stages. Cardiovascular diseases were not consistently associated with depression but were associated with greater apathy odds in cognitively normal participants. Nearly all odds ratios for all three affective NPS tended to attenuate to 1 as cognition worsened, potentially suggesting that neurodegeneration may drive affective NPS beyond other risk factors. Other associations with angina, osteoarthritis, blood pressure, heart rate, tobacco use, and race were noted.

CONCLUSIONS: Clinical associations often vary by NPS metric choice. Hearing and sleep deficits may be important therapeutic targets to increase quality of life by reducing affective NPS in older adults. Further research into the specific biological mechanisms whereby neurodegeneration can cause affective NPS presentation may be warranted, separate from other risk factors for affective NPS in older adults.},
}

@article {pmid41896089,
year = {2026},
author = {Orunmuyi, AT and Wang, M and Rogeau, A and Dickson, J and Groves, AM and Bomanji, J and Fraioli, F and Weil, RS},
title = {Structured reading for Tau PET Imaging in Alzheimer's disease and related dementias.},
journal = {Seminars in nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.semnuclmed.2026.02.005},
pmid = {41896089},
issn = {1558-4623},
abstract = {Tau PET provides in vivo characterisation of tau pathology, offering crucial insights into Alzheimer's disease and related disorders (ADRD). This article describes an evidence-based approach to the review and reporting of tau PET in ADRD, aligned with recent international consensus guidelines. We describe visual interpretation using validated scoring systems and harmonising thresholds for quantitative analysis for structured reporting. Implementing a standardised practice enhances reproducibility and clinical decision-making, preparing tau PET for routine clinical use.},
}