@article {pmid41936903,
year = {2026},
author = {Senkowska, Z and Weglarz-Tomczak, E},
title = {Decoding the Secretase Puzzle in Amyloid-β Generation: A State-of-the-Art Overview of the Protease-Mediated APP Processing Cascade in Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103116},
doi = {10.1016/j.arr.2026.103116},
pmid = {41936903},
issn = {1872-9649},
abstract = {The accumulation of amyloid β (Aβ) protein in the brain is a central pathological hallmark of Alzheimer's disease (AD). This process has become a major focus of interdisciplinary research and a critical target in drug development. Aβ is produced through the proteolytic processing of amyloid precursor protein (APP) by a group of enzymes known as secretases. They belong to different protease classes and operate through proteolytic cleavage of the peptide bond through several catalytic hydrolysis. Dysregulation of the expression or/and activity of proteases involved in APP processing disrupts the balance between the amyloidogenic and non-amyloidogenic pathways-often shifting it toward the amyloidogenic route. This shift leads to excessive production and further aggregation of Aβ peptides, ultimately resulting in neuronal toxicity. In this review, we integrate current state-of-the-art knowledge on all proteases reported to cleave APP, encompassing both canonical and non-canonical pathways, and offer detailed examination of cleavage-site topology, and catalytic mechanisms. By integrating the spatial and sequential hierarchy of APP proteolysis across cellular compartments, we establish a unifying mechanistic framework that captures the complexity of the process. We further delineate how distinct proteases-through defined active-site architectures, conserved catalytic motifs, and nucleophile-driven peptide bond hydrolysis-precisely regulate APP processing. This mechanistic perspective advances our molecular understanding of A pathogenesis and delineates critical catalytic control nodes amenable to therapeutic intervention. By defining these targets at a mechanistic level, it establishes a rational framework for precision drug design and the development of next-generation therapeutics.},
}

@article {pmid41936993,
year = {2026},
author = {Lizard, G and Sassi, K and Mackrill, JJ and Ghzaiel, I and Meziane, S and Hassen, E and Abdelkarim, M and Masmoudi-Kouki, O and Ghrairi, T and Brahmi, F and Gargouri, A and Rezig, L and Benkalifa, R and Khallouki, F and El Midaoui, A and Pincemail, J and Atanasov, AG and Vejux, A and Millot, N},
title = {7-ketocholesterol as a theranostic target: potential applications and future perspectives.},
journal = {Chemistry and physics of lipids},
volume = {},
number = {},
pages = {105588},
doi = {10.1016/j.chemphyslip.2026.105588},
pmid = {41936993},
issn = {1873-2941},
abstract = {7-Ketocholesterol (7KC) is mainly formed by cholesterol autoxidation and is a pro-oxidant and pro-inflammatory bioactive lipid that also induces different types of cell death, including oxiapoptophagy. It is frequently associated with major age-related diseases, such as cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease. 7KC can therefore be considered a biomarker for these diseases, offering the possibility of developing theranostic strategies combining diagnosis and treatment. Currently, all the elements are in place to develop tools for the design of theranostic therapies targeting 7KC in diseased organs: antibodies, nanoparticles used as nanoplatforms, molecules that neutralize 7KC such as enzymes which degrade it, as well as natural or synthetic compounds that inhibit the cytotoxic signaling pathways associated with oxidative stress, inflammation and cell death activated by 7KC. Identifying and neutralizing 7KC biological activities using a theranostic approach could also be of interest for growing medical fields such as space medicine widely concerned by oxidative stress, aging and age-related diseases, driven by microgravity. This review supports that most of key tools are now available to develop theranostic treatments targeting 7KC in age-related pathologies, especially in cardiovascular diseases associated with atheroma, but also in age-related macular degeneration and Alzheimer's disease. Discovery of effective treatments for these diseases is a major challenge and will answer an important need for both patients and caregivers.},
}

@article {pmid41937092,
year = {2026},
author = {Baldasso, GM and Paes, RS and Moreira, AG and Salvadori, SG and Limberger, C and Roviezzo, F and Capasso, R and Dutra, RC},
title = {The role of cannabinoid ligands in neurodegenerative diseases: emerging anti-inflammatory, immunomodulation and disease-modifying perspectives.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108185},
doi = {10.1016/j.phrs.2026.108185},
pmid = {41937092},
issn = {1096-1186},
abstract = {Neurodegenerative diseases (NDs) constitute a growing global health burden driven by population aging and remain without disease-modifying therapies. Although chronic neuroinflammation and aberrant protein aggregation are widely recognized as shared pathological hallmarks of major NDs - including Alzheimer's, Parkinson's, Huntington's diseases and multiple sclerosis - the causal relationships linking immunoinflammatory signaling to neurodegenerative progression remain contentious. Therapeutic strategies targeting neuroinflammation have thus far yielded limited clinical success, underscoring the need for mechanistically grounded and context-specific interventions. The endocannabinoid system (ECS) is a key regulator of synaptic function, glial activity, and immune homeostasis in the central nervous system (CNS), and its dysregulation has been consistently reported in neurodegenerative settings. However, ECS alterations across NDs are heterogeneous and often disease- and stage-dependent, with conflicting findings regarding cannabinoid receptor expression, endocannabinoid tone, and functional outcomes. Moreover, while preclinical studies demonstrate robust anti-inflammatory and neuroprotective effects of cannabinoid ligands, clinical translation has been constrained by issues of receptor specificity, psychoactive side effects, limited brain penetration, and an incomplete understanding of long-term ECS modulation. In this Review, we critically evaluate current evidence linking ECS signaling to neuroinflammatory mechanisms in neurodegeneration, highlighting both convergent pathways and unresolved controversies. We discuss the translational implications of ECS-targeted strategies, including the development of selective receptor modulators, allosteric and/or bitopic/dualsteric ligands, and enzyme inhibitors, as well as emerging approaches to mitigate adverse effects and improve therapeutic precision. By integrating mechanistic insights with clinical challenges, this Review delineates key obstacles and opportunities for advancing ECS-based interventions toward disease-modifying therapies for neurodegenerative disorders.},
}

@article {pmid41937403,
year = {2026},
author = {Borda, MG and O'Hara-Veintimilla, K and Aarsland, D},
title = {Older Adults, Anti-Amyloid Therapy, and Frailty: What Oncology Can Teach Us.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70567},
doi = {10.1111/ene.70567},
pmid = {41937403},
issn = {1468-1331},
support = {//Helse Vest/ ; //Nasjonalforeningen for Folkehelsen/ ; },
mesh = {Humans ; *Frailty/diagnosis ; Aged ; *Geriatric Assessment/methods ; *Alzheimer Disease/drug therapy ; *Medical Oncology/methods ; Clinical Decision-Making ; Frail Elderly ; },
abstract = {BACKGROUND: Anti-amyloid therapies, such as lecanemab or donanemab, represent the first disease-modifying treatments approved for early Alzheimer's disease (AD) in individuals with confirmed amyloid pathology. Their implementation in routine care raises important challenges, particularly in older adults with heterogeneous functional reserve and multimorbidity. We address the role of frailty in refining clinical decision-making for anti-amyloid therapies.

METHODS: This short communication presents a conceptual discussion informed by geriatric oncology, where frailty assessment and comprehensive geriatric assessment (CGA) are routinely used to individualize treatment in heterogeneous older populations. We describe how similar principles may be applied to anti-amyloid monoclonal antibodies once regulatory eligibility has been established, and outline a frailty-informed conceptual framework to support clinical decision-making in routine care.

RESULTS: This conceptual analysis proposes a stepwise, frailty-informed clinical framework that integrates regulatory eligibility assessment with brief frailty screening and targeted comprehensive geriatric assessment. The framework defines differentiated clinical pathways for robust, pre-frail, and frail individuals, linking frailty status to specific decisions regarding treatment initiation, need for prehabilitation, intensity of monitoring, and consideration of treatment deferral. By embedding frailty assessment within routine clinical workflows, the framework operationalizes evaluation of physiological reserve, anticipates treatment burden and monitoring feasibility, and provides a structured approach to individualized risk-benefit appraisal for anti-amyloid therapies.

CONCLUSIONS: Frailty-informed frameworks may offer a pragmatic and ethically grounded approach to support real-world implementation of anti-amyloid therapies, guiding treatment selection as well as longitudinal decisions on monitoring, continuation, and reassessment over time.},
}

Humans
*Frailty/diagnosis
Aged
*Geriatric Assessment/methods
*Alzheimer Disease/drug therapy
*Medical Oncology/methods
Clinical Decision-Making
Frail Elderly

@article {pmid41937689,
year = {2026},
author = {Helphrey, JH and Hart, J and McClintock, SM and Peters, ME and Thakkar, VJ and LoBue, C},
title = {A scoping review of frontal cortex tDCS on neuropsychological functioning in older adults with mild cognitive impairment and Alzheimer's Clinical Syndrome.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/09540261.2026.2647921},
pmid = {41937689},
issn = {1369-1627},
abstract = {Mild cognitive impairment (MCI) and Alzheimer's Clinical Syndrome (ACS) are prevalent, incurable, and are expected to increase in incidence over the next 30 years. Finding new treatments to address the cognitive and behavioral problems in MCI and ACS represent an urgent need. Brain circuitry disruption can cause cognitive dysfunction and neuropsychiatric symptoms (NPS) in both MCI and ACS. Therefore, one promising avenue of treatment is non-invasive brain stimulation through transcranial direct current stimulation (tDCS). This scoping review examined the current knowledge base for the potential neuropsychological and neuropsychiatric effects of frontal cortex tDCS in older adults with MCI and ACS. Of the 17 randomized controlled trials reviewed, treatment parameters such as session length, current intensity, number of treatments, and time between treatments varied widely across studies, which restricted identification of optimal tDCS treatment protocols. Mixed findings on neuropsychological outcomes were observed, though significant improvements were most commonly seen in studies measuring global cognition (10) followed by executive function (6). Only three studies yielded clinically significant cognitive improvement, and few studies assessed NPS outcomes. Additional rigorous research is indicated to enhance our understanding of tDCS as a treatment for cognitive and neuropsychiatric symptoms in older adults with MCI and ACS.},
}

@article {pmid41937703,
year = {2026},
author = {Salim, MW and Zhang, W and Collins-Praino, L and Wang, Y and Care, A},
title = {Small Extracellular Vesicles from Neural Cells: Physiological and Pathological Roles, and Potential in Neurodegenerative Therapy.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e04608},
doi = {10.1002/adhm.202504608},
pmid = {41937703},
issn = {2192-2659},
support = {//Higher Education Commission/ ; //International Macquarie University Research Excellence Scholarship/ ; FT210100737//ARC Future Fellowship/ ; //Dementia Australia Research Foundation/ ; //Mason Foundation/ ; //National Foundation for Medical Research & Innovation/ ; },
abstract = {Small extracellular vesicles (sEVs) have emerged as central mediators of intercellular communication in the central nervous system (CNS) and are increasingly recognized for their dual roles in the pathogenesis and treatment of neurodegenerative diseases (NDDs). In disease contexts, sEVs facilitate the intercellular dissemination of pathogenic proteins and nucleic acids, thereby contributing to the propagation of Alzheimer's disease (AD) and Parkinson's disease (PD) pathology. Conversely, their intrinsic biocompatibility, capacity to traverse brain barriers, and inherent organotropic properties position sEVs as highly promising nanocarriers for CNS drug delivery. While mesenchymal stem cell-derived sEVs have been widely investigated in preclinical NDD models, accumulating evidence suggests that sEVs derived from neural cells, including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes, and brain endothelial cells may offer superior brain targeting, disease relevance, and functional efficacy. This review provides a comprehensive and critical analysis of current knowledge on neural cell-derived sEVs, encompassing their physiological roles in brain homeostasis, their involvement in AD and PD pathogenesis, and their emerging therapeutic applications. We discuss cell-type-specific sEV cargo profiles, mechanisms underlying blood-brain and blood-cerebrospinal fluid barrier traversal, and recent advances in endogenous and exogenous engineering strategies that enhance cargo loading, targeting precision, and therapeutic performance. Importantly, we address key translational challenges that currently limit clinical implementation. By integrating mechanistic insights with therapeutic and engineering perspectives, this review highlights neural cell-derived sEVs as a biologically informed and versatile platform, underscoring their potential to advance next-generation neuro-nanomedicine for NDDs.},
}

@article {pmid41937809,
year = {2026},
author = {Mehmood, A and Farman, M and Afzal, F and Nisar, KS and Ahmed, MA and Hafez, M},
title = {Correction: A Physics Informed Neural Network (PINN) framework for fractional order modeling of Alzheimer's disease.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1821637},
doi = {10.3389/fninf.2026.1821637},
pmid = {41937809},
issn = {1662-5196},
abstract = {[This corrects the article DOI: 10.3389/fninf.2026.1748481.].},
}

@article {pmid41938067,
year = {2026},
author = {Cao, H and Liang, J and Dong, X and Xia, Z and Luo, X and Liu, B},
title = {Protein lactylation in Alzheimer's disease: bridging metabolism, pathology, and therapeutic opportunity.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1790090},
pmid = {41938067},
issn = {1663-4365},
abstract = {Lactate, long regarded as a mere by-product of glycolysis, is increasingly recognized as a signaling metabolite and epigenetic regulator through protein lactylation. This lysine-specific post-translational modification functionally couples cellular metabolic states to gene regulatory programs and orchestrates cell type-specific functions across neurons, astrocytes, and microglia, thereby shaping synaptic plasticity, neuroinflammatory responses, and protein aggregation. Accumulating evidence implicates dysregulated lactylation in the pathogenesis of Alzheimer's disease (AD), where it modulates amyloid-β deposition, tau aggregation, and glial reactivity. In this Review, we summarize the enzymatic regulation of protein lactylation, delineate its context-dependent roles in distinct central nervous system cell types, and highlight its function as a metabolic-epigenetic-immune nexus in AD progression. We further discuss emerging therapeutic strategies targeting lactate metabolism and lactylation pathways, and outline critical knowledge gaps that must be addressed to translate these insights into innovative diagnostic and therapeutic approaches. By integrating metabolic reprogramming, epigenetic control, and cell-specific mechanisms, this Review positions lactylation as a compelling and emerging frontier in AD research.},
}

@article {pmid41938070,
year = {2026},
author = {Samokhina, E and Buskila, Y},
title = {Astrocytic K[+] regulation during neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1782460},
pmid = {41938070},
issn = {1663-4365},
abstract = {Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in specific areas of the central nervous system. Historically, a "neurocentric" paradigm viewed glial cells, such as astrocytes, as cells that provided adequate support for neuronal energy metabolism and controlled local cerebral blood flow. However, studies from the past two decades found that astrocytes are involved in synaptic function through different mechanisms, including the uptake of extracellular glutamate molecules and potassium ions following synaptic neuronal transmission. Also, astrocytes respond to neurotransmitters and neuromodulators through alterations of intracellular ion concentrations (e.g., Na[+], Ca[2+], K[+]) and the release of gliotransmitters. Astrocytes play a pivotal role in preserving potassium homeostasis within the central nervous system through their potassium channels, a process known as "potassium clearance." Impaired astrocytic potassium clearance mechanisms can result in neuronal hyperexcitability, leading to increased glutamate release, overactivation of glutamate receptors, and cytotoxicity. Recent studies suggest that these factors can cause cell death and neurodegeneration, and further indicate a region-specific glial dysfunction in neurodegeneration, which reflects the heterogeneity of glial cell function and sensitivity across different brain regions. Overall, this manuscript offers novel insights into a relatively new concept that glial cells can actively shape neuronal activity and survival.},
}

@article {pmid41938171,
year = {2026},
author = {He, Y and Qu, M and Yu, L and He, L and Lu, Y and Hong, J and Sun, M and Yang, H and Mi, W and Guo, H and Ma, Y},
title = {Blood-Brain Barrier: Structure, Function, Diseases, and Drug Delivery Systems.},
journal = {MedComm},
volume = {7},
number = {4},
pages = {e70712},
pmid = {41938171},
issn = {2688-2663},
abstract = {The blood-brain barrier (BBB) is a highly selective and dynamic neurovascular interface essential for maintaining central nervous system homeostasis. This specialized barrier comprises brain microvascular endothelial cells interconnected by tight junctions, supported by pericytes and astrocytic end-feet within the neurovascular unit. While protecting the brain from circulating pathogens and toxins, the BBB presents formidable obstacles to drug delivery, restricting approximately 98% of small-molecule therapeutics and nearly all large biomolecules from reaching the brain parenchyma. BBB dysfunction is critically implicated in the pathogenesis and progression of numerous neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and brain tumors. This comprehensive review systematically examines the structural organization and functional characteristics of the BBB, elucidates its pathophysiological roles across major neurological diseases, and critically evaluates innovative drug delivery strategies designed to overcome this biological barrier. We analyze passive targeting approaches, active targeting mechanisms via receptor-mediated transcytosis, and stimuli-responsive systems including focused ultrasound and magnetic guidance. Additionally, we discuss multifunctional nanoplatforms, biomimetic cell membrane-coated delivery systems, current preclinical evidence, and clinical translation challenges. Finally, we propose future research directions and identify specific experimental pathways to accelerate the development of next-generation BBB-targeted therapeutics from preclinical promise to clinical application.},
}

@article {pmid41938337,
year = {2026},
author = {Saranya, K and Joseph, ER and Kalaiarasi, T and Karthiga, M},
title = {Generative AI in drug repurposing and biomarker discovery: a multimodal approach.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1755412},
pmid = {41938337},
issn = {2673-7647},
abstract = {INTRODUCTION: Computational drug repurposing has been widely explored using similarity-based methods, network diffusion, matrix factorization, deep learning, and graph neural networks (GNNs). However, recent heterogeneous GNN models, such as TxGNN and GAT-based models, demonstrate serious limitations for real-world biomedical applications, including poor generalization to sparsely annotated diseases, limited disease-level adaptation, and inability to effectively combine heterogeneous evidence from curated databases, multi-omics profiles, and unstructured biomedical literature.

METHODS: This article proposes a heterogeneous attention-based meta-learning graph neural network named HAMGNN, which employs three major innovations: (i) relation-sensitive multi-head attention to prioritize biologically significant interactions among heterogeneous edge types, (ii) a disease-focused meta-learning framework enabling rapid adaptation to newly observed or under-informed diseases, and (iii) a literature-enhanced knowledge graph construction pipeline encoding high-confidence, LLM-extracted therapeutic information. The model was tested on a large multimodal biomedical knowledge graph assembled from DrugBank, DisGeNET, and Hetionet, comprising more than 2.2 million edges, using a stringent disjoint disease-based (cold-start) evaluation protocol.

RESULTS: HAMGNN achieved a receiver operating characteristic-area under the curve (ROC-AUC) of 0.98 and precision of 0.95, representing a 10%-15% improvement over TxGNN and GAT-GNN on unseen disease generalization. Translational applicability was demonstrated through Alzheimer's disease and Long COVID case studies, identifying clinically plausible repurposing candidates and disease-associated biomarker signatures via mechanistic pathways.

DISCUSSION: HAMGNN offers a generalized, biologically grounded, and unified framework for evidence-based drug repurposing and biomarker discovery in complex and emerging diseases.},
}

@article {pmid41938524,
year = {2026},
author = {Raj, N and R, SP and Ammar, RB and Rajendran, P and Chellappan, BV},
title = {Non-Coding DNA-Derived Mimotopes of Aβ42 as Novel Candidates for Alzheimer's Peptide Vaccine Design.},
journal = {International journal of medical sciences},
volume = {23},
number = {4},
pages = {1320-1332},
pmid = {41938524},
issn = {1449-1907},
mesh = {*Amyloid beta-Peptides/immunology/chemistry/genetics ; *Alzheimer Disease/immunology/therapy/prevention & control/genetics ; Humans ; *Peptide Fragments/immunology/chemistry/genetics ; *Vaccines, Subunit/immunology ; Epitopes, B-Lymphocyte/immunology/genetics/chemistry ; *Alzheimer Vaccines/immunology ; Molecular Docking Simulation ; Peptide Library ; Protein Subunit Vaccines ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and characteristic neuropathology involving amyloid-β (Aβ) plaques and tau tangles. Among emerging therapeutic strategies, Aβ-targeted immunotherapy using monoclonal antibodies or peptide vaccines offers the most promising disease-modifying potential. Mimotopes, short peptides that mimic antigenic epitopes of Aβ, have recently gained attention as safe and effective candidates for vaccine development. In this study, we employed a computational immunoinformatics approach to identify novel Aβ42-mimicking peptides derived from non-coding DNA sequences, representing an unconventional yet rich source of bioactive peptides. A virtual peptide library was generated from intergenic regions of the Escherichia coli genome and screened using B-cell epitope prediction, MHC-binding analysis, and structural similarity modeling to identify potential immunogenic mimotopes. Selected candidates were further evaluated through peptide-antibody docking with Aβ42-specific antibody fragments to assess binding affinity and epitope mimicry. Our findings demonstrate a novel computational framework for mining non-coding DNA to identify therapeutic peptide mimotopes. The identified Aβ42-like peptides exhibit strong potential as synthetic vaccine candidates for Alzheimer's disease, supporting a new direction in rational vaccine design against neurodegenerative disorders.},
}

*Amyloid beta-Peptides/immunology/chemistry/genetics
*Alzheimer Disease/immunology/therapy/prevention & control/genetics
Humans
*Peptide Fragments/immunology/chemistry/genetics
*Vaccines, Subunit/immunology
Epitopes, B-Lymphocyte/immunology/genetics/chemistry
*Alzheimer Vaccines/immunology
Molecular Docking Simulation
Peptide Library
Protein Subunit Vaccines

@article {pmid41938573,
year = {2026},
author = {Mulligan, MD and Scott, MR and Yang, Q and Wang, R and Ghosh, S and Johnson, KA and Beiser, AS and Seshadri, S and McGrath, ER},
title = {Association of Circulating Vitamin D in Midlife With Increased Tau-PET Burden in Dementia-Free Adults.},
journal = {Neurology open access},
volume = {2},
number = {2},
pages = {},
pmid = {41938573},
issn = {2998-7601},
abstract = {BACKGROUND AND OBJECTIVES: Low circulating vitamin D in later-life has been associated with increased risk of cognitive impairment and clinical dementia. However, whether serum vitamin D in early mid-life is associated with neuroimaging markers of preclinical dementia is unknown. We aimed to determine the association between early mid-life serum vitamin D and subsequent tau- and amyloid- burden on brain-PET, in a cohort of dementia-free adults.

METHODS: This was a prospective cohort study of Framingham Heart Study Generation 3 cohort participants who were dementia-free at time of PET, had serum 25-hydroxyvitamin D [25(OH)D] measured at examination cycle 1 (2002-2005) and had available 11C-Pittsburgh Compound-B (PiB)- and/or 18F-Flortaucipir (FTP)-PET completed between 2016 and 2019. Outcomes included global tau-PET deposition (across all 34 FreeSurfer defined cortical regions), composite tau (those regions most susceptible to early tau involvement in AD dementia, namely entorhinal cortex, parahippocampal gyrus, fusiform gyrus, amygdala and inferior and middle temporal cortices) and amyloid-PET deposition (composite region including the frontal, lateral temporal, parietal and retrosplenial cortices [FLR]). Data were analyzed using multivariable linear regression models adjusted for age, sex, time from blood sampling to PET, PET camera type, depression, season, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, cardiovascular disease, and body mass index.

RESULTS: In our sample (n= 793, 53% women, mean age 39±8years) with available serum 25(OH)D and amyloid (n=424) and/or tau-PET (n=369), the mean time between blood sampling and PET was 16±2 years. On multivariable linear regression analysis, higher serum 25(OH)D was associated with lower global (β= -0.022; 95% CI: -0.040 to -0.004; p = 0.010]) and composite tau-PET deposition (β= -0.023; 95% CI: -0.043 to -0.003; p = 0.016]),but was not associated with amyloid-PET burden.

DISCUSSION: In a group of dementia-free individuals, higher serum 25(OH)D at early mid-life was associated with lower tau deposition on brain PET a mean of 16 years later. Low vitamin D in mid-life may represent a potentially modifiable target to mitigate the risk of neuroimaging signs of preclinical dementia.},
}

@article {pmid41938657,
year = {2026},
author = {Clare, L and Gamble, LD and Martyr, A and Knapp, M and Matthews, FE},
title = {Sources of inequality in "living well" with dementia: an intersectional analysis using a British cohort study.},
journal = {Innovation in aging},
volume = {10},
number = {4},
pages = {igag009},
pmid = {41938657},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: A key aim of national dementia policies is to enable people to "live well" with the condition, but the experience of living with dementia, including access to health and social care services, is markedly affected by numerous sources of socioeconomic disparity. We explored how combinations of these disparities among groups of people with dementia are associated with the capability to "live well."

RESEARCH DESIGN AND METHODS: We used baseline data from 1,537 people with mild-to-moderate dementia in the British IDEAL cohort (2014-2016). This included personal characteristics, living situation, socioeconomic position, and geographical area, and 3 indices of "living well"-quality of life, satisfaction with life, and well-being. Through regression-tree analyses, we explored how the intersection of factors beyond type of dementia and co-morbidity is associated with subgroups of people with dementia experiencing higher or lower capability for "living well."

RESULTS: Age, education, living situation, income, and home ownership emerged as the strongest differentiators. Drawing on the concept of precarity, we show how the connections between unequal distribution of resources and personal vulnerabilities lead to an accumulation of pressures and shape outcomes.

DISCUSSION AND IMPLICATIONS: These findings from a cohort of people with dementia in a major Western economy represent the tip of the iceberg relative to the full extent of national and especially global inequalities. Addressing the impact of these social inequalities requires a sustained focus on developing and implementing policies that improve equity of access to care and support and increase the potential for "living well."},
}

@article {pmid41938695,
year = {2026},
author = {Kaur, S and Tyler, AL and Durante, GL and Cary, GA and Carter, GW and Mahoney, JM},
title = {Identifying transcriptomic signatures that mediate the causal effect of genotype on Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1716828},
pmid = {41938695},
issn = {1662-4548},
abstract = {The combined effects of thousands of genetic polymorphisms account for Alzheimer's disease (AD) genetic risk. Most AD polymorphisms affect gene expression. Thus, the transcriptome, the set of all gene expression levels for every gene in the genome, is a major mediator between the genotype to phenotype. This study uses genotypes, transcriptomes, and clinical phenotypes to identify the transcriptomic signature that mediates the causal effect of genotype on AD. By utilizing a causal inference method known as high dimensional mediation analysis (HDMA) on the Religious Orders Study/Memory and Aging Project (ROSMAP) longitudinal cohort, the genotype, transcriptome, and phenotype data were reduced to single scores encoding genotype, transcriptome, and phenotype correlations, and produce a ranked gene list based on putative causal importance of each gene for AD. Analysis of the up- and down-regulated genes prevalent in AD through Gene Ontology (GO) and KEGG databases reveals findings such as up-regulated functions which include angiogenesis and immune responses while down-regulated functions of genes include synaptic activity. Furthermore, utilizing Clue.io to identify candidate drugs to suppress AD-pathology reveals a plausible list of therapeutic candidates, including targeted genes and compounds such as SMAD3, TM7SF2, and ABCB1, which counteract the transcriptomic signature identified and may block the devastating effects of AD related to inflammatory responses, Aβ-induced toxicity, and neuronal death.},
}

@article {pmid41938770,
year = {2026},
author = {Kuang, L and Lei, M and Mu, X and Wang, Y and Li, Y and Xu, H and Li, T and Huang, L and Zheng, Y and Xie, X and Li, C and Fu, W},
title = {Data-independent acquisition quantitative proteomics analysis of milk fat globule membrane proteins in rabbit colostrum and mature milk.},
journal = {Frontiers in veterinary science},
volume = {13},
number = {},
pages = {1703387},
pmid = {41938770},
issn = {2297-1769},
abstract = {Proteomics has been widely used to identify proteins in the milk fat globule membrane (MFGM). However, the characteristics of MFGM proteins in rabbit colostrum (RC) and mature milk (RM) remain largely unexplored. This study aimed to profile the rabbit MFGM proteins and assess differences in component and functional profiles between RC and RM through data-independent acquisition (DIA) quantitative proteomics. We established the proteomic profile of rabbit MFGM, identifying 3,548 proteins across RC and RM. Notably, typical MFGM proteins, such as Perilipin 2 (PLIN2), Xanthine dehydrogenase/oxidase (XDH/XO), and Apolipoprotein, were detected in rabbit milk, and 10 of these were confirmed by Parallel reaction monitoring (PRM) detection. Comparative analysis revealed 480 differentially expressed MFGM proteins (DEMPs), with 379 up-regulated and 101 down-regulated DEMPs in RC compared to RM. This included 68 unique proteins in RC, 5 in RM, and 407 DEMPs expressed in both groups. The GO analysis indicated that DEMPs are predominantly involved in processes such as proteolysis, cell adhesion, and ion transport, with enrichments of 32, 14, and 14 DEMPs, respectively. KEGG analysis gathered 56 significant pathways, most of which were categorized into Human Diseases (20/56) and Metabolism (14/56). Protein-protein interaction (PPI) network analysis emphasized the core role of DEMPs (e.g., proteasome subunits and integrins) in human diseases (e.g., Alzheimer's disease) and in signal transduction (e.g., the PI3K-Akt signaling pathway). These results offer theoretical insights into the components and functions of rabbit milk, suggesting a novel way to enhance the economic benefit of the rabbit industry.},
}

@article {pmid41938851,
year = {2026},
author = {Fan, W and Wang, Z and Wan, S and Liu, M and Han, Y and Liu, X and Xu, L and Wang, X and Zhang, D and Cai, Q},
title = {A study on the correlation between APOE gene polymorphism, white matter hyperintensities, and neuropsychiatric symptom phenotypes in Alzheimer's disease.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1795598},
pmid = {41938851},
issn = {1664-0640},
abstract = {OBJECTIVE: This study investigates the independent and interactive effects of apolipoprotein E (APOE) genotypes and white matter hyperintensities (WMH) on distinct neuropsychiatric symptom (NPS) phenotypes in patients with Alzheimer's disease (AD).

METHODS: We enrolled 325 AD patients consecutively diagnosed at a specialized memory clinic between May 2024 and May 2025. All participants underwent comprehensive clinical assessments-including the Chinese Mini-Mental State Examination (CMMSE), Activities of Daily Living (ADL) scale, and the Neuropsychiatric Inventory (NPI)-as well as 3T brain MRI for WMH quantification and APOE genotyping. First, we compared NPS profiles and cognitive/functional scores across APOE genotype groups (ϵ2/ϵ2-ϵ2/ϵ3, ϵ3/ϵ3, ϵ3/ϵ4, ϵ4/ϵ4) using analysis of variance (ANOVA) or Kruskal-Wallis tests, as appropriate. Second, we applied mediation analysis (PROCESS macro Model 4, 5,000 bootstrap samples) to examine whether WMH burden mediates the association between APOE genotype (X) and outcomes including CMMSE total score and domain-specific NPS subscores (delusions, agitation, irritability, euphoria).

RESULTS: Significant differences emerged across APOE genotypes in both cognition (CMMSE, p < 0.05) and functional status (ADL, p < 0.05). At the symptom level, carriers of at least one ϵ4 allele exhibited higher agitation scores than non-carriers (p < 0.05); notably, the ϵ4/ϵ4 homozygotes showed significantly greater severity in delusions, agitation, irritability, and euphoria compared with all other genotype groups (all p < 0.05). Mediation analyses revealed no statistically significant indirect effect of APOE genotype on any outcome via WMH, indicating that WMH does not mediate these associations. Instead, APOE genotype exerted robust direct effects on both cognitive performance and specific NPS domains.

CONCLUSION: APOE genotype-particularly the ϵ4/ϵ4 homozygous status-is associated with more pronounced cognitive decline and a distinct, severe NPS profile in AD, especially involving delusions, agitation, Euphoria, and irritability. These associations are independent of WMH burden, suggesting that APOE exerts direct neurobiological effects on neuropsychiatric manifestations. Thus, APOE genotyping holds dual clinical value: not only as a well-established biomarker for AD risk and diagnosis but also as a potential prognostic indicator for behavioral and psychological symptoms-offering actionable insights beyond conventional neuroimaging markers.},
}

@article {pmid41940019,
year = {2026},
author = {Yang, S and Sang, HW and Kim, S and Cho, EJ and Choi, Y and Kang, DW and Jang, YC and Park, DH and Kwak, HB and Yook, JS},
title = {Therapeutic potential of exerkines in neurodegenerative and mental disorders: a narrative review.},
journal = {Frontiers in physiology},
volume = {17},
number = {},
pages = {1793043},
pmid = {41940019},
issn = {1664-042X},
abstract = {Neurodegenerative and mental disorders impose significant global disease burdens and pose serious social and economic challenges. Physical exercise (PE) exerts beneficial effects on brain health, contributing to a reduction in the risk of Alzheimer's disease (AD), Parkinson's disease (PD), depression, anxiety, and post-traumatic stress disorder (PTSD). To understand these effects of PE, a variety of molecules released from various tissues in response to PE have been discovered, which are collectively called 'exerkines'. In particular, the skeletal muscle acts as an endocrine organ, secreting exerkines and is included in the category of myokines that facilitate direct or indirect crosstalk between the muscle and the brain. Although muscles actively interact with organs such as the liver, pancreas, and adipose tissue, the precise mechanisms of muscle-brain communication have yet to be fully elucidated. In the skeletal muscle, the types of exerkines secreted and their effects vary depending on the PE modality. Furthermore, these exerkines can cross the blood-brain barrier (BBB) to exert direct effects or act indirectly via molecular signaling pathways, contributing to the modulation of the brain microenvironment, attenuation of neuroinflammation, and neurodegeneration. Previous studies have indicated that brain-derived neurotrophic factor (BDNF), irisin, cathepsin B (CTSB), interleukin-6 (IL-6), and insulin-like growth factor 1 (IGF-1) are involved in enhancing cognitive performance and improving behavioral outcomes by promoting neurogenesis and synaptic plasticity. This review comprehensively discusses the effects of exerkines on the brain and the physiological responses manifested in neurodegenerative and mental disorders focusing primarily on findings from rodent models. Based on these insights, this review proposes future research directions to translate preclinical findings into therapeutic strategies.},
}

@article {pmid41940185,
year = {2026},
author = {Mukherjee, C and Bajaj, S and Adhikari, BM and Dhamala, M},
title = {Sex-dependent grey matter atrophy in Alzheimer's disease progression.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag103},
pmid = {41940185},
issn = {2632-1297},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive and functional deterioration, with mild cognitive impairment as an intermediate stage. Using high-resolution structural MRI from 332 Alzheimer's Disease Neuroimaging Initiative participants, we examined sex-specific grey matter volume (GMV) differences across healthy controls, mild cognitive impairment and Alzheimer's disease. Whole-brain parcellation into 82 regions revealed a significant group-by-sex interaction [F(164,488) = 1.42; P = 0.002; ηp[2] = 0.32], with 10 regions showing pronounced sex-dependent effects. GMV trajectories exhibited a clear sex-specific pattern. In healthy cohort, males and females displayed comparable GMVs. From healthy control to mild cognitive impairment, females remained relatively stable, whereas males showed a moderate decline. From mild cognitive impairment to Alzheimer's disease, however, females demonstrated steep and widespread GMV loss, contrasting with the slower, region-limited atrophy observed in males. Females also showed significantly greater reductions in key regions, including the left frontal pole during Alzheimer's disease progression [F(1,243) = 10.68; P < 0.001; ηp[2] = 0.14] and the right caudal middle frontal cortex during mild cognitive impairment [F(1,243) = 10.62; P < 0.001; ηp[2] = 0.14]. Structural differences were mirrored in behavioural associations. Females showed more widespread associations between GMV and cognitive and functional performance: higher GMV was associated with better Mini-Mental State Examination scores, whereas lower GMV was associated with greater independence on the Functional Activities Questionnaire. These findings highlight a sex-dependent vulnerability in Alzheimer's disease, with females exhibiting both more extensive atrophy and more widespread atrophy-cognition coupling across disease stages.},
}

@article {pmid41940186,
year = {2026},
author = {Hunter, TR and Lyra E Silva, NM and de Freitas, GB and Rody, T and Santos, LE and Zhang, J and Bullock, A and Tartaglia, MC and Abraham, S and Nicolini, C and Nelson, AJ and Heisz, JJ and Fahnestock, M and De Felice, FG},
title = {Fibronectin type III domain-containing protein 5/irisin in extracellular vesicles is reduced in older individuals.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag085},
pmid = {41940186},
issn = {2632-1297},
abstract = {The progressive accumulation of physiological stress as we age, known as allostatic load, is linked to an increased risk of dementia. Fostering brain resilience through physical exercise can counteract allostatic load and improve adaptation to age-related brain alterations. Fibronectin type III domain-containing protein 5 (FNDC5)/irisin is a neuroprotective exercise-linked hormone found in extracellular vesicles (EV-FNDC5/irisin). Here, we sought to analyse EV-FNDC5/irisin in ageing as a promising biomarker of brain resilience. We measured exercise-associated factors, including EV-FNDC5/irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B in the serum of 31 young (18-28 years) and 19 older subjects (65-79 years). Levels of FNDC5/irisin in serum-derived EVs are markedly reduced in older subjects compared to young (P = 0.004). We report a reduction in nanoparticles isolated from the serum of older participants (P = 0.009). While EV-FNDC5/irisin positively correlates with BDNF in young subjects (Spearman r = 0.40, P = 0.038), this correlation is absent in elderly subjects (Spearman r = -0.25, P = 0.34). This study provides initial evidence that EV-FNDC5/irisin is reduced in older individuals and loses correlation with BDNF. Our identification of peripheral, exercise-linked factors associated with age may inform biomarker discovery and interventions to promote brain resilience.},
}

@article {pmid41940301,
year = {2026},
author = {Donner, L and Christl, J and Kujovic, M and Supprian, T and Elvers, M},
title = {Platelets from early-stage Alzheimer patients show enhanced amyloid binding, an elevated open canalicular system and sex-specific differences in their activation profile.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1759268},
pmid = {41940301},
issn = {1664-2295},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with neurodegeneration and dementia. Key clinical hallmarksinclude the deposition of amyloid-ß (Aβ) into senile plaques in the brain parenchyma and in cerebral vessels known as cerebral amyloid angiopathy (CAA). Currently, anti-Aß antibodies are emerging as possible therapy for AD. Several biomarkers, such as Aß and tau-protein have gained diagnostic relevance for early AD; however, their assessment requires cerebrospinal fluid. Therefore, blood-based biomarkers for AD screening are urgently needed.

METHODS: Patients diagnosed with early AD were analyzed for extracellular Aß binding to platelets, platelet morphology and platelet activation, and were compared with age-matched controls.

RESULTS: Platelet number and size were unaltered between groups. However, platelets isolated from AD patients exhibited increased surface APP/Aβ immunoreactivity compared with age-matched controls. Transmission electron microscopy revealed altered platelet morphology in AD patients, including changes in the number of dense granules and an increased area of the open canalicular system (OCS). While only minor differences in platelet activation were detected between patients and controls, a significant reduction in integrin αIIbβ3 (fibrinogen receptor) activation was observed in platelets from female compared to male AD patients, as determined by flow cytometry.

CONCLUSION: The results presented here emphasize the importance of understanding whether platelets contribute to AD pathology in a sex-specific manner. Furthermore, platelet parameters may serve as promising biomarker for early AD prognosis, as platelets are easily accessible via blood sampling. These parameters may include sex-specific platelet activation profiles, the ability of platelets to bind APP/Aß at their surface, and OCS dimensions assessed by electron microscopy.},
}

@article {pmid41940407,
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 = {Engineering with computers},
volume = {42},
number = {2},
pages = {78},
pmid = {41940407},
issn = {0177-0667},
abstract = {UNLABELLED: 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-[Formula: see text] 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.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00366-026-02313-5.},
}

@article {pmid41940752,
year = {2026},
author = {Paidi, RK and Gorai, S and Mondal, S and Pahan, K},
title = {L-Leucine Upregulates Lysosomal Biogenesis and Autophagy to Lower Plaques in 5XFAD Mouse Model of Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {4},
pages = {e70432},
doi = {10.1111/jnc.70432},
pmid = {41940752},
issn = {1471-4159},
support = {1IK6 BX004982//U.S. Department of Veterans Affairs/ ; I01BX005613//U.S. Department of Veterans Affairs/ ; AT10980/NH/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/drug therapy/genetics ; Mice ; *Leucine/pharmacology/therapeutic use ; *Autophagy/drug effects/physiology ; *Lysosomes/drug effects/metabolism ; Mice, Transgenic ; *Plaque, Amyloid/pathology/metabolism/drug therapy ; Disease Models, Animal ; Humans ; Up-Regulation/drug effects ; PPAR alpha/metabolism/genetics ; Brain/drug effects/metabolism ; Male ; Astrocytes/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {Twenty different amino acids are required for the human body for proper functioning as amino acids serve as building blocks for proteins. We screened different essential and non-essential amino acids for the ability to stimulate lysosomal biogenesis and, interestingly, found an essential amino acid L-leucine as the most potent one in stimulating lysosomal biogenesis in astrocytes. However, D-leucine remained weaker than L-leucine in terms of stimulation of lysosomal biogenesis. Accordingly, L-leucine increased autophagy in cultured brain cells and in vivo in the brain of 5XFAD mice, one of the animal models of Alzheimer's disease (AD). L-Leucine also stimulated the uptake and degradation of amyloid-β in astrocytes and reduced the plaque load and improved cognitive functions in 5XFAD mice. Although L-leucine was discovered about 200 years back, until now, no receptor has been identified for L-leucine. Here, we noticed that L-leucine binds to the ligand-binding domain of peroxisome proliferator-activated receptor α (PPARα) to activate this nuclear hormone receptor. Accordingly, L-leucine remained ineffective in increasing lysosomal biogenesis and autophagy in PPARα[-/-] brain cells. Lentiviral establishment of full-length PPARα, but not Y314D-PPARα, reinstated the autophagy-stimulating effect of L-leucine in PPARα[-/-] astrocytes, emphasizing the importance of leucine's interaction with the Y314 residue. Moreover, oral L-leucine decreased the plaque load and improved spatial learning and memory in 5XFAD mice, but not in 5XFAD[ΔPPARα] mice (5XFAD lacking PPARα), highlighting the involvement of PPARα in the neuroprotective effects of L-leucine. These results may be beneficial for AD patients.},
}

Animals
*Alzheimer Disease/pathology/metabolism/drug therapy/genetics
Mice
*Leucine/pharmacology/therapeutic use
*Autophagy/drug effects/physiology
*Lysosomes/drug effects/metabolism
Mice, Transgenic
*Plaque, Amyloid/pathology/metabolism/drug therapy
Disease Models, Animal
Humans
Up-Regulation/drug effects
PPAR alpha/metabolism/genetics
Brain/drug effects/metabolism
Male
Astrocytes/drug effects/metabolism
Mice, Inbred C57BL

@article {pmid41940797,
year = {2026},
author = {Rus Prelog, P and Kores Plesničar, B and Zupan, M and Frol, S and Kramberger, MG},
title = {The value and risks of antidepressant therapy in Alzheimer's disease: a field update and its clinical implications.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/14737175.2026.2653170},
pmid = {41940797},
issn = {1744-8360},
abstract = {INTRODUCTION: Depression is one of the most frequent and disabling neuropsychiatric syndromes in Alzheimer's disease (AD), yet antidepressant use is still largely extrapolated from late‑life depression and is poorly aligned with emerging evidence on 'neurodegenerative depression' and disease‑modifying therapies. This article critically re‑examines the clinical value and risks of antidepressants in AD.

AREAS COVERED: Drawing on a narrative search of PubMed/MEDLINE and Embase (January 2000-December 2025) and targeted review of recent guidelines and anti‑amyloid trials, the article synthesizes randomized and observational data on efficacy and safety across antidepressant classes, highlighting modest and inconsistent benefits alongside adverse outcomes such as falls, hyponatremia, bleeding, mortality and possible acceleration of cognitive decline. It integrates mechanistic work on synaptic loss, neuroinflammation and network disruption, discusses the exclusion of depressed patients from anti‑amyloid trials, and reviews rapid‑acting, neuromodulatory and psychosocial strategies within a proposed precision‑prescribing framework based on biomarkers, vascular burden and symptom dimensions.

EXPERT OPINION: Monoaminergic antidepressants in AD should not be abandoned but repositioned as time‑limited, closely monitored options for clearly defined, functionally impairing depressive syndromes, embedded in multimodal care rather than used as default, long‑term treatment for non‑specific distress. Future priorities include biomarker‑stratified AD depression trials, evaluation of interactions with anti‑amyloid therapies and rigorous testing of non‑monoaminergic interventions.},
}

@article {pmid41940807,
year = {2026},
author = {Sayar, G and Parlar, S and Tarikogullari, AH and Erdoğan, MA and Armagan, G and Alptuzun, V},
title = {Synthesis, Bioactivity and Molecular Modeling Studies on Benzimidazole Derivatives and Its Isosteres as Potent AChE/BChE and GSK3β Inhibitors for Alzheimer's Disease.},
journal = {Chemical biology & drug design},
volume = {107},
number = {4},
pages = {e70285},
doi = {10.1111/cbdd.70285},
pmid = {41940807},
issn = {1747-0285},
support = {14-ECZ-044//Ege University Research Foundation/ ; },
mesh = {*Benzimidazoles/chemistry/chemical synthesis/pharmacology/metabolism ; Humans ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; *Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology/therapeutic use/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Cell Line, Tumor ; *Acetylcholinesterase/metabolism/chemistry ; Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Butyrylcholinesterase/metabolism/chemistry ; Hydrogen Peroxide ; Molecular Docking Simulation ; Oxidative Stress/drug effects ; Kinetics ; Structure-Activity Relationship ; },
abstract = {A series of benzimidazoles and its analogs (benzoxazoles and benzothiazoles) bearing a benzohydrazide-hydrazones moiety at the 2-position were designed and synthesized as potential acetylcholinesterase (AChE) inhibitors. Cholinesterase (ChE) inhibitory activity results showed that all compounds displayed good inhibition of AChE, whereas only some of the compounds were active against BChE. Among the title compounds, it was found that all benzimidazole series were selective towards AChE. Kinetic analysis and molecular modeling studies were conducted on the most active compounds, namely 1j for AChE and 3g for BChE inhibition. The kinetic results showed that the tested compounds exhibited a mixed-type inhibition mechanism on both enzymes. In cell culture studies, all compounds were evaluated for their neuroprotective effects against hydrogen peroxide (H2O2)-induced oxidative stress in the SH-SY5Y human neuroblastoma cell line. Several compounds demonstrated more than 30% neuroprotection at a low concentration (1 μM) in the presence of H2O2. Selected compounds, chosen based on their EC50 values, were further examined for their effects on glycogen synthase kinase-3 beta (GSK3β), an enzyme whose activity has been reported to be increased in the brains of patients with Alzheimer's disease (AD). The inhibition of GSK3β was assessed by measuring phosphorylated GSK3β (pGSK3β, Ser9) protein expression via Western Blot analysis under oxidative stress conditions. Among the tested compounds, 1l, 2b, 2j, and 3l significantly increased pGSK3β (Ser9) protein levels compared to cells treated with tideglusib, a known GSK3β inhibitor.},
}

*Benzimidazoles/chemistry/chemical synthesis/pharmacology/metabolism
Humans
*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism
*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology/therapeutic use/metabolism
*Alzheimer Disease/drug therapy/metabolism
Cell Line, Tumor
*Acetylcholinesterase/metabolism/chemistry
Neuroprotective Agents/pharmacology/chemical synthesis/chemistry
*Butyrylcholinesterase/metabolism/chemistry
Hydrogen Peroxide
Molecular Docking Simulation
Oxidative Stress/drug effects
Kinetics
Structure-Activity Relationship

@article {pmid41940817,
year = {2026},
author = {Sigg-Alonso, J and Mondragón, JD and González-López, M and Pasaye Alcaraz, EH and Fernández, T},
title = {Functional connectivity alterations in objectively defined subtle cognitive decline: A cross-sectional functional MRI study in cognitively healthy older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435619},
doi = {10.1177/13872877261435619},
pmid = {41940817},
issn = {1875-8908},
abstract = {BackgroundThe aging of the population is leading to an increase in the incidence of neurocognitive disorders, particularly Alzheimer's disease, which has become a significant public health priority. Given the importance of early intervention in neurocognitive disorders, the identification of objectively defined subtle cognitive decline (Obj-SCD) may lead to early identification and better odds of slowing disease progression.ObjectiveTo characterize the connectivity patterns of subjects with Obj-SCD.MethodsFifty-one healthy adults (21 with Obj-SCD and 30 controls) over 55 years old underwent functional MRI and neuropsychological evaluations. MRI scans were conducted using a 3.0 Tesla scanner, and the data were preprocessed and denoised with CONN and SPM software, followed by independent component analysis (ICA) for identifying 20 brain networks and region-of-interest (ROI) analyses for assessing functional connectivity. The thresholds for the results were p < 0.05 for connections and FDR-corrected p < 0.05 for clusters.ResultsCompared with controls, individuals with Obj-SCD exhibited both hyperconnectivity and hypoconnectivity across key brain networks; increased activity was observed in the left angular and right lingual gyri, which showed greater connectivity with the language and visual networks but reduced connectivity with the somatosensory and dorsal attention networks. The default mode and central executive networks also showed functional connectivity alterations, whereas the salience network exhibited hypoconnectivity.ConclusionsThe connectivity alterations of individuals with Obj-SCD may reflect compensatory mechanisms, early network disruptions, or both. fMRI-based analyses could aid in detecting these early changes, providing opportunities for interventions that may slow or prevent further cognitive decline.},
}

@article {pmid41940821,
year = {2026},
author = {Munro, CE and Beltran, J and Palmer, P and Farrell, M and Hanseeuw, B and Rentz, DM and Buckley, R and Properzi, M and Vannini, P and Amariglio, RE and Quiroz, YT and Yang, HS and Blacker, D and Sperling, RA and Johnson, KA and Marshall, GA and Gatchel, JR},
title = {Baseline cortical amyloid-β levels are associated with subsequent study-partner-rated apathy in community-dwelling older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261436755},
doi = {10.1177/13872877261436755},
pmid = {41940821},
issn = {1875-8908},
abstract = {BackgroundApathy is a common neuropsychiatric symptom in Alzheimer's disease (AD) and has been linked to greater levels of AD biomarkers (amyloid-β, tau). However, it is unclear whether early patterns of amyloid deposition may impact development of apathy symptoms in the future.ObjectiveWe sought to examine whether amyloid-β levels, both globally and in brain regions associated with motivation, could predict future apathy symptoms.MethodsParticipants (n = 199, mean age = 79.9) were part of the Harvard Aging Brain Study, a longitudinal observational cohort of individuals without cognitive or psychiatric impairment at baseline. All underwent MRI and Pittsburgh Compound B (PiB)-PET for amyloid-β at baseline and completed questionnaires of self- and study-partner-rated apathy 7.8 ± 1 years later using the Apathy Evaluation Scale. Linear regression models assessed whether regional PiB levels predicted future apathy scores.ResultsHigher baseline cortical PiB levels in a frontal, lateral parieto-temporal, and retrosplenial aggregate were associated with greater study-partner-rated apathy, but not self-rated apathy, and no specific regional associations were observed outside of the aggregate.ConclusionsThese results provide insight into early neurobiological underpinnings of AD-related apathy. Additionally, these data may have clinical implications regarding the risk of developing apathy symptoms in amyloid-β-positive individuals as cognition declines.},
}

@article {pmid41940826,
year = {2026},
author = {Hayakawa, N and Takeda, S and Takahashi, H and Arisawa, A and Matsuo, C and Tomiyama, N and Nakajima, T and Miki, S and Kishino, Y and Teshirogi, S and Yamamoto, S and Okawara, M and Ito, Y and Takami, Y and Takeya, Y and Yamamoto, K and Morishita, R},
title = {Distinct patterns of microstructural brain changes in Alzheimer's disease subtypes: Diffusion MRI metrics in braak stage-related regions.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261436754},
doi = {10.1177/13872877261436754},
pmid = {41940826},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is pathologically defined by the accumulation of amyloid-β and phosphorylated tau and subsequent neuronal death. These neuropathological changes typically accumulate in the medial temporal lobe before spreading to other cortical regions (Braak staging pattern). Recent studies using postmortem brain tissue and neuroimaging data have revealed AD subtypes with distinct neuropathological patterns. Hippocampal-sparing (HpSp) subtype of AD shows the preservation of medial temporal lobe volume, compared to typical AD; however, underlying changes in the brain microstructure remain largely unclear.ObjectiveWe used Neurite Orientation Dispersion and Density Imaging (NODDI) to investigate the microstructural signatures in each AD subtype.MethodsWe defined typical and HpSp AD based on visual assessment scales of brain MRI, among individuals with mild cognitive impairment who were positive for core AD cerebrospinal fluid markers. We set regions of interest in Braak stage (BS)-related areas (hippocampus (BS II), precuneus (BS V), and postcentral gyrus (BS VI)) and compared NODDI metrics, including intracellular volume fraction, orientation dispersion index, and isotropic volume fraction (Viso), among typical AD, HpSp AD, and non-AD control groups.ResultsNODDI metrics in the hippocampus were significantly different between the typical and HpSp AD groups. Notably, the hippocampal NODDI values in the HpSp AD group were comparable to those of the control group. Viso values in the precuneus were significantly higher in HpSp AD, compared to typical AD.ConclusionsThis suggests that AD subtypes have distinct patterns of microstructural changes in BS-related brain regions.},
}

@article {pmid41940827,
year = {2026},
author = {Ding, K and Jiang, W and Lei, M and Gao, Y},
title = {Uncovering polygenic and local genetic overlap between sarcopenia and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261436016},
doi = {10.1177/13872877261436016},
pmid = {41940827},
issn = {1875-8908},
abstract = {BackgroundSarcopenia and Alzheimer's disease (AD) are prevalent comorbidities in older adults. Their common genetic basis remains unclear.ObjectiveUtilizing Genomic Structural Equation Modeling, we used European-ancestry genome-wide association study (GWAS) summary statistics to model sarcopenia-related traits. Multiple AD GWAS datasets and the sarcopenia GWAS dataset were used to conduct cross-trait analyses.MethodsGenome-wide and local genetic correlations were assessed using LDSC and LAVA. MiXeR was applied to evaluate shared versus trait-specific variants. Shared loci were identified using conjFDR. Candidate genes were further explored via tissue-specific expression (MetaXcan) and Mendelian randomization (MR).ResultsLDSC analysis revealed no significant genome-wide genetic correlation between AD and sarcopenia (rg = 0.020, p = 0.178). Bivariate LAVA analysis identified significant local genetic correlations at three specific genomic regions (chr3:183.2-184.5 Mb, chr8:144.9-146.3 Mb, and chr8:27.4-28.3 Mb; p < 0.05/90). MiXeR indicated moderate polygenic overlap (228 shared variants). ConjFDR identified 20 shared loci, and MetaXcan highlighted ETHE1, FEZ2, PHLDB3, and PINLYP. MR analysis indicated a positive causal effect of FEZ2 in excitatory neurons on AD and sarcopenia risk (FDR < 0.05).ConclusionsThis study indicates no significant genome-wide genetic correlation between sarcopenia and AD, while suggesting the presence of localized shared genetic signals at specific genomic regions. Dysregulation of the cytoskeleton and autophagy pathways may contribute to both sarcopenia and AD. FEZ2, ETHE1, PHLDB3, and PINLYP expression in muscle and brain may contribute to the comorbidity between sarcopenia and AD. Overall, these findings provide exploratory evidence for local shared genetic architecture between sarcopenia and AD.},
}

@article {pmid41940830,
year = {2026},
author = {Zou, H and Wang, T and Huynh, K and Meikle, PJ and Kaddurah-Daouk, R and Luo, S and , and , },
title = {Plasma lipid trajectories improve prediction of future Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435212},
doi = {10.1177/13872877261435212},
pmid = {41940830},
issn = {1875-8908},
abstract = {BackgroundEarly identification of individuals at elevated risk for Alzheimer's disease (AD) is critical for prevention. Blood-based biomarkers offer scalable alternatives to cerebrospinal fluid and imaging, but the prognostic value of longitudinal plasma lipid trajectories remains unclear.ObjectiveTo evaluate whether multi-year plasma lipid trajectories improve prediction of AD conversion beyond demographic, clinical, genetic, and neuropsychological measures.MethodsWe studied 1150 cognitively normal or mildly impaired Alzheimer's Disease Neuroimaging Initiative participants; 329 progressed to AD dementia over a mean follow-up of 2.3 years. Plasma lipidomics quantified 749 lipid species by high-resolution LC-MS. Trajectories were summarized using functional principal component analysis and related to time to conversion using covariate-adjusted Cox proportional hazards models. Predictive performance was assessed by concordance index and likelihood-ratio tests.ResultsCross-sectional lipid profiles modestly improved prediction beyond demographic and clinical covariates, and longitudinal lipid trajectories yielded small additional gains. Ether-linked triglycerides showed the strongest longitudinal associations with conversion, with TG(O-50:1) [NL-18:1] exhibiting the most robust signal. Neuropsychological measures provided substantially stronger discrimination, and lipid trajectories added limited value once cognitive information was included. Nevertheless, longitudinal lipid changes contributed consistent improvements in models without neuropsychological predictors, supporting their role as complementary blood-based markers in settings where standardized cognitive assessments are unavailable or impractical.ConclusionsPlasma lipid trajectories capture biologically relevant metabolic change associated with AD progression and provide complementary predictive information. Longitudinal lipidomic profiling may support early risk stratification and cohort enrichment when cognitive assessments are unavailable.},
}

@article {pmid41940832,
year = {2026},
author = {Gu, Q and Xie, Y and Zhao, Z and Zhuang, Z and Yang, L and Huang, H and Li, H and Pi, S and Chen, F and Gong, C and He, Y},
title = {CeRNA regulatory network of cerebral microvascular dysfunction in early development of APP/PS1 mice model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435563},
doi = {10.1177/13872877261435563},
pmid = {41940832},
issn = {1875-8908},
abstract = {BackgroundGiven the global aging trend and the rising challenge of Alzheimer's disease (AD), accumulating evidence identifies cerebral microvascular dysfunction as an early pathological event. Hence, elucidating the key molecular regulators of cerebral microvascular function is critical for developing early intervention strategies.ObjectiveTo identify key genes associated with cerebral microvascular dysfunction in early-stage AD based on transcriptomics and to investigate the competing endogenous RNA (ceRNA) network involving long non-coding RNA (lncRNA).MethodsImmunofluorescence staining for CD31 was conducted on cerebral cortical sections from 1-month-old APP/PS1 and wild-type (WT) mice. Cerebral cortex and microvascular fractions were isolated for qPCR and western blot analysis of microvascular functional molecules. Following differential expression analysis, we performed functional and pathway enrichment, PPI network construction, ClueGo module analysis, and CFG prioritization to screen for core genes regulating cerebral microvascular function. A comprehensive ceRNA network was then established by integrating multi-database miRNA target predictions with RNA expression correlation data.ResultsOne-month-old AD mice exhibited both reduced cerebral microvascular density and average vessel length, along with significant disruption in the expression of blood-brain-barrier proteins. Transcriptomic profiling identified 956 differentially expressed transcripts, including 539 lncRNAs, 412 mRNAs, and 5 miRNAs. By integrative bioinformatics analysis, we identified 11 hub genes primarily involved in vascular contraction and circadian regulation, and constructed a comprehensive ceRNA network comprising 7 mRNAs, 41 miRNAs, and 46 lncRNAs.ConclusionsOur results reveal that early-stage AD is characterized by cerebral microvascular dysfunction, primarily mediated through impaired vascular contraction and disrupted circadian rhythm regulation.},
}

@article {pmid41940846,
year = {2026},
author = {Costa, T and Liloia, D and Premi, E and Ashton, N and Zettemberg, H and Blennow, K and Padovani, A and Borroni, B},
title = {A Bayesian classification model for differential diagnosis of Alzheimer's disease and frontotemporal dementia using plasma biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261439950},
doi = {10.1177/13872877261439950},
pmid = {41940846},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and frontotemporal dementia (FTD) have distinct pathologies but frequently overlapping clinical presentations, making early and atypical differential diagnosis challenging. Blood-based biomarkers offer a minimally invasive alternative to cerebrospinal fluid and neuroimaging measures, yet their diagnostic performance-alone and in combination-remains to be fully established.ObjectiveTo quantify the discriminative ability of plasma biomarkers for differentiating AD, FTD, and healthy controls (HC).MethodsWe used a fully Bayesian classification framework, estimating Bayesian logistic regression models for all single, pairwise, and triplet combinations of six plasma biomarkers-phosphorylated tau at threonine 217 (pTau217), brain-derived tau (BD-Tau), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), amyloid-β40 (Aβ40), and amyloid-β42 (Aβ42)-in AD (n = 97), FTD (n = 255), and HC (n = 70). Models were fitted across three contrasts (AD versus HC, FTD versus HC, AD versus FTD) and evaluated via posterior distributions of cross-validated AUC, precision, recall, F1 score, and Brier score.ResultsAcross 41 candidate models, NfL was the top single biomarker (mean AUC = 0.85), achieving strong discrimination for FTD versus HC (AUC = 0.94). The best two-marker panel (pTau217 + NfL) improved AD versus HC (AUC = 0.96) and AD versus FTD (AUC = 0.90). Adding Aβ42 produced the highest-ranked triplet (AUC = 0.95) with modest, consistent gains. Posterior coefficients were biologically coherent (AD-specific pTau217 effects; severity-linked NfL), and calibration was satisfactory, with minor overconfidence only at extreme probabilities.ConclusionsA parsimonious pTau217 + NfL panel captures most diagnostic information in the full plasma profile, providing an accurate probabilistic classifier with interpretable uncertainty to support differential diagnosis and clinical triage in precision neurology.},
}

@article {pmid41940848,
year = {2026},
author = {Kuchipudi, JD and Menon, J and Kantipudi, SJ and Vinoth, S and Vanisree, AJ and Hemamalini, AJ},
title = {Gender differences in methylcobalamin, folate, homocysteine, and hemoglobin levels among urban, community dwelling, elderly with mild cognitive impairment in a South Indian city: A cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261436756},
doi = {10.1177/13872877261436756},
pmid = {41940848},
issn = {1875-8908},
abstract = {BackgroundVitamin B12 and folate deficiencies are associated with cognitive decline, yet evidence for their role in mild cognitive impairment (MCI) remains inconclusive, particularly how it differs across genders.ObjectiveTo evaluate the prevalence of vitamin B12, vitamin B9, Homocysteine, and hemoglobin levels among male and female urban, community-dwelling elderly individuals with MCI and to assess gender-specific differences in these biochemical parameters.MethodsA cross-sectional study was conducted among 128 urban, community-dwelling elderly individuals (60 + years) with MCI in South India. Serum levels of vitamin B12, folate, homocysteine, and hemoglobin were evaluated alongside cognitive assessment. Multiple regression analysis was performed to evaluate the association between biomarkers and cognitive function adjusting for sociodemographic variables.ResultsThis study revealed a high prevalence of vitamin B12 (78.1%), folate (99.2%) deficiencies and anemia (64.1%), alongside elevated homocysteine levels in 87.5% of participants. No significant association was found between mean scores of cognition in MCI and vitamin B12, folate, or homocysteine levels. Females had significantly lower mean hemoglobin levels than males (p = 0.03). Cognitive scores were relatively higher in females despite their lower socioeconomic status and hemoglobin levels.ConclusionsGender disparities in hemoglobin levels highlight the importance of addressing nutritional inequities. However, vitamin B12 and folate levels may not strongly influence MCI. Routine assays for these vitamins in elderly individuals with cognitive impairment should be reconsidered in resource-constrained settings.},
}

@article {pmid41940849,
year = {2026},
author = {de Levante Raphael, D},
title = {Persistent functional impairment as a preclinical signal of Alzheimer's disease: Advancing dementia prognostication through the natural history of function.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438521},
doi = {10.1177/13872877261438521},
pmid = {41940849},
issn = {1875-8908},
abstract = {Early identification of Alzheimer's disease remains restricted due to overreliance on cognitive testing and biomarker accessibility. The study by Ghahremani et al. demonstrates that persistent, however not transient, functional impairment in cognitively normal older adults robustly predicts incident cognitive decline and dementia. This commentary positions their findings within social, behavioral, and public-health frameworks, emphasizing functional trajectories as ecologically valid, scalable markers of preclinical disease. By operationalizing function through persistence over time, this work advances dementia projections beyond cross-sectional assessment and supports integration of functional monitoring into population-level prevention, clinical trials, and equity-focused early detection strategies.},
}

@article {pmid41940854,
year = {2026},
author = {Alcalá Ramírez Del Puerto, JM and Ortega-Madueño, I and Gil-Moreno, MJ and Abizanda-Saro, P and Palacios-Sarmiento, M and Millán-Guirado, R and Cruz-Cárdenas, M and Matías-Guiu, JA},
title = {Apolipoprotein E proteotyping as a valid alternative to genotyping in clinical practice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438522},
doi = {10.1177/13872877261438522},
pmid = {41940854},
issn = {1875-8908},
abstract = {The apolipoprotein E ε4 allele (APOE ε4) is associated with higher incidence of amyloid-related imaging abnormalities in patients with Alzheimer's disease undergoing anti-amyloid therapy, underscoring the importance of allele status testing. In this study, plasma ApoE4 levels were measured in 70 participants using Lumipulse[®]G Pan-ApoE and ApoE4 assays and compared with traditional genotyping. ApoE4 concentrations and ratio ApoE4/Pan-ApoE differed significantly across non-ε4, ε3/ε4, and ε4/ε4 groups. No correlation was observed with age, sex, creatinine levels, or AD cerebrospinal fluid biomarkers. Diagnostic performance was excellent, indicating that proteotyping of ApoE can accurately classify the main APOE haplotypes.},
}

@article {pmid41940855,
year = {2026},
author = {Liu, M and Bhatt, K and Giaever, MF and Ardekani, BA and Reichert Plaska, C and , and Ghanbarian, E},
title = {Sex differences in cognitive performance in Alzheimer's disease: Insights from the ADAS-Cog-13.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261440125},
doi = {10.1177/13872877261440125},
pmid = {41940855},
issn = {1875-8908},
abstract = {BackgroundSex differences in Alzheimer's disease (AD) are well recognized, yet their implications for cognitive assessment remain unclear. Females often demonstrate better cognitive performance than males despite comparable levels of neurodegeneration, which may delay diagnosis.ObjectiveTo evaluate sex differences in cognitive performance across AD continuum.MethodsUsing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we examined sex differences in total and item-level performance on the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-13) among cognitively normal (CN) individuals and patients with AD. Regression models were performed, adjusting for hippocampal parenchymal fraction, age, and education.ResultsThe study included 656 CN participants (59% female) and 193 AD patients (45% female). Among CN individuals, female sex was associated with lower total ADAS-Cog-13 scores (β = -2.09, p < 0.0001). CN females demonstrated superior performance on multiple verbal subdomains, including word recall, delayed word recall, naming, and word recognition. In contrast, no significant sex difference was observed in total ADAS-Cog-13 scores among AD patients, although males performed better than females on delayed word recall. Across both groups, greater hippocampal integrity was strongly associated with better global and domain-specific cognitive performance.ConclusionsSex differences in ADAS-Cog-13 performance are evident in cognitively normal individuals but largely attenuated in AD patients. Superior verbal performance in CN females, independent of hippocampal integrity, may mask early cognitive decline and contribute to delayed diagnosis. These findings highlight the importance of accounting for sex when interpreting cognitive test results, particularly in preclinical stages of AD.},
}

@article {pmid41940859,
year = {2026},
author = {Geda, YE and Krell-Roesch, J and Bekele, K and Gunning, JA and Zaniletti, I and Eagan, D and Demeke, M and Khan, N and Chahal, G and Smith, T and DeCuna, C and Aliskevich, EL and Hettiwatte, Y and Ransdell, M and Racette, SB},
title = {Time-restricted eating in Alzheimer's disease (TREAD): A call for research.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438520},
doi = {10.1177/13872877261438520},
pmid = {41940859},
issn = {1875-8908},
abstract = {Fasting is part and parcel of the practice of various religious groups. In the scientific literature, the term intermittent fasting (IF) was first reported in a 1946 paper demonstrating its association with increased longevity in rodents. Research has extended IF, particularly time-restricted eating (TRE), to Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by neuritic plaques, neurofibrillary tangles, and neuronal loss. AD manifests in asymptomatic, mild cognitive impairment (MCI), and dementia phases. Delaying progression from MCI to dementia by one year could reduce dementia prevalence by millions. Currently, no pharmacological treatments can reverse or arrest MCI progression to dementia, making exploration of non-pharmacological interventions critical. TRE is a promising approach. AD brains exhibit decreased glucose uptake, while ketone utilization remains intact. Fasting for at least 8-12 h induces a cascade of molecuar events that lead to a metabolic switch from glucose to ketone utilization, providing an alternative energy source for AD brains. Preclinical studies demonstrate that TRE enhances cognitive function via hippocampal neurogenesis, autophagy, and reduced neuroinflammation. Human studies on TRE in MCI are limited but promising, often focusing on cardiometabolic outcomes, with little known about TRE targeting MCI. This review synthesizes current evidence on TRE and cognitive outcomes in humans, non-human primates, and rodents, and describes ongoing trials in MCI patients. We propose a theoretical model of direct and indirect pathways linking TRE with resistance to AD in the brain parenchyma, and identify gaps in knowledge regarding long-term cognitive effects and mechanistic pathways of TRE in MCI, urging rigorous clinical trials to establish TRE as a safe and possibly effective strategy to delay MCI progression to dementia.},
}

@article {pmid41940869,
year = {2026},
author = {Sharif-Askari, Z and Atoui, K and El Zein, W and Rizk, M and Sharif Askari, E},
title = {From periodontitis to neurodegeneration: Can probiotics modulate the P. gingivalis-amyloid pathway in Alzheimer's disease?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261432686},
doi = {10.1177/13872877261432686},
pmid = {41940869},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the gradual destruction of cognitive and behavioral functions. Despite the continuous research efforts, there is still no cure for this disease. In recent years, researchers have investigated Porphyromonas gingivalis (P. gingivalis) as a potential cause of AD. P. gingivalis-lipopolysaccharides (LPS) and gingipains have been implicated in neuroinflammatory cascades relevant to AD. The gut-brain axis provides a pathway for microbial migration, immune activation, and regulation of the central nervous system function. Emerging evidence suggests that selected probiotics may modulate these pathways by restoring microbial balance, reinforcing epithelial barrier function, and regulating innate and adaptive immunity. Importantly, much of the evidence and mechanistic support for these effects derives from preclinical and animal studies, whereas human data remain limited to associative findings and early-stage clinical trials. Early clinical trials report modest improvements in cognitive scores and systemic inflammatory markers. Strain selection, dose, and treatment duration make direct comparisons challenging. This review integrates the literature on the links between P. gingivalis and AD, suggesting that probiotics may be used as neuroprotective agents. Taken together, current preclinical signals are consistent with the potential of probiotics as feasible adjuncts, pending confirmatory trials with standardized formulations.},
}

@article {pmid41941099,
year = {2026},
author = {Hayibor, LA and Anokhin, A and Fisher, SL and Goate, A and Foroud, TM and Schindler, SE and Bierut, LJ and Hartz, SM},
title = {The relationship between alcohol use disorder, measures of cognitive decline, and Alzheimer disease biomarkers in middle aged and older adults.},
journal = {Alcohol, clinical & experimental research},
volume = {50},
number = {4},
pages = {e70278},
doi = {10.1111/acer.70278},
pmid = {41941099},
issn = {2993-7175},
support = {R01 AG065234/AG/NIA NIH HHS/United States ; R01 AG084723/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AA029308/AA/NIAAA NIH HHS/United States ; U10 AA008401/AA/NIAAA NIH HHS/United States ; UL1TR002345/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; Aged ; Male ; Female ; *Alzheimer Disease/blood/epidemiology/diagnosis/psychology ; Biomarkers/blood ; Middle Aged ; Aged, 80 and over ; Amyloid beta-Peptides/blood ; *Alcoholism/blood/epidemiology/psychology/complications ; *Cognitive Dysfunction/blood/epidemiology ; tau Proteins/blood ; Peptide Fragments/blood ; },
abstract = {BACKGROUND: Alcohol use disorder (AUD) is associated with increased risks of some neuropsychiatric conditions and early-onset dementia. However, the association between Alzheimer disease (AD) and AUD is poorly characterized. To address this, we studied associations between AUD, cognition, and measures of AD neuropathology.

METHODS: We measured a lifetime history of AUD, cognitive decline, and blood biomarkers for AD in middle-aged and older participants (47-87 years) from the St. Louis site of the Collaborative Study on the Genetics of Alcoholism (COGA) (N = 392). Cognitive decline was measured using the Eight-item Informant Interview to Differentiate Aging and Dementia (AD8) (N = 366); 154 individuals had AD biomarkers derived from plasma measurements (Amyloid Probability Score 2, Aβ42/Aβ40, and %p-tau217). We used Poisson regression models to evaluate the relationship between AUD, age, and cognitive decline. AUD was categorized as no AUD, mild AUD, or moderate-to-severe AUD, and age was modeled as a piecewise linear variable segmented by decade. Linear regressions were used to assess the association between AD blood biomarkers and AUD.

RESULTS: Analyses revealed a significant association between moderate-to-severe AUD and increased cognitive decline in middle-aged and older adults (RR = 1.4, p < 0.001). While a greater proportion of participants with moderate-to-severe AUD met the Aβ42/Aβ40 threshold for predicting elevated brain amyloid compared to those with mild or no AUD, consistent with our hypothesis, this trend did not achieve statistical significance.

CONCLUSIONS: These results underscore the importance of addressing AUD as a potentially modifiable risk factor for cognitive decline in middle aged and older adults. Further study is needed to understand the link between AUD and AD biomarkers.},
}

Humans
Aged
Male
Female
*Alzheimer Disease/blood/epidemiology/diagnosis/psychology
Biomarkers/blood
Middle Aged
Aged, 80 and over
Amyloid beta-Peptides/blood
*Alcoholism/blood/epidemiology/psychology/complications
*Cognitive Dysfunction/blood/epidemiology
tau Proteins/blood
Peptide Fragments/blood

@article {pmid41941130,
year = {2026},
author = {Tosun, S and Karalı, FS and Eskioğlu, Eİ and Çavdar, D and Dicle, M and Çınar, N and Macoir, J},
title = {Normative data and clinical validity of verb and phonemic fluency tasks in Turkish-speaking older adults.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001089},
pmid = {41941130},
issn = {1931-1559},
abstract = {OBJECTIVE: Verbal fluency tasks are commonly used in clinical neuropsychology to assess language and executive functions. Verb fluency and phonemic fluency are sensitive to age-related cognitive decline and neurodegenerative conditions such as mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, normative data for these tasks remain limited in Turkish-speaking populations, especially when culturally adapted phonemic fluency measures are employed. This study aimed to (a) provide normative data for verb fluency and Turkish-adapted K-A-S phonemic fluency tasks in healthy middle-aged and older adults, and (b) examine the discriminant validity of these tasks in distinguishing healthy controls from individuals with MCI and AD.

METHOD: In the normative phase, 357 healthy adults were assessed and stratified by age and education. Norms were reported as regression-based z scores and percentile tables.

RESULTS: In the clinical phase, 150 participants (50 healthy, 60 MCI, and 40 AD) completed the tasks. Kruskal-Wallis and post hoc analyses revealed significant group differences across all fluency measures. Healthy controls outperformed both clinical groups, and the MCI group scored higher than the AD group, especially on K fluency and total K-A-S scores.

CONCLUSIONS: These findings highlight the diagnostic value of verb and phonemic fluency tasks and the importance of using culturally appropriate norms in Turkish-speaking populations for early detection of cognitive impairment. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid41941131,
year = {2026},
author = {Zhao, Y and Zhang, J and Zhao, Y and Yuan, Y and Shen, J and Peng, H and Li, J},
title = {Cognitive health on the fingertips: Fine motor deficiencies for assessing the risk of mild cognitive impairment in the aging adults.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001074},
pmid = {41941131},
issn = {1931-1559},
support = {//National High Level Hospital/ ; //Chinese Academy of Medical Sciences; Interdisciplinary Research Program on Frontiers of Medical Health/ ; //Artificial Intelligence Beijing Municipal Science & Technology Commission/ ; },
abstract = {OBJECTIVE: Mild cognitive impairment (MCI) represents a critical prodromal stage associated with Alzheimer's disease and other age-related neurocognitive conditions in middle-old aging adults, yet research exploring its association with fine motor skill deficits remains relatively limited. This study explores the specific characteristics of fine motor function in middle-old aging adults with MCI using the latest wearable inertial motion capture technology.

METHOD: A computerized system with wearable inertial motion capture technology captured and assessed fine motions. The least absolute shrinkage and selection operator-based machine learning algorithm was utilized to construct a nomogram. The discriminatory ability of the model was determined by calculating the area under the curve. Decision curve analysis, clinical impact curve analysis, and bootstrap validation were used to evaluate and validate the stability of models.

RESULTS: A total of 289 participants aged ≥50 were recruited, of which 140 participants experienced MCI. Compared with the control group, patients with MCI showed significantly poorer fine motor performance in hand function assessment tasks. Spearman correlation analysis revealed a stronger correlation between fine motor function and visuospatial/executive function. A multivariable nomogram model based on fine motion parameters showed satisfactory discrimination, with an area under the curve of .773. Decision curve analysis, clinical impact curve analysis, and bootstrap validation demonstrated the good clinical utility and stability of the model.

CONCLUSIONS: Poor motor functioning was associated with MCI status. The nomogram model, based on fine motion parameters, demonstrated moderate discriminative performance in assessing the risk of MCI, serving as a valuable clinical supplement. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid41941206,
year = {2026},
author = {Andrews, SJ and Yaffe, K},
title = {Advancing Precision Dementia Care With Genetic-Exposome Risk Assessment.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0573},
pmid = {41941206},
issn = {2168-6157},
}

@article {pmid41941211,
year = {2026},
author = {Kumari, K and Kumar, N and Ramakrishnan, V},
title = {Electric Field Directed Structural Modulation and Nanoassembly of Peptide Hydrogels.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.5c06894},
pmid = {41941211},
issn = {1520-5827},
abstract = {This study presents a novel approach to modulate peptide self-assembly, solubility, and functional properties by utilizing an electric field as an external stimulus. Three short, heterochiral tripeptides, P1, P2, and P3, were designed based on their ability to form hydrogels. We demonstrate that the structural and functional properties of peptide-based hydrogels can be modulated upon exposure to an electric field. Our findings indicate that the external electric field does not alter the secondary structure of the designed peptides, however, the electric field plays a significant role in regulating the supramolecular assembly at the nanoscale. Morphological studies using field emission-scanning electron microscopy (FE-SEM), field emission-transmission electron microscopy (FE-TEM), and atomic force microscopy (AFM) images indicate a pronounced transition from a nanofibrillar architecture in control experiments with no electric field to the formation of nanoflakes, vesicular structures, and globular aggregates upon exposure to varying electric fields. We further examined the effect of the electric field in modulating the electrical conductivity of the peptide hydrogel. Additionally, an inverse relationship was observed between the peptide solubility and the mechanical robustness of the hydrogel. These findings suggest that the electric field can noninvasively perturb and modulate the solubility and aggregation characteristics of peptides. This approach also suggests a promising option for developing therapeutic interventions that enhance the solubility and reduce the fibrillation for several disease conditions, such as Alzheimer's and Parkinson's.},
}

@article {pmid41941234,
year = {2026},
author = {Oo, WJ and Sia, WT and Lee, JY and Chen, CH and Chang, WL and Chye, SM},
title = {The Role of Presynaptic Cytomatrix Protein Bassoon (BSN) in Tau Pathology and Propagation.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273400895251129055504},
pmid = {41941234},
issn = {1996-3181},
abstract = {Neurodegenerative disorders have become a global health threat following a prolonged lifespan, with the majority involving the accumulation and propagation of pathological tau. Tau oligomers can migrate to presynaptic terminals and interact with surrounding proteins, among which Bassoon (BSN) is one that selectively binds to and colocalises with misfolded tau. Studies have reported numerous implications of BSN mutations in tau pathology, including promoting tau seeding activity, hyperphosphorylation, misfolding, and aggregation. These eventually lead to the formation of neurofibrillary tangles in tauopathies. Given the BSN's physiological role in maintaining synapses, its mutation also impairs synaptic integrity. These abnormalities are consistently attenuated by downregulating BSN levels. However, BSN downregulation can lead to tau hyperphosphorylation via an alternative pathway, CDK5 hyperactivity. Current findings hypothesize that BSN reduces tau clearance by inhibiting proteasome activity. It is also suggested that BSN can impair dopaminergic pathways prior to the detection of tau pathological features. Tunnelling nanotubes also emerge as a potential interneuronal route for BSN-mediated tau spread. Despite a lack of clinical evidence, findings from postmortem samples, in vitro, and preclinical models highlight BSN as a potential candidate for tau-targeting therapies, indicating its role in the pathological development of tau. The involvement of BSN in tau seeding might also resolve challenges posed by tau-targeting drugs during clinical trials. Hence, this article aims to provide new insights into recent findings on BSN and tau with reference to previous studies. We will discuss the possible mechanisms involved, along with the future therapeutic value of BSN in the treatment of tauopathies.},
}

@article {pmid41941239,
year = {2026},
author = {Wang, N and Wen, H and Sun, Y and Xu, W and Shen, X and Wang, R},
title = {Effects of Hesperetin Early Intervention on Brain Neurons and Microglia in APPswe/PS1dE9 Mice.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273418623251203072424},
pmid = {41941239},
issn = {1996-3181},
abstract = {INTRODUCTION: Neuroinflammation and microglial dysfunction play central roles in the pathogenesis of Alzheimer's disease (AD). This study investigated whether early intervention with hesperetin, a citrus flavonoid, could attenuate neuroinflammation and modulate microglial polarization in both wild-type (WT) and APPswe/PS1dE9 transgenic (TG) mice.

METHODS: Three-month-old male C57BL/6J WT and APPswe/PS1dE9 TG mice were administered hesperetin (10 or 20 mg/kg/day for WT; 20, 40, or 80 mg/kg/day for TG) or vehicle for six months. Neuronal morphology was assessed using thionine staining. Microglial polarization was evaluated via CD11b/iNOS and CD11b/Arginase-1 immunofluorescence. Protein expression of CD11b, iNOS, Arginase-1, and TREM2 was measured by Western blot, and cytokine levels (TNF-α, IL-10) were quantified by ELISA.

RESULTS: In WT mice, hesperetin improved neuronal integrity, reduced M1 markers (CD11b⁺/ iNOS⁺ cells, iNOS, TNF-α), and enhanced M2 markers (CD11b⁺/Arginase-1⁺ cells, Arginase-1, TREM2). TG mice exhibited exacerbated neuroinflammation and neuronal loss compared to WT controls, which was significantly mitigated by hesperetin treatment. All hesperetin doses in TG groups reduced pro-inflammatory markers and increased anti-inflammatory and repair-associated factors.

DISCUSSION: These results indicate that hesperetin shifts microglial polarization toward the protective M2 phenotype, potentially via TREM2 upregulation, thereby reducing neuroinflammation and neuronal damage. This effect was observed in both age-related and Aβ-driven pathology, suggesting a dual role for hesperetin in immunomodulation and neuroprotection.

CONCLUSION: Early hesperetin intervention exerts neuroprotective effects by rebalancing microglial polarization and enhancing TREM2 expression, highlighting its potential as a preventive strategy against AD-related neuroinflammation.},
}

@article {pmid41941281,
year = {2026},
author = {Subramanian, I and Surajambika, RR and Sekar, D and Natarajan, R and Nagarajan, NC},
title = {A Systematic Review on Isoquinoline Derivatives as Emerging Multi-target Agents in Alzheimer's and Parkinson's Disorder Therapy.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249401454260108062419},
pmid = {41941281},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's, Parkinson's, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, are characterized by progressive neuronal loss driven by damage or apoptosis. Although their precise etiologies remain unclear, neuronal degeneration is a common pathological hallmark.

METHODS: This review compiles and critically evaluates studies investigating the potential of isoquinoline derivatives to mitigate neurodegeneration. Particular attention is given to their inhibitory effects on key enzymes implicated in these disorders and structural modifications aimed at improving potency and reducing toxicity.

RESULTS: Experimental findings demonstrate that isoquinoline derivatives exhibit significant inhibitory activity against several neurodegeneration-related enzymes. These compounds show promise in attenuating disease progression in preclinical models, supporting their potential as therapeutic leads.

DISCUSSION: Isoquinoline derivatives display multitarget properties, and structural optimization has enhanced their efficacy and safety profiles. Their multifunctional nature could offer advantages over current single-target therapies by improving efficacy and reducing adverse effects.

CONCLUSION: Isoquinoline derivatives represent promising scaffolds for developing novel therapeutics targeting neurodegenerative disorders. However, most data are limited to in vitro and earlystage preclinical studies. Comprehensive mechanistic investigations, standardized in vivo evaluations, and early-phase clinical trials are required to establish their pharmacokinetics, blood-brain barrier permeability, safety, and therapeutic potential.},
}

@article {pmid41941282,
year = {2026},
author = {Agrawal, MM and Mittal, P},
title = {Emerging Therapies and Research in Alzheimer's Disease: A Critical Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249403872251208145159},
pmid = {41941282},
issn = {1875-6166},
abstract = {Alzheimer's disease, an extremely prevalent neurological illness and the leading cause of dementia globally, is an extremely prevalent neurological illness and is the leading cause of dementia globally. There are a few treatment options for AD, and those that do exist only slightly reduce symptoms, even after several clinical studies. The formation of Aβ plaques, neuroinflammation, and hyperphosphorylated tau neurofibrillary tangles are the characteristics of AD. While monoclonal antibodies such as lecanemab, donanemab, and aducanumab have demonstrated potential in addressing Aβ, their clinical efficacy and safety over an extended period of time remain uncertain. Novel avenues for tackling the underlying genetic causes of AD have been made possible by developments in genome editing tools, most notably CRISPR-Cas9. In preclinical animals, CRISPR-Cas9 has effectively edited genes relevant to AD, such as APP and PSEN1, leading to decreased levels of Aβ and enhanced cognitive function. Additionally, base and prime editing, two precision gene-editing techniques, have increased the medicines' selectivity and decreased their offtarget effects. However, before clinical applications are deployed, challenges related to technology, ethics, and safety must be resolved. This review highlights how monoclonal antibodies, neuroinflammation research, and CRISPR-Cas9 have the potential to revolutionize therapy choices for AD by examining the most current developments in the field.},
}

@article {pmid41941283,
year = {2026},
author = {Natarajan, J and Ranganathan, S},
title = {Hydrogel-forming Microneedles: A Next-generation Approach for Enhanced Dermal Drug Delivery in Alzheimer's and Neurological Disorders.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249400208251205125114},
pmid = {41941283},
issn = {1875-6166},
abstract = {Hydrogel-Forming Microneedles (HFMNs) offer a minimally invasive, patient-friendly, and sustained-release platform for transdermal delivery. By swelling upon insertion to form a hydrogel matrix, they enable efficient delivery of small molecules, biologics, and nanoparticles while bypassing gastrointestinal degradation and first-pass metabolism. In neurological disorders such as Alzheimer's and Parkinson's disease, they can improve bioavailability and overcome Blood-Brain Barrier (BBB) restrictions. However, limitations remain, including limited macromolecule payload, variable skin penetration, and regulatory challenges. To critically review recent progress in HFMNs for neurological drug delivery and assess their translational readiness. The objective is to evaluate advances in design, materials, fabrication, and therapeutic applications, and identify key challenges and future prospects. A literature review (2018-2024) covering polymer selection, crosslinking strategies, smart-material integration, and CNS-targeted applications. HFMNs successfully deliver donepezil, memantine, rivastigmine, and neurotrophic factors, achieving sustained release, improved bioavailability, and enhanced patient compliance. Smart HFMNs with biosensors and nanocarriers show improved BBB penetration. HFMNs represent a promising alternative to conventional CNS drug delivery. Addressing payload, penetration consistency, and scalable manufacturing will be vital for clinical adoption.},
}

@article {pmid41941323,
year = {2026},
author = {Marselli, G and Corbo, I and Pecchinenda, A and Forte, G and Favieri, F and Troisi, G and Blasutto, B and Casagrande, M},
title = {Emotional-cognitive integration in aging: the role of alexithymia in mild cognitive impairment.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1737901},
doi = {10.3389/fpubh.2026.1737901},
pmid = {41941323},
issn = {2296-2565},
mesh = {Humans ; *Cognitive Dysfunction/psychology ; *Affective Symptoms/psychology ; Aged ; Female ; Male ; Middle Aged ; Aged, 80 and over ; *Aging/psychology ; Neuropsychological Tests ; *Cognition ; *Emotions ; },
abstract = {INTRODUCTION: Aging is accompanied by a range of cognitive and emotional changes. Among these, difficulty in identifying and describing feelings and a tendency toward externally oriented thinking have been associated with frank cognitive decline. This pattern is known as alexithymia and reflects emotional dysregulation. Research Questions-This study aimed to investigate the largely unexplored relationship between alexithymia and cognitive functioning in older adults within the context of mild cognitive impairment (MCI).

METHODS: Three hundred and twenty adults aged 50-80 years classified as healthy controls, amnestic MCI (aMCI), or non-amnestic MCI (naMCI), completed a comprehensive neuropsychological assessment and the 20-item Toronto Alexithymia Scale (TAS-20).

RESULTS AND DISCUSSION: Participants with aMCI showed significantly higher levels of alexithymia, compared to healthy controls. This pattern suggests that emotional dysregulation is more pronounced in individuals with memory-related cognitive decline. In both the aMCI and naMCI groups, correlations between alexithymia scores and cognitive measures were negative, indicating that higher alexithymia was associated with poorer cognitive performance. In contrast, these associations were weak in healthy controls, implying that the link between emotional processing difficulties and cognitive inefficiency emerges primarily in MCI. Taken together, these findings point to a specific interplay between emotional and cognitive domains in the early stages of neurodegenerative decline. Accordingly, elevated alexithymia in aMCI individuals might represent a socio-emotional marker of prodromal Alzheimer's disease, highlighting the importance of considering emotional regulation in the assessment of cognitive aging.},
}

Humans
*Cognitive Dysfunction/psychology
*Affective Symptoms/psychology
Aged
Female
Male
Middle Aged
Aged, 80 and over
*Aging/psychology
Neuropsychological Tests
*Cognition
*Emotions

@article {pmid41941399,
year = {2026},
author = {, },
title = {Correction: Exploring emotion recognition in patients with mild cognitive impairment and Alzheimer's dementia undergoing a rehabilitation program emotion recognition in patients with dementia.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346658},
doi = {10.1371/journal.pone.0346658},
pmid = {41941399},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0322213.].},
}

@article {pmid41941495,
year = {2026},
author = {Taniguchi, N and Ohkawa, Y and Nakano, M and Gu, J and Takahashi, M},
title = {The Role of Glycans and Glycosyltransferases Involved in N-glycan Branching in Cancer, COPD, Alzheimer's Disease, and Redox Regulation.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {229},
pages = {},
doi = {10.3791/69958},
pmid = {41941495},
issn = {1940-087X},
mesh = {*Alzheimer Disease/metabolism/enzymology ; Animals ; *Glycosyltransferases/metabolism ; *Polysaccharides/metabolism/biosynthesis/chemistry ; Mice ; *Pulmonary Disease, Chronic Obstructive/metabolism/enzymology ; Oxidation-Reduction ; *Neoplasms/metabolism/enzymology ; Humans ; },
abstract = {Glycosyltransferases that biosynthesize glycans and their genes (glycogenes) play important roles in health and disease. In general, pathophysiological changes are defined by comparing knock-out (KO) or knock-in mice generated using CRISPR-Cas9 and other technologies to normal mice. Next, target molecules such as glycoproteins, glycolipids, and proteoglycans to which various biosynthetic glycans bind were identified. As a result, we found that N-glycan branches biosynthesized by glycosyltransferases are intrinsically involved in Alzheimer's disease, cancer metastasis, epithelial mesenchymal transition (EMT)/mesenchymal epithelial transition (MET), type 2 diabetes, chronic obstructive pulmonary disease (COPD), and ulcerative colitis. For example, the addition of core fucose biosynthesized by α1,6-fucosyltransferase (Fut8) leads to dysregulation of TGF-β receptors. Bisecting N-acetylglucosamine (GlcNAc) biosynthesized by β-1,4-GlcNAc transferase III (GnT-III) affects the subcellular localization of Beta-site Amyloid Precursor Protein Cleaving Enzyme 1 (β-secretase 1, referred to as BACE1). β1,6GlcNAc branching biosynthesized by GnT-V leads to the modification of matrix metalloproteinase (MMP). Identification and characterization of N-glycan structures on these proteins were performed using a glycoproteomic approach based on lectin blotting, western blotting, liquid chromatography-electron spray ionization mass spectrometry, and histochemical staining. Recently, studies concerning redox regulation of N-glycans, termed Glyco-Redox, have emerged as a promising approach. Functional and pathophysiological glycan studies are one of the main goals of glycobiology research. In this review, we describe the role of N-glycan branching glycosyltransferases and their biosynthesized glycans in relation to various diseases, such as cancer metastasis, COPD, Alzheimer's disease, and ulcerative colitis.},
}

*Alzheimer Disease/metabolism/enzymology
Animals
*Glycosyltransferases/metabolism
*Polysaccharides/metabolism/biosynthesis/chemistry
Mice
*Pulmonary Disease, Chronic Obstructive/metabolism/enzymology
Oxidation-Reduction
*Neoplasms/metabolism/enzymology
Humans

@article {pmid41941608,
year = {2026},
author = {Wang, T and Sun, Y and Lin, YR and Yao, L and Qiang, W},
title = {Controlled Seeding of β-Amyloid Fibrillation Reveals Propagation of Structural Polymorphisms in Cellular Environments.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.6c00013},
pmid = {41941608},
issn = {1520-4995},
abstract = {Molecular-level structural polymorphisms of β-amyloid (Aβ) aggregates in Alzheimer's disease patients are pathologically important. However, tracking the propagation and modulation of Aβ structural polymorphisms via ex vivo approaches remains challenging. The successful application of cryogenic transmission electron microscopy (cryo-TEM) in this area relies on the availability of morphologically distinct micrographs, which then enable unambiguous three-dimensional structural reconstruction of individual fibrillar polymorphs to achieve optimal resolution. As a complementary approach, solid-state nuclear magnetic resonance (ssNMR) spectroscopy with guided isotope-labeling schemes can provide site-specific and quantitative information on the populations of individual polymorphs. Such ssNMR sample preparations require ex vivo seeding, in which key parameters─including seed concentration and seeding time─must be carefully controlled for individual Aβ-cell systems to avoid the introduction of self-nucleated fibrillar polymorphs. In this work, we show that the application of controlled ex vivo seeding combined with quantitative ssNMR spectroscopy reveals the propagation of molecular-level structural polymorphs, depending on the types of seeds and cells.},
}

@article {pmid41941651,
year = {2026},
author = {Colwell, CS},
title = {Timing the decline: Cellular circadian rhythms and Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {15},
pages = {e2604049123},
doi = {10.1073/pnas.2604049123},
pmid = {41941651},
issn = {1091-6490},
}

@article {pmid41941947,
year = {2026},
author = {Srilakshmi, V and Devarasetty, P and Chetana, VL and Vinta, S and Kowtharapu, R},
title = {Alzheimer's Disease Staging Using Enhanced Inception-ResNet-V2 and Improved XceptionNet Models for 3D MRI Classification and Segmentation.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110767},
doi = {10.1016/j.jneumeth.2026.110767},
pmid = {41941947},
issn = {1872-678X},
abstract = {BACKGROUND: Neurologists have a significant challenge due to the progressive nature of Alzheimer's disease (AD) and its severe effects on cognitive function. Recent advances in neuroimage analysis have opened the door to novel machine-learning techniques that could greatly improve AD diagnosis, progression prediction, and detection.

NEW METHOD: In this research, we provide an enhanced hybrid deep learning approach for combined AD classification and segmentation. An enhanced inception-ResNet-V2 model is used for the multi-class classification of AD and an improved XceptionNet model is used to segment affected brain region of AD. The spatial features present in 3D MRI scans are effectively extracted by the parallel convolutional neural network (PCNN) model.

RESULTS: The OASIS and ADNI datasets were used in this research to detect and classify the AD stage. The proposed approach yielded consistently excellent testing accuracy and outstanding training accuracy. For testing, a higher accuracy of 99.5% for the OASIS dataset and 99.7% for the ADNI dataset is attained using the proposed approach.

Based on 3D MRI brain scans, these results demonstrate the exceptional ability of the proposed models, especially the Improved XceptionNet, to identify AD reliably. Based on the findings of the experiment, the proposed model outperforms cutting-edge deep learning models for classification and segmentation.

CONCLUSIONS: The experimental results show that incorporating advanced architectures significantly improves the precision of detecting and assessing brain changes associated with AD, offering practical tools for early diagnosis and monitoring the disease naturally.},
}

@article {pmid41941989,
year = {2026},
author = {Sun, Z and Peng, Q and Qiu, C and Jia, X and Wang, H and Wu, S and Tao, W},
title = {A specific Pilose antler peptide LVLVEAELRE ameliorates cognitive deficits in SAMP8 mice via Celsr2.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121649},
doi = {10.1016/j.jep.2026.121649},
pmid = {41941989},
issn = {1872-7573},
abstract = {Pilose antler peptide (PAP), an extract derived from the traditional Chinese medicinal material Pilose antler, has shown promise in the treatment of neurodegenerative diseases. However, the precise molecular mechanisms underlying its anti-Alzheimer's disease (AD) effects remain to be fully elucidated.

AIM OF THE STUDY: This study focuses on a specific PAP monomer with a defined sequence (LVLVEAELRE), herein referred to as PAP, to explore its potential role and molecular mechanisms in AD treatment.

MATERIALS AND METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice were employed to evaluate the effects of PAP on cognitive function, classical AD pathologies (Aβ and p-Tau), and synaptic plasticity. To further elucidate the causal role of Cadherin EGF LAG seven-pass G-type receptor 2 (Celsr2), bidirectional viral manipulations (AAV-shCelsr2 for knockdown and AAV-OECelsr2 for overexpression) were performed in vivo. Furthermore, cellular thermal shift assays (CETSA), molecular docking, and microscale thermophoresis (MST) were utilized to validate the direct interaction between PAP and Celsr2.

RESULTS: PAP administration significantly improved cognitive impairment, mitigated Aβ deposition and Tau hyperphosphorylation, and enhanced synaptic plasticity in SAMP8 mice. Mechanistically, PAP upregulated Celsr2 expression, restored AMPA receptor subunits, and inhibited neuronal senescence. Crucially, Celsr2 knockdown abolished these neuroprotective benefits, whereas Celsr2 overexpression synergistically amplified the therapeutic efficacy of PAP. Finally, MST and docking analyses confirmed that PAP possesses a high and specific binding affinity for WT Celsr2.

CONCLUSIONS: This study demonstrates that PAP ameliorates AD-like pathology by regulating Celsr2, highlighting its potential as a promising preclinical drug candidate. The research findings provide a theoretical basis for the development of PAP-based therapeutic strategies for Alzheimer's disease.},
}

@article {pmid41941996,
year = {2026},
author = {Wagner, S and Danz, K and Hyvärinen, J and Fischer, AL and Kanninen, KM and Gynther, M and Puris, E},
title = {Characterisation of a patient-derived iPSC-based model for studying the blood-brain barrier in Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111872},
doi = {10.1016/j.brainresbull.2026.111872},
pmid = {41941996},
issn = {1873-2747},
abstract = {The blood-brain barrier (BBB) comprised of the brain capillary endothelial cells (BCECs), with its tight junctions (TJ), transporters and receptors, regulates the passage of solutes, such as nutrients, metabolites, and xenobiotics, including drugs. In Alzheimer's disease (AD), characterised by the accumulation of amyloid-β peptide (Aβ) and the formation of hyperphosphorylated tau aggregates, a compromised BBB integrity was reported. There is a lack of knowledge about the effects of tau pathology on BBB function in AD. Advances in developing BBB models using human induced pluripotent stem cell (hiPSC)-derived BCECs have opened a new avenue for investigating AD-related changes in BBB functional integrity. Here, we characterised the BBB model derived from hiPSCs generated from an AD patient with a tau-related mutation (STBCi 062-A) versus the one based on a healthy person's cells (UKKi 011-A) in terms of mimicking AD-related changes in paracellular permeability, TJs, transporters, receptors and other proteins playing a role in BBB integrity. The STBCi 062-A-derived BCECs showed lower TEER values and increased permeability associated with downregulation of proteins regulating TJ organization and BBB integrity, as compared to UKKi 011-A-derived BCECs. We revealed AD-relevant increase in protein expression of efflux transporter BCRP and amino acid transporter ASCT1, as well as transferrin receptor protein 1 in the STBCi 062-A-derived BCECs compared to UKKi 011-A-derived BCECs. The developed AD-patient-hiPSC-derived BCEC model possesses several important characteristics that recapitulate changes in BBB integrity in AD and can serve as a robust tool for developing AD treatments.},
}

@article {pmid41942124,
year = {2026},
author = {Liu, Z and Ai, Y and Wu, Y and Zhang, Y and Hua, J and Liu, T and Liu, D and Chen, GC and Xu, G and Chen, LH},
title = {Association of circulating branched-chain or aromatic amino acids based on metabolome and apolipoprotein E genotype with incident dementia: a large cohort study.},
journal = {International journal of food sciences and nutrition},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/09637486.2026.2649766},
pmid = {41942124},
issn = {1465-3478},
abstract = {The associations between branched-chain amino acids (BCAAs) and dementia in individuals with chronic diseases remain unclear, and evidence on aromatic amino acids (AAAs) is limited. Using metabolic biomarker data from 117,892 UK Biobank participants, we found that higher circulating levels of BCAAs (HR=0.56, 95% CI: 0.41-0.76) and AAAs (HR=0.74, 95% CI: 0.55-0.98) were associated with lower risks of all-cause dementia and Alzheimer's disease, but not vascular dementia. Stratified analyses showed stronger inverse associations for BCAAs among women and individuals without diabetes (both P for interaction = 0.001). Similarly, AAAs were inversely associated with dementia risk primarily in non-diabetic participants, but not modified by hypertension or dyslipidemia. These findings highlight the potential protective roles of BCAAs and AAAs and underscore the importance of sex and diabetes status in dementia prevention.},
}

@article {pmid41942157,
year = {2026},
author = {Ngwa, CH and Abdulrahim, S and Nehme, R and Saad, M and Kabalan, M and Lteif, MR and Yazbek, Y and Chaaya, M and Elbejjani, M},
title = {Adverse childhood experiences and cognitive outcomes among older adults in low-income and middle-income countries: a systematic review.},
journal = {BMJ open},
volume = {16},
number = {4},
pages = {e112648},
doi = {10.1136/bmjopen-2025-112648},
pmid = {41942157},
issn = {2044-6055},
mesh = {Humans ; *Developing Countries ; *Adverse Childhood Experiences/statistics & numerical data ; *Cognitive Dysfunction/epidemiology/etiology ; Aged ; *Cognition ; Middle Aged ; Dementia/epidemiology ; Adult ; },
abstract = {OBJECTIVES: While adverse childhood experiences (ACEs) have been consistently linked to poorer cognitive outcomes in later life, far less is known about ACEs' contribution to dementia and cognitive ageing risk in low-income and middle-income countries (LMICs), despite their growing and disproportionate share of global Alzheimer's disease and related dementias (ADRD) burden. This study aimed to systematically review existing evidence on the association between individual ACEs and cognitive outcomes among adults aged 40 years and older in LMIC settings.

DESIGN: Systematic review and narrative synthesis.

DATA SOURCE: We searched Medline, Embase, PsycINFO and CINAHL from the inception of each database to January 2026.

ELIGIBILITY CRITERIA: Observational studies examining the association between individual ACEs and cognitive outcomes among adults aged 40 and older in LMICs.

DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened each record, assessed risk of bias using the Joanna Briggs Institute critical appraisal tool and extracted data. Results were illustrated using descriptive forest plots and a narrative synthesis.

RESULTS: Our systematic review included 14 studies, primarily from upper-middle-income countries, that assessed the relationship between individual ACEs and cognitive impairment (n=4) and function (n=10). 10 studies reported significant associations between ACEs and poorer cognitive function and increased risk of cognitive impairment. No study assessed the association between ACEs and ADRD. Parental death, neglect and mental health issues in the family showed consistent associations with cognitive outcomes, whereas experiencing hunger and poor health in childhood showed inconsistent associations.

CONCLUSIONS: Our review corroborated evidence from high-income countries that exposure to ACEs is associated with a long-term risk of poorer cognitive outcomes among older populations in LMICs. However, the available literature remains limited, with most studies originating from upper-middle-income countries, few examining cognitive impairment and none assessing ADRD. These findings underscore substantial gaps in knowledge and highlight the need for research across diverse LMIC settings to clarify the role of broader psychosocial and contextual childhood experiences in shaping cognitive ageing and dementia risk.

PROSPERO REGISTRATION NUMBER: CRD42024501816.},
}

Humans
*Developing Countries
*Adverse Childhood Experiences/statistics & numerical data
*Cognitive Dysfunction/epidemiology/etiology
Aged
*Cognition
Middle Aged
Dementia/epidemiology
Adult

@article {pmid41942332,
year = {2026},
author = {Kim, Y and Jung, J and Cirunduzi, AC and Yoon, S and Bang, S and Yang, SH},
title = {Inflammatory Signatures and Biomarkers: The Renal-Vesical Axis in Alzheimer Progression.},
journal = {International neurourology journal},
volume = {30},
number = {1},
pages = {3-10},
doi = {10.5213/inj.2652008.004},
pmid = {41942332},
issn = {2093-4777},
support = {RS-2024-00350442//Korea Health Industry Development Institute/Republic of Korea ; 2020R1F1A1076240//Korea Health Industry Development Institute/Republic of Korea ; 2021R1C1C1009743//Korea Health Industry Development Institute/Republic of Korea ; RS-2024-00507256//Ministry of Health and Welfare/ ; },
abstract = {Alzheimer disease (AD) has long been viewed as a disorder confined to the central nervous system. Accumulating evidence, however, indicates that systemic inflammation and peripheral organ dysfunction are closely linked to disease progression. Notably, the bladder and kidney have emerged as peripheral organs that respond sensitively to neuroinflammation and systemic inflammatory signaling. In this review, we synthesize current evidence supporting a bladder-kidney-brain axis in AD, with emphasis on inflammatory pathways that connect central neurodegeneration with peripheral organ responses. We categorize biomarkers reflecting functional alterations, cellular stress responses, and tissue injury in the bladder and kidney, highlighting mediators reported in both organs. Importantly, many of these biomarkers are measurable in serum and urine, offering accessible peripheral readouts of AD-associated systemic pathology. This integrated framework underscores the biological relevance of urological organs in AD progression and provides a conceptual basis for identifying peripheral signatures associated with early disease-related changes.},
}

@article {pmid41942439,
year = {2026},
author = {Ohya, T and Arakawa, R and Sakayori, T and Nogami, T and Uchiyama, S and Tateno, A},
title = {Tau accumulation increases the susceptibility to effective seizures of electroconvulsive therapy.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04016-3},
pmid = {41942439},
issn = {2158-3188},
abstract = {Electroconvulsive therapy (ECT) is a very valuable treatment for mood disorders. While previous studies have examined predictors of ECT responsiveness, there is a scarcity of neuroimaging studies examining these predictors. In previous studies, it has been reported that epilepsy is significantly more common in patients with Alzheimer's disease, and it has been suggested that tau accumulation is related to the susceptibility to seizures. Positron emission tomography (PET) with florzolotau (18 F) ([[18]F]PM-PBB3) allows accurate quantification of tau in the brain cortex. We therefore performed tau PET with florzolotau (18 F) in 14 patients with mood disorders undergoing ECT to determine whether there is a relationship between tau accumulation and susceptibility to ECT. As a result, we found that the more tau accumulates, the more likely it is to produce effective seizures in ECT. Although our study has some limitations, it is suggested that ECT would be the first choice for treatment of depression associated with degenerative pathology such as Alzheimer's disease because tau accumulation might enhance the therapeutic efficacy of ECT.},
}

@article {pmid41942574,
year = {2026},
author = {Ceylan, S and Çalışkan, ME and Çelik, N and Atalay, E},
title = {Differentiating Alzheimer's disease and vascular dementia via combined OCT and OCT‑angiography analysis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-47556-w},
pmid = {41942574},
issn = {2045-2322},
support = {1919B012222136//Scientific and Technological Research Council of Türkiye (TUBITAK)/ ; },
}

@article {pmid41942585,
year = {2026},
author = {Jahanbani, P and Hosseinzadeh, L and Mahmoudi, M and Jalilian, F and Eftekhari, M and Modarresi, M},
title = {Beyond the root: licorice (Glycyrrhiza glabra L.) fruit extract modulates oxidative stress and apoptotic markers in PC12 cells.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-46382-4},
pmid = {41942585},
issn = {2045-2322},
support = {4020639//Kermanshah University of Medical Sciences/ ; },
abstract = {The rising global prevalence of neurodegenerative disorders underscores the urgent need for novel therapeutic strategies. Oxidative stress is a well-established central driver in the pathogenesis of conditions like Alzheimer's and Parkinson's disease. While the root of Glycyrrhiza glabra L. (licorice) is a renowned source of natural antioxidants, its fruit remains a largely unexplored reservoir of bioactive compounds with potential neuroprotective properties. This in vitro study aimed to systematically evaluate the neuroprotective potential of different licorice fruit extracts and elucidate the underlying mechanisms against hydrogen peroxide (H2O2)-induced oxidative damage in PC12 neuronal cells. Different licorice fruit extracts were prepared sequentially with n-hexane, chloroform, ethyl acetate, methanol, and water by the maceration method. The protective effects of these extracts against H2O2-induced cytotoxicity were assessed using the MTT assay. Phytochemical profiling of the active ethyl acetate extract (EA extract) was performed using TLC, total flavonoid assay, and HPLC-DAD. EA extract exhibited the strongest protective activity. Pre-treatment with non-toxic concentrations of EA extract (12.5 and 25 µg/mL) significantly increased cell viability against H2O2 (IC50 = 70 µg/mL approximately 2.06 mM) by 33% and 38%, respectively. This extract possessed the highest total flavonoid content (50.08 ± 0.31 mg of quercetin equivalents per gram of dry extract) among all extracts, and HPLC-DAD analysis confirmed the presence of glabridin 27.75 ± 0.01 mg per gram of dry EA extract. EA extract also notably restored mitochondrial membrane potential, reduced caspase-3 activity, and decreased ROS production in H2O2-stressed cells. Our findings indicate that the ethyl acetate extract of licorice fruit attenuates H2O2-induced oxidative stress in PC12 cells, and its neuroprotective effect is likely associated with its high flavonoid content. Further research on licorice fruit may facilitate the discovery of novel therapeutic agents for oxidative stress-related disorders.},
}

@article {pmid41942685,
year = {2026},
author = {Lim, Z and Nguyen, HL and Zeng, Y and Qu, Q and Le, Y and Sun, M and Wang, X and Zhu, H and Qian, Y and Saeed, S and Wang, H and Rong, D and Wang, Y and Zhang, X and Hu, S},
title = {Life Cycle and Circadian Rhythms in Central Resident Immunity and Neuropsychiatric Pathology.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41942685},
issn = {1995-8218},
abstract = {The central resident immune system, commonly known as the glial system, comprises various glial cells that play a critical role in neuropsychiatric disorders. However, a systematic review exploring the relationships between the life cycles and daily rhythms of these immune cells and the pathological features of neuropsychiatric disorders is lacking. These immune cells exhibit unique developmental origins and circadian characteristics, resulting in rhythmic variations in functions such as phagocytosis, immune clearance, neurogenesis, and neurotransmitter recycling. These properties are crucial for understanding the pathological mechanisms underlying developmental disorders like major depressive disorder, autism spectrum disorder, and schizophrenia, as well as age-related conditions such as Alzheimer's and Parkinson's diseases. The daily rhythms of these immune cells correlate with diurnal variations in emotion, cognition, and motor function, involving shared processes like oxidative stress and neuroinflammation. This article systematically reviews the composition, life cycle changes, and circadian characteristics of central immune cells, highlighting their roles in neuropsychiatric diseases.},
}

@article {pmid41942725,
year = {2026},
author = {Neth, BJ and Huynh, K and Giles, C and Wang, T and Mellett, NA and Duong, T and Blach, C and Schimmel, L and Register, TC and Blennow, K and Zetterberg, H and Batra, R and Schweickart, A and Dilmore, AH and Martino, C and Arnold, M and Krumsiek, J and Han, X and Dorrestein, PC and Knight, R and Meikle, PJ and Craft, S and Kaddurah-Daouk, R},
title = {Author Correction: Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
doi = {10.1038/s43856-026-01571-0},
pmid = {41942725},
issn = {2730-664X},
}

@article {pmid41942750,
year = {2026},
author = {Haq, I and Ngo, JC and Roy, N and Lee, E and Choudhury, MA and Soni, RK and Teich, AF and Mayeux, RP and De Jager, PL and He, Y and Wu, X and Bennett, DA and Olah, M and Sher, F},
title = {Alzheimer's disease risk protein SorLA regulates ER homeostasis and lipid metabolism in human microglia, with conserved effects in neurons.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {41942750},
issn = {1432-0533},
support = {R01AG070118/NH/NIH HHS/United States ; },
mesh = {Humans ; *Lipid Metabolism/physiology ; *Microglia/metabolism ; *Neurons/metabolism ; *Alzheimer Disease/metabolism/pathology/genetics ; Homeostasis/physiology ; *Endoplasmic Reticulum/metabolism ; *Membrane Transport Proteins/metabolism/genetics ; *LDL-Receptor Related Proteins/metabolism/genetics ; Endoplasmic Reticulum Stress/physiology ; Brain/metabolism ; },
abstract = {Microglial dysfunction is a hallmark of Alzheimer's disease (AD), yet the molecular mechanisms driving these impairments remain poorly defined. Genetic studies implicate several AD-associated genes in regulating microglial activity, including SORL1, which encodes the sorting receptor SorLA. Although SorLA is highly expressed in microglia, its functional role in cellular homeostasis has remained unclear. Here, we investigated SorLA function using human brain tissue, primary microglia from rapid autopsies, and CRISPR-engineered human iPSC-derived microglia and neurons. Integrated multi-omics analyses, including single-cell RNA sequencing, lipidomics, and proteomics, together with biochemical and functional assays, revealed that SorLA deficiency induces endoplasmic reticulum (ER) stress and interferon signaling, promotes lipid droplet accumulation, and impairs phagocytic and immune functions. Protein co-complex mapping and structural modeling identified ER-associated proteins co-enriched with SorLA, including SUN2, calnexin (CANX), and multiple COPI complex components (COPA, COPB1, COPG1, ARCN1), implicating SorLA in ER proteostasis and intracellular trafficking. Notably, SORL1 deletion in iPSC-derived neurons recapitulated key phenotypes observed in microglia, including lipid droplet accumulation and SorLA-SUN2 co-immunoprecipitation, indicating that this ER-associated pathway operates across distinct brain cell types. Together, these findings identify an ER-related role for SorLA that extends beyond its established function in endocytic trafficking. Loss of SorLA triggers maladaptive stress responses, perturbs lipid handling, and compromises cellular resilience, thereby contributing to AD-relevant cellular dysfunction.},
}

Humans
*Lipid Metabolism/physiology
*Microglia/metabolism
*Neurons/metabolism
*Alzheimer Disease/metabolism/pathology/genetics
Homeostasis/physiology
*Endoplasmic Reticulum/metabolism
*Membrane Transport Proteins/metabolism/genetics
*LDL-Receptor Related Proteins/metabolism/genetics
Endoplasmic Reticulum Stress/physiology
Brain/metabolism

@article {pmid41942760,
year = {2026},
author = {Bernocchi, F and Bonomi, CG and Poli, M and Di Donna, MG and Terrinoni, A and Motta, C and Martorana, A},
title = {Opposing patterns of blood-brain barrier permeability and Alzheimer's disease biomarkers across APOE genotype.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {5},
pages = {},
pmid = {41942760},
issn = {1590-3478},
}

@article {pmid41942821,
year = {2026},
author = {Melikyan, ZA and Al-Darsani, Z and Jiang, L and Colcord, KA and Paganini-Hill, A and Bukhari, SA and Montine, TJ and Kawas, CH and Corrada, MM},
title = {Contribution of health history and neuropathologic changes to the likelihood of dementia in those with intermediate/high Alzheimer's pathology: findings from The 90 + Study.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {41942821},
issn = {1432-0533},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/pathology/epidemiology ; Aged, 80 and over ; Cross-Sectional Studies ; *Brain/pathology ; Longitudinal Studies ; *Dementia/pathology/epidemiology ; Aged ; },
abstract = {Although intermediate/high Alzheimer's Disease Neuropathologic Change (ADNC) is associated with dementia in many older adults, some remain cognitively normal and are often referred to as resilient to ADNC. We aim to examine health, lifestyle, and neuropathologic factors that distinguish older adults with dementia vs. normal cognition in the presence of intermediate/high ADNC. Participants were from The 90 + Study, a longitudinal study of aging in southern California. This cross-sectional analysis included participants with an intermediate/high ADNC on neuropathologic exam and normal cognition or dementia diagnosis on case conference. We analyzed 11 neuropathologic changes, both vascular and neurodegenerative, dichotomized as present/absent, and the total number of neuropathologies. To examine the association of health and lifestyle factors and neuropathologic changes (predictors) with cognitive diagnosis at consensus case conference, dementia vs. normal cognition, (outcome), we used logistic regression adjusted for demographics. Among 235 participants (mean age at death = 98 years, 70% women), 33% maintained normal cognition. Participants with heart disease (OR = 0.45; 95% CI = 0.25, 0.81) and hypertension (OR = 0.53; 95% CI = 0.29, 0.95) had lower likelihood of dementia. In contrast, participants with a history of transient ischemic attacks (OR = 3.00; 95% CI = 1.46, 6.18), Lewy Body Disease (OR = 2.73; 95% CI = 1.14, 6.58), hippocampal sclerosis (OR = 2.70; 95% CI = 1.06, 6.86), Limbic-predominant Age-related TDP-43 Encephalopathy neuropathologic change (OR = 2.80; 95% CI = 1.53, 5.12), and a high number of non-ADNCs (OR = 4.46; 95% CI = 2.01, 9.92) had higher likelihood of dementia. Arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, and microvascular lesions were not associated with dementia. In this study, the presence of neurodegenerative neuropathologic changes other than ADNC and the absence of hypertension distinguish oldest old individuals with dementia from those with normal cognition. Understanding mechanisms underlying normal cognition in those with ADNC may provide important clues to prevention and resilience to the effects of AD neuropathology.},
}

Humans
Female
Male
*Alzheimer Disease/pathology/epidemiology
Aged, 80 and over
Cross-Sectional Studies
*Brain/pathology
Longitudinal Studies
*Dementia/pathology/epidemiology
Aged

@article {pmid41942948,
year = {2026},
author = {Kouassi, KL and Ehoulan, FREA and Beuseize, AMR and Broh, NYC and Essoin-De Souza, ANT and Yeo, NS and Abbé, AS and Doumbia-Ouattara, M},
title = {Epidemiologic and clinical features of Alzheimer's disease: a hospital study based on the memory clinic in Abidjan, Côte D'ivoire, Sub-Saharan Africa.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04867-9},
pmid = {41942948},
issn = {1471-2377},
}

@article {pmid41943029,
year = {2026},
author = {Rashad, A and Hinrichs-Puladi, B and Wieker, H and Berens, J and Ulbrich, M and Röhrig, R and Hölzle, F and Reetz, K and Klein, M},
title = {Can supermicrosurgery treat Alzheimer's disease? - Current evidence and hope.},
journal = {Head & face medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13005-026-00615-z},
pmid = {41943029},
issn = {1746-160X},
}

@article {pmid41935184,
year = {2026},
author = {Lei, Y and Chen, Y and Guo, M and Patel, F and Bai, Y and Goo, B and Du, Q and Weintraub, NL and Lu, XY},
title = {Neuronal HDAC9: A key regulator of cognitive and synaptic aging, rescuing Alzheimer's disease-related phenotypes.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41935184},
issn = {1476-5578},
support = {AG076235//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG064895//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG083841//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG062166//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG076235//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG064895//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Epigenetic regulation is a key determinant of the aging process, and its dysregulation contributes to cognitive aging and increased vulnerability to Alzheimer's disease (AD). As major regulators of epigenetic processes, histone deacetylases (HDACs) have emerged as potential therapeutic targets for cognitive enhancement in neurodegenerative diseases. However, the distinct roles of individual HDAC isoforms remain to be defined. Here, we report that HDAC9 is specifically expressed in neurons of human and mouse brains, and its expression declines with age. HDAC9 deficiency impairs cognitive function and synaptic plasticity in young mice. Selective deletion of HDAC9 in hippocampal CA1 neurons also induces cognitive impairment. In contrast, overexpression of HDAC9 in forebrain glutamatergic neurons preserves cognitive function in aged mice. Moreover, HDAC9 is also downregulated in the brain of AD mouse models, whereas neuronal overexpression of HDAC9 alleviates AD-related cognitive and synaptic deficits and reduces Aβ deposition. Together, these findings suggest neuronal HDAC9 is necessary and sufficient for maintaining cognitive and synaptic functions in the context of aging and AD.},
}

@article {pmid41935248,
year = {2026},
author = {Basak, A and Erol, FMB and De Rosa, MC and Dong, Z and Ogbolu, V and Glover, HJ and Rausch, R and Hargus, G and Creus-Muncunill, J and Buchanan, H and Bai, Y and Su, Q and Chang, B and Adler, C and Flaherty, D and Ciener, B and Xiao, H and Reddy, H and Aime-Wilson, P and Reitz, C and Sleeman, MW and Altarejos, JY and Leibel, RL and Qiang, LO and Teich, AF and Doege, CA},
title = {Cellular signatures of melanocortin pathway genes across the locus coeruleus.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02287-x},
pmid = {41935248},
issn = {2051-5960},
}

@article {pmid41935326,
year = {2026},
author = {Jati, S and Taheri, S and Kal, S and Sinha, SC and Head, BP and Mahata, SK and Sahoo, D},
title = {AI guided discovery of a murine model of asymptomatic Alzheimer's disease.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02286-y},
pmid = {41935326},
issn = {2051-5960},
}

@article {pmid41935371,
year = {2026},
author = {Moftakhar-Bazkiaei, A and Farzaneh, M},
title = {Network-based Transcriptomic Profiling of Fetal Astrocyte Differentiation Reveals Therapeutic Targets for Neurodegenerative Disease.},
journal = {Current molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665240412373260224061022},
pmid = {41935371},
issn = {1875-5666},
abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Age-related Macular Degeneration (AMD), are marked by the progressive loss of specific neuronal populations. Astrocytes, the glial cells surrounding neurons, play a critical role in maintaining neuronal health by providing neurotrophic support, producing antioxidants, and clearing waste. Dysfunctional astrocytes contribute to disease progression, yet their developmental trajectory and molecular regulation remain incompletely understood.

METHOD: This study aims to computationally characterize transcriptional differences between fetal astrocytes and neural stem cell lines to identify key regulatory genes, pathways, and therapeutic targets relevant to astrocyte-linked neurodegeneration. Using microarray data and bioinformatics pipelines, 359 Differentially Expressed Genes (DEGs) were identified, including 249 upregulated and 110 downregulated transcripts.

RESULTS: Protein-Protein Interaction (PPI) network analysis revealed ten hub genes- COL1A1, TIMP1, LOX, COL6A1, COL6A3, COL5A1, CD44, LTBP2, ACTA2, and PLAU-central to extracellular matrix remodeling and cell adhesion. Drug-gene interaction analysis linked these genes to compounds such as Estradiol valerate, Retinoic acid, and Calcitriol, suggesting therapeutic relevance.

DISCUSSION: Enrichment analysis highlighted transcriptional regulation, apoptosis, and ECM-receptor interaction as dominant biological themes. Key miRNA-mRNA interactions, including hsa-miR-877-5p and hsa-miR-767-5p targeting LOX and COL6A3 were also identified.

CONCLUSION: Overall, this study integrates transcriptomic profiling, network modeling, and drug-gene interaction analysis to uncover astrocyte-specific molecular targets, offering a computational framework for therapeutic exploration in neurodegenerative disease.},
}

@article {pmid41935386,
year = {2026},
author = {Dhanawat, M and Malik, G and Wilson, K and Bhushan, B},
title = {Anti-alzheimer Drugs Development and Small Molecules: Mechanistic Understanding of the 5HT4 and 5-HT6 Receptor.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X428162260224193303},
pmid = {41935386},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) affects millions worldwide, yet currently approved therapies provide only symptomatic relief without altering disease progression. Increasing evidence shows that serotonergic dysfunction contributes to cognitive decline in AD, particularly through altera-tions in the 5-HT4 and 5-HT6 receptor pathways. Modulation of these receptors influences acetyl-choline release, APP processing, amyloid burden, and synaptic plasticity. This review summarizes the mechanistic roles of 5-HT4 and 5-HT6 receptors in AD pathology, highlights key structure-activity relationship (SAR) trends in ligand development, and evaluates clinical outcomes of recep-tor-targeted therapies. Recent work supports 5-HT4 agonists and 5-HT6 antagonists as promising candidates for cognitive enhancement and disease modification. However, challenges in target en-gagement, receptor selectivity, and clinical translation underscore the need for more refined drug-design strategies.},
}

@article {pmid41935406,
year = {2026},
author = {Sannemann, L and Gerards, M and Bohr, L and Brosseron, F and Escher, C and Kalthegener, F and Müller, T and Ramírez, A and Zeyen, P and Jessen, F and Rostamzadeh, A},
title = {Dementia risk factor assessment in a local Alzheimer's prevention population: a German cross-sectional, observational study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100556},
doi = {10.1016/j.tjpad.2026.100556},
pmid = {41935406},
issn = {2426-0266},
abstract = {BACKGROUND: The risk for dementia is to a significant extent driven by potentially modifiable factors. Prevention strategies are increasingly aiming at individually tailored risk reduction approaches, particularly in light of emerging Brain Health Services for dementia prevention (dBHS).

METHODS: The cross-sectional observational study "Individual Risk Profiling for Alzheimer's and Dementia Prevention" (INSPIRATION) assessed the individual risk factors of 162 participants of the local Cologne Alzheimer Prevention Registry and provided individual feedback on risk profiles during a single visit. We analysed the frequency and patterns of risk factors and explored their association with cognition and Alzheimer's disease (AD) plasma biomarkers.

FINDINGS: The most common risk factors in this population were obesity, non-adherence to a Mediterranean diet, low subjective sleep quality, subjective experience of stress, and hearing impairment. A principal component analysis (PCA) revealed six principal components (PC), which we labeled as (1) psychosocial factors, (2) blood pressure, (3) physical condition, (4) hearing impairment, (5) lifestyle, and (6) substance use. We found isolated associations between PCs, cognition, and AD plasma biomarkers.

INTERPRETATION: These findings provide initial insights into which risk factors may be most relevant and actionable for highly-educated and prevention-motivated populations likely to seek dBHS. Interventions addressing the domains of psychosocial factors, physical condition, and lifestyle may be particularly relevant to consider for a personally tailored risk reduction approach in comparable populations.

FUNDING: The study was funded by research funds of the Medical Faculty and the University Hospital Cologne, University of Cologne and the non-profit association Kölner Verein für seelische Gesundheit e.V.},
}

@article {pmid41935407,
year = {2026},
author = {Wu, J and Zhou, J and Shan, S and Tang, K and Zhu, L and Ying, J and Liu, X and Song, P},
title = {Global, regional, and national burden of dementia attributable to mood disorders: a comparative risk assessment study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100559},
doi = {10.1016/j.tjpad.2026.100559},
pmid = {41935407},
issn = {2426-0266},
abstract = {BACKGROUND: Mood disorders, particularly depressive and bipolar disorders, have emerged as potentially modifiable risk factors for dementia. However, the burden of dementia attributable to mood disorders remains unquantified. We aimed to quantify that burden among adults aged 45 years and older using a comparative risk assessment approach.

METHODS: A literature search was performed in PubMed, Embase, and MEDLINE to identify cohort studies that assessed the association between mood disorders and subsequent dementia from database inception to 9th April 2025. Random-effects models were used to derive pooled risk ratios (RRs). Assuming a 5-year lag between mood disorders and dementia onset, we calculated population attributable fractions (PAFs) and age-standardized disability-adjusted life year (DALY) rates (ASDRs) at global, regional, and national levels. Temporal trends in ASDR were analyzed using joinpoint regression to estimate average annual percentage change.

RESULTS: 77 articles were included. The pooled RR for all-cause dementia was 1.90 (95% confidence interval [CI]: 1.70, 2.12) for depressive disorders, and 3.10 (95% CI: 2.21, 4.35) for bipolar disorder. For dementia subtypes, depressive disorders showed an association with Alzheimer's disease (RR: 2.57, 95% CI: 2.05, 3.23), and bipolar disorder was associated with vascular dementia (RR: 3.67, 95% CI: 2.42, 5.57). In 2016, the global PAFs of dementia attributable to depressive disorders were 4.79% (95% CI: 3.19%, 6.58%) in males and 5.56% (95% CI: 3.56%, 7.84%) in females. PAFs for bipolar disorder were 1.22% (95% CI: 0.65%, 2.01%) in males and 1.34% (95% CI: 0.71%, 2.18%) in females. In 2021, the global ASDR of dementia attributable to depressive disorders was 89.61 (95% CI: 34.80, 192.24) per 100,000 population, while the global ASDR for bipolar disorder was 15.91 (95% CI: 5.56, 37.87) per 100,000 population.

CONCLUSION: Since mood disorders are a substantial contributor to dementia burden, integrating mental health management into public health policies is essential.},
}

@article {pmid41935590,
year = {2026},
author = {Wang, J and Mao, X and Zheng, R and Gao, H and Chen, G and Zhang, Y and Xu, M and Lin, Q and Nivar, J and Tao, YX and Sun, M and Cao, H and Zhang, J and Li, J},
title = {Chloride intracellular channel 4 contributes to Aβ-induced cognitive impairment in mice through the regulation of mitochondrial fission. CLIC4 promotes mitochondrial fission.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112499},
doi = {10.1016/j.cellsig.2026.112499},
pmid = {41935590},
issn = {1873-3913},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by impaired memory and cognitive decline. The early stages of AD in mice present with neuropathy in the hippocampus. Excessive mitochondrial fragmentation and dysfunction are critical pathological features of AD. Chloride intracellular channel 4 (CLIC4) is involved in neuronal apoptosis and regulates mitochondrial functions. Glial maturation factor β (GMFβ) inhibits mitochondrial DNA replication and energy metabolism, causes mitochondrial dysfunction, and regulates apoptosis. Dynamic related protein 1 (DRP1), a key protein in mitochondrial division, exhibits increased activity when its Ser616 site is phosphorylated. However, the role of CLIC4 in Aβ-induced cognitive impairment through the modulation of GMFβ and p-DRP1 (Ser616) to induce mitochondrial dysfunction remains unclear. This study examined the role of CLIC4 in Aβ-induced cognitive impairment in AD mice, focusing on its regulation of GMFβ and p-DRP1 (Ser616) and the subsequent effects on mitochondrial hyperfission and dysfunction. Our findings demonstrate that overexpression of CLIC4 in the mouse hippocampus or in HT22 cells resulted in pathological changes analogous to those observed following Aβ exposure. These changes include elevated levels of GMFβ and p-DRP1 (Ser616) proteins, mitochondrial fission, and increased intracellular ROS production. Conversely, CLIC4 knockdown mitigated Aβ-induced neuronal damage. These findings indicate that CLIC4 may be crucial in Aβ-induced hippocampal neurological damage in mice by regulating GMFβ and DRP1 phosphorylation.},
}

@article {pmid41935644,
year = {2026},
author = {Aumont-Rodrigue, G and Poirier, A and Picard, C and Poirier, J and , },
title = {Human APOB mice translates molecular phenotypes across the Alzheimer's disease spectrum.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106575},
doi = {10.1016/j.bbi.2026.106575},
pmid = {41935644},
issn = {1090-2139},
abstract = {BACKGROUND: Apolipoprotein B (APOB), a structural component of low-density lipoproteins (LDL), has historically been associated with peripheral lipid transport and cardiovascular disease. Recent studies have revealed a link between APOB and Alzheimer's disease (AD), with increased cerebrospinal fluid (CSF) APOB levels correlating with tau pathology. Although APOB is known to be locally expressed in the brain, albeit at very low levels, its function in the central nervous system and contribution to neurodegenerative processes remains poorly understood. To investigate the effects of chronic APOB overexpression on brain molecular homeostasis, we used a transgenic mouse model expressing human APOB-100 and integrated findings with human cohort data to assess its functional relevance to AD pathology.

METHODS: Human APOB transgenic (hAPOB) and wild-type mice were aged to 6 and 12 months. Frontal cortices were analyzed using RNA sequencing and mass spectrometry-based proteomics. Differentially expressed genes and proteins were analyzed via pathway enrichment and cell type deconvolution. Findings were contrasted to post-mortem proteomic alterations observed in brain tissue (ROSMAP) and in the CSF (ADNI).

RESULTS: hAPOB overexpression in mice induced a robust and persistent upregulation of innate immune genes, particularly those associated with type I interferon responses (Irf7, Ifit1, Oas2), in both young and old transgenic mice. Reduced microglial and endothelial cell signatures were observed through cell type deconvolution, which suggests immune activation without proliferation and possible blood-brain barrier damage. Proteomic analyses showed differentially expressed proteins associated with oxidative stress and dendritic remodeling. Proteins dysregulated in mice-such as CTSD, CRK, and SULT4A1-also showed altered expression in AD human brain and CSF. Remarkably, these proteins are dysregulated in the opposite direction in humans than in mice, unveiling a complex downstream regulation of APOB overexpression.

CONCLUSION: Chronic hAPOB overexpression drives sustained neuroinflammatory and oxidative responses, potentially mimicking viral-like immune activation in the brain. The proteins dysregulated in hAPOB transgenic mice brains were also dysregulated in humans on opposite side of the APOB level spectrum. Nevertheless, this result shows a consistency across species on hAPOB-driven downstream effects. Some of these proteins were also shown to associate with key features of AD pathology, namely Aβ, Tau and pTau. Our findings support a novel role for APOB in modulating brain immune homeostasis and neurodegenerative processes, offering a mechanistic link between vascular risk and Alzheimer's disease.},
}

@article {pmid41935672,
year = {2026},
author = {Hao, X and Wang, X and Liu, R and Li, Y and Dong, C and Liu, J},
title = {Amyloid pathology drives cognitive decline in Alzheimer's Disease through impairing neurovascular coupling: An [[18]F]-Florbetapir PET/MRI Study.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111863},
doi = {10.1016/j.brainresbull.2026.111863},
pmid = {41935672},
issn = {1873-2747},
abstract = {BACKGROUND: Neurovascular coupling (NVC) impairment is implicated in Alzheimer's disease (AD), but its relationship with amyloid-β (Aβ) pathology and diagnostic value remain unclear. We examined Aβ-related NVC changes and their mediating role in cognitive decline.

METHODS: Using [¹⁸F]-florbetapir PET/MRI, we assessed Aβ deposition, neural activity, and cerebral blood flow (CBF) in 96 participants (24 Aβ-negative mild cognitive impairment [MCI⁻], 30 Aβ-positive MCI [MCI⁺], and 42 Aβ-positive AD [AD⁺]). Neural activity was quantified using amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and degree centrality (DC). Multidimensional NVC was derived from spatial correlations between CBF and these neural activity metrics.

RESULTS: Global NVC progressively decreased (MCI⁻ > MCI⁺ > AD⁺). Compared to MCI⁻, the MCI⁺ group exhibited reduced NVC in default mode network hubs, including posterior cingulate gyrus, angular gyrus, and precuneus. These regional metrics demonstrated good diagnostic performance in distinguishing MCI⁺ from MCI⁻, with the combined model achieving an AUC of 0.935 and robust internal validation. The AD⁺ group showed extended impairment to frontal, visual, limbic, and subcortical areas compared to MCI⁺. Mediation analysis identified CBF-DC coupling in left posterior cingulate gyrus as a key mediator between Aβ burden and cognitive impairment for MMSE (β = -1.893, 95% CI: [-4.237, -0.253]) and MoCA (β = -2.614, 95% CI: [-5.472, -0.472]).

CONCLUSION: NVC impairment links Aβ pathology to cognitive decline, with the left posterior cingulate gyrus as a key region. This supports AD's neurovascular hypothesis in vivo and highlights NVC as a potential biomarker and target for early diagnosis and intervention.},
}

@article {pmid41935791,
year = {2026},
author = {Juanlu, C and Chen, PS},
title = {Transcriptomic Dissociation Between Synaptic Plasticity Suppression and Structure-Related Maintenance Signaling in the Alzheimer's Frontal Cortex: A Molecular Analysis.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116202},
doi = {10.1016/j.bbr.2026.116202},
pmid = {41935791},
issn = {1872-7549},
abstract = {BACKGROUND: Early Alzheimer's disease (AD) frequently presents with frontal lobe-related behavioral abnormalities, such as executive dysfunction and confabulation, despite minimal frontal cortical atrophy on neuroimaging. The molecular basis of this dissociation between behavioral dysfunction and preserved structure remains poorly understood.

METHODS: To address this paradox, we performed a transcriptomic re-analysis of postmortem frontal cortex samples from individuals with AD, vascular dementia (VaD), and cognitively normal controls (GSE122063). Gene set enrichment analysis was applied to interrogate functional pathways related to synaptic plasticity and structure-related maintenance pathways represented by the KEGG focal adhesion gene set.

RESULTS: In Alzheimer's disease, synaptic plasticity pathways were strongly negatively enriched in the frontal cortex (normalized enrichment score = -1.86, false discovery rate q < 0.001), whereas the KEGG focal adhesion pathway showed significant positive enrichment within the original GSEA framework (normalized enrichment score = 1.20, false discovery rate q = 0.17). This pattern indicates profound suppression of synaptic functional programs alongside relative preservation of structure-related maintenance signaling. In vascular dementia, frontal synaptic suppression was also observed but was less pronounced (normalized enrichment score = -1.48, false discovery rate q = 0.07).

CONCLUSIONS: These findings support a transcriptomic dissociation in the Alzheimer's frontal cortex in which synaptic dysfunction may emerge in the context of relative preservation of structure-related maintenance signaling. This framework may help explain early frontal behavioral impairment despite limited or delayed frontal cortical atrophy on neuroimaging. However, the focal adhesion pathway is biologically broad, and this significant enrichment signal related to structure-associated processes should therefore not be interpreted as a pure or exclusive measure of preserved cortical structural integrity.},
}

@article {pmid41935801,
year = {2026},
author = {Kong, L and Wu, Y and Zeng, H and Wu, R and Xu, X and Lu, Z and Zhang, W and Ma, C},
title = {The preclinical evidence and clinical translational prospects of medicarpin.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108183},
doi = {10.1016/j.phrs.2026.108183},
pmid = {41935801},
issn = {1096-1186},
abstract = {Medicarpin (MED) is an isoflavonoid compound derived from traditional Chinese medicine (TCM). Numerous preliminary experimental studies have shown that MED has significant pharmacological effects in the treatment of cancer, osteoporosis, osteoarthritis, Alzheimer's disease (AD), arthritis, and other diseases. However, the clinical application of MED has not yet been reported. Summarizing the preclinical drug research of MED is helpful for clarifying its pharmacological activities and evaluating its research prospects. In this review, we search for the preliminary experimental research of MED, encompassing pharmaceutics, pharmacodynamics, pharmacology, pharmacokinetics, clinical studies, and toxicology. A comprehensive review of the chemical synthesis and biosynthesis, biological activities, mechanisms, bioavailability, and clinical research of MED is conducted to systematically evaluate its safety, efficacy, and druggability. Ultimately, our work promotes the understanding of MED and facilitates its clinical translation and application.},
}

@article {pmid41936289,
year = {2026},
author = {Ullah, U and Habib, S and Islam, M},
title = {LADNET: An MRI-based deep learning approach for Alzheimer's disease detection.},
journal = {Computers in biology and medicine},
volume = {208},
number = {},
pages = {111647},
doi = {10.1016/j.compbiomed.2026.111647},
pmid = {41936289},
issn = {1879-0534},
abstract = {Alzheimer's disease (AD) is considered a leading form of dementia, found in the majority of individuals, and it accounts for the highest prevalence of all the types of dementia. It is a gradually progressing condition which can begin with mild memory impairment and may lead to the inability to engage in meaningful conversations in the future. In addition to that, it is also capable of reacting appropriately to the environment around it. According to official data, there has been an increase in reported cases of AD-related mortality in recent years, along with rising rates of the disease itself. Therefore, it is beneficial for patients to be diagnosed with AD as early as possible in order to maximize their chance of survival. In medical field, deep learning (DL) is employed in many applications, especially the identification of Alzheimer's disease, has shown considerable success. Based on the fact that these methods are capable of acquiring and extracting features from extensive datasets autonomously, they are highly suitable for analyzing intricate medical images with the aid of these methods. Design the Lightweight Alzheimer's Disease Net (LADNET) model for the current task. Accurate detection of AD using magnetic resonance imaging (MRI)-based scans is presented in this work. The model classifies the three dementia types, namely Mild Dementia (MD), Moderate Dementia (MDD), and Very Mild Dementia (VMD), while also accurately categorizing the non-demented (ND) category based on the severity of the condition. We measure the performance of the model we recommend against a publicly available Kaggle dataset that contains over six thousand images from four different types of images. LADNET model achieves 99.4% accuracy and 99% AUC, outperforming existing methods. With a lightweight design of approximately 1.2 million parameters and fast inference (4.2 ms per image), LADNET demonstrates strong potential for practical clinical deployment, where it could help extract biomarker information from conventional MRIs, potentially reducing patient burden and diagnostic costs.},
}

@article {pmid41936347,
year = {2026},
author = {Rirash, AF and Franzen, S and Bourdage, R and Kreuk, E and Visser, NC and Babulal, GM and van den Berg, E and Papma, JM},
title = {Barriers and facilitators to recruitment, engagement, and retention of underrepresented populations in dementia prevention research: a scoping review.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100557},
doi = {10.1016/j.tjpad.2026.100557},
pmid = {41936347},
issn = {2426-0266},
abstract = {Underrepresented populations in dementia prevention research, including minoritized racial/ethnic groups, individuals with lower socioeconomic status, and others facing social and structural disadvantages, are disproportionately affected by dementia risk. This scoping review examined barriers and facilitators to recruitment, engagement, and retention of these populations in Alzheimer's disease and related dementias (ADRD) prevention studies, synthesizing evidence from both empirical studies and review articles. Guided by PRISMA-ScR and the conceptual structure described by Gilmore-Bykovskyi et al., findings were synthesized from 19 reviews and 53 empirical studies. Findings were interpreted with attention to how overlapping factors-such as ethnicity, age, gender, and structural inequities-may influence study participation. Studies originated primarily from the United States (U.S.). Five key themes were identified: 1) mistrust, 2) stigma and limited research literacy, 3) logistical and financial constraints, 4) communication gaps and lack of team diversity, and 5) systemic-level barriers. Facilitators included culturally tailored outreach, long-term community partnerships, and inclusive study design. Retention strategies remain underreported, and little is known about the non-U.S. context. These findings highlight the need for context-specific, multi-level strategies that address the intersecting barriers faced by underrepresented groups to support equitable participation in dementia prevention research, and ultimately, dementia prevention.},
}

@article {pmid41936348,
year = {2026},
author = {Shimasaki, R and Kurihara, M and Bannai, T and Hatano, K and Suzuki, F and Tokumaru, AM and Ishii, K and Ihara, R and Iwata, A},
title = {Amyloid-related imaging abnormalities in Japanese patients with Alzheimer's disease treated with Lecanemab: A real-world study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100562},
doi = {10.1016/j.tjpad.2026.100562},
pmid = {41936348},
issn = {2426-0266},
abstract = {BACKGROUND: Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice.

OBJECTIVES: This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting.

DESIGN: A real-world observational study with a follow-up period of up to 18 months.

SETTING: A single center in Japan.

PARTICIPANTS: We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion.

MEASUREMENTS: Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation.

RESULTS: The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8).

CONCLUSION: In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy.},
}

@article {pmid41936465,
year = {2026},
author = {Zhang, H and Liu, X and Lyu, D and Hou, T and Xue, F and Du, Y},
title = {Association of Cardiovascular-Kidney-Metabolic Health With Structural Brain Imaging and the Risk of Specific-Cause Dementia: A Cohort Study.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.03.205},
pmid = {41936465},
issn = {1545-7214},
abstract = {OBJECTIVES: CKM syndrome may represent the coexistence of multiple risk factors for dementia; however, its large sample-based effects on the risk of specific-cause dementia and the alterations revealed by brain imaging remain unclear.

MEASUREMENTS: The 239,617 dementia-free participants from the UK Biobank were included in this study. Multivariate Cox regression analyses and stratifications were used to assess longitudinal associations. Linear regression analyses were employed to evaluate CKM-brain structure links. Sensitivity and Mendelian randomization (MR) analyses were performed to confirm the robustness of the results.

RESULTS: Over a 13.6-year median follow-up duration, 3,503 participants developed dementia that included 1,526 Alzheimer's disease (AD) and 770 vascular dementia (VaD) cases. Advanced CKM syndrome stages showed a dose-dependent risk of dementia: stage 3 (Hazard Ratio [HR] = 1.74 versus stage 0, χ² = 19.92, df = 1, p <0.001) and stage 4 (HR = 1.92, χ² = 38.52, df = 1, p <0.001). This pattern held for VaD but not AD, although CKM syndrome stage progression elevated the risk of AD by 130%. MR analysis confirmed significant associations. As a component of the CKM syndrome, metabolic disorders (MD) (abdominal obesity and metabolic syndrome) significantly elevated the risk of VaD but not that of AD. Notably, midlife adults, women, non-APOEε4 carriers, and those displaying low physical activity and education exhibited heightened susceptibility to dementia. Further, there was a spatial correlation pattern between CKM syndrome and brain atrophy (imaging biomarker of dementia): early sensorimotor-limbic shrinkage expanded to prefrontal-parietal and posterior cingulate regions, culminating in hippocampal degeneration.

CONCLUSIONS AND IMPLICATIONS: CKM syndrome stages may serve as a comprehensive predictor of dementia. Individualized monitoring of CKM factors across the lifespan of a person may mitigate progressive neurodegeneration and the risk of dementia.},
}

@article {pmid41936484,
year = {2026},
author = {Ho, A and Ngala, B and Yamada, C and Garcia, C and Duarte, C and Akkaoui, J and Ciolac, D and Nusbaum, A and Kochen, W and Efremova, D and Groppa, S and Nathanson, L and Bissel, S and Oblak, A and Kacena, MA and Movila, A},
title = {Corrigendum to "IL-34 exacerbates pathogenic features of Alzheimers disease and calvaria osteolysis in triple transgenic (3x-Tg) female mice" [Biomed. Pharmacother. 166 (2023) 115435].},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {119293},
doi = {10.1016/j.biopha.2026.119293},
pmid = {41936484},
issn = {1950-6007},
}

@article {pmid41936849,
year = {2026},
author = {Pavanello, C and Ossoli, A and Comi, C and Turri, M and Tremolizzo, L and Conti, E and D'Incecco, P and Barbiroli, A and Parini, P and Mitro, N and Caruso, D and Sierri, G and Re, F and Chinello, C and Fumagalli, C and Magni, F and Fernandes, K and Calabresi, L},
title = {Cerebrospinal fluid CEFA composition is enriched in saturated fatty acids and it is altered in Alzheimer's Disease.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {101034},
doi = {10.1016/j.jlr.2026.101034},
pmid = {41936849},
issn = {1539-7262},
abstract = {Cholesterol esterification is a fundamental step in cholesterol metabolism and transport, and in humans it is operated by three enzymes. Lecithin:cholesterol acyltransferase (LCAT) is responsible of cholesterol esterification in plasma and other biological fluids including cerebrospinal fluid (CSF), where it is mainly activated by apolipoprotein E. Esterification of cholesterol within cells is instead operated by sterol O-1 and O-2 acyltransferases (SOAT1 and SOAT2). SOAT1 is expressed in all cell types, while SOAT2 is expressed in hepatocytes and enterocytes, where it produces cholesteryl esters (CEs) to be assembled within VLDL and chylomicrons. LCAT and SOAT1/2 have different substrate specificity; LCAT has a preference for the unsaturated fatty acids, while the SOAT enzymes prefer the saturated and monounsaturated fatty acids. Here we show that CSF CEs have a different composition compared to plasma CEs and specifically are more enriched in saturated and monounsaturated fatty acids, typical substrates of the SOAT2 enzyme, and less frequently used by LCAT. Protein and RNA analysis in astrocytes, the main lipoprotein-producing cells in the central nervous system, excluded the presence of SOAT2, thus suggesting that CSF CEs are product of the LCAT enzyme. In line with this hypothesis, CSF phosphatidylcholine, the substate of LCAT, is enriched in saturated and monounsaturated fatty acids and depleted in polyunsaturated fatty acids. Moreover, we show that in AD patients, CSF CEs are enriched in saturated fatty acids, thus adding new insights into our recent observation that LCAT-mediated cholesterol esterification is hampered in AD. In conclusion, the present findings not only clarify the enzymatic origin of CSF CEs but also open avenues for developing enzyme-specific biomarkers and therapeutic strategies aimed at restoring lipid homeostasis in the brain.},
}

@article {pmid41936874,
year = {2026},
author = {Wang, YX and Zhou, XW and Du, WR and Qin, SH and Zhang, CY and Ma, ZY},
title = {Novel 2-aminopyrimidine carboxamide derivatives as potential anti-Alzheimer's disease agents: Design, synthesis, biological activity and computational simulation evaluation.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130650},
doi = {10.1016/j.bmcl.2026.130650},
pmid = {41936874},
issn = {1464-3405},
abstract = {In this study, a series of 2-amino-5-formamidopyrimidine derivatives were designed and synthesized. Their potential as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD) were evaluated by the Ellman method. Meanwhile, the antioxidant activity of these compounds were assessed by the DPPH (2,2-diphen-yl-1-picrylhydrazyl) free radical scavenging assay. The cholinesterase (ChE) inhibition test showed that most compounds exhibited excellent to moderate inhibitory effects on acetylcholinesterase (AChE), while most of them did not show significant inhibitory effects on butyrylcholinesterase (BuChE), demonstrating significant selectivity. Among them, compound 9 s (AChE: IC50 = 1.60 μM) whose AChE inhibitory activity is superior to the positive control galantamine (AChE: IC50 = 5.10 μM) is the most promising representative compound. Meanwhile, compound 9 s has high selectivity with a SI (IC50 ratio of BuChE to AChE) value of 29.85. The results of enzyme kinetics study determined that compound 9 s was a mixed-type inhibitor. Additionally, the molecular docking studies results indicated that compound 9 s could simultaneously interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, which was consistent with the results of the enzyme kinetics experiments. Molecular dynamics (MD) simulation study further verified the stability of the 9 s-AChE complex. In addition, the DPPH radical scavenging assay indicated that these compounds also possessed relatively weak antioxidant activities. Among them, compound 9p exhibited the best antioxidant activity with an IC50 value of 113.93 μM, which was lower than that of the positive control ascorbic acid (IC50 = 41.17 μM). Overall, these experimental results suggested that compound 9 s as AChE inhibitor had potential value for further research.},
}

@article {pmid41936902,
year = {2026},
author = {Li, X and Feng, X and Cai, A and Guo, X and Li, J and Liao, W and Long, H and Luan, P},
title = {Research Progress on Carotid Artery Changes and Cognitive Impairment in Alzheimer's Disease Patients.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103127},
doi = {10.1016/j.arr.2026.103127},
pmid = {41936902},
issn = {1872-9649},
abstract = {This article aims to comprehensively analyze the vascular factors in Alzheimer's Disease (AD), particularly the changes in the carotid arteries, and their complex correlations with hippocampal atrophy and cognitive function. Besides the traditional β-amyloid protein (Aβ) and Tau protein hypotheses, vascular factors are increasingly regarded as crucial factors in the development of AD. This article systematically reviews the roles of cerebral blood flow perfusion changes and micro-infarctions in the vascular pathophysiological processes during the progression of AD, and focuses on how thickening of the carotid intima-media thickness (IMT) and plaque formation in large vessels affect cerebral perfusion, thereby accelerating the deterioration of cognitive function (measured by the Montreal Cognitive Assessment (MoCA) score and the Mini-Mental State Examination (MMSE) score). Through the integration and analysis of existing literature and research data up to 2025, it is found that a large number of basic and clinical studies have confirmed the close connection between carotid artery changes and AD, but there is still a significant evidence gap regarding the association between carotid artery changes and the hippocampal region related to cognition.},
}

@article {pmid41933197,
year = {2026},
author = {Tabuena, DR and Jang, SS and Grone, B and Yip, O and Aery Jones, EA and Blumenfeld, J and Liang, Z and Mann, RS and Li, Y and Necula, D and Koutsodendris, N and Rao, A and Ding, L and Zhang, AR and Hao, Y and Xu, Q and Yoon, SY and De Leon, S and Huang, Y and Zilberter, M},
title = {Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer's disease pathogenesis.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41933197},
issn = {2662-8465},
support = {R01AG061150//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG087323//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG092390//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; F32AG085961//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG055682//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG071697//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01AG073082//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {The full impact of APOE4 (apolipoprotein E4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal and network function remains unclear, particularly during early preclinical stages of disease. Here we show that young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability that predicts later cognitive deficits. This early phenotype arises from cell-type-specific subpopulations of smaller, hyperexcitable neurons and is eliminated by selective removal of neuronal APOE4. With aging, E4-KI mice develop granule cell hyperexcitability, progressive inhibitory dysfunction and excitation-inhibition imbalance in the dentate gyrus. Single-nucleus RNA sequencing with multilevel gene filtering reveals age-dependent and cell-type-specific transcriptional changes and identifies candidate mediators of early neuronal hyperexcitability, including Nell2. Targeted CRISPR interference knockdown of Nell2 rescues abnormal excitability, implicating Nell2 as a contributor to APOE4-driven dysfunction. Together, these findings define molecular and circuit mechanisms linking neuronal APOE4-induced early network impairment to AD pathogenesis with aging.},
}

@article {pmid41933339,
year = {2026},
author = {Huang, N and Hong, R and Cui, X and Cao, L and Shi, L and Chen, B and Su, Y and Xu, X and Hua, C and Ying, T},
title = {Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04297-2},
pmid = {41933339},
issn = {1477-3155},
support = {82272018//the National Natural Science Foundation of China/ ; ynnkxzd202404//Shanghai Sixth People's Hospital Institutional Brain Science and Brain-Inspired Research Project/ ; },
abstract = {BACKGROUND: Impaired clearance of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). Although histone deacetylase (HDAC) inhibitors show therapeutic potential, their clinical translation for AD is hampered by poor blood brain barrier (BBB) penetration and an incomplete understanding of their mechanism in Aβ clearance. Here, angiopep2-conjugated nanoparticles (SAHA@LIPO-ANG2) for efficient BBB translocation and delivery of the HDAC inhibitor vorinostat (SAHA) was developed and its underlying mechanisms were validated.

RESULTS: Our result demonstrates that SAHA@LIPO-ANG2 potently inhibits HDAC4 nuclear translocation, which was identified as a key upstream event responsible for the transcriptional repression of sodium-hydrogen exchanger 6 (NHE6). Restoration of NHE6 expression rectifies endosomal hyperacidification, thereby rescuing the trafficking and plasma membrane expression of the Aβ clearance receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Furthermore, this HDAC4-NHE6-pH axis modulates the neuroimmune microenvironment to enhance Aβ clearance through multiple synergistic mechanisms: it upregulates phagocytic receptors and recruit microglial to phagocytize Aβ plaques, while concurrently reactivating autophagy-lysosomal function in astrocytes by increasing LAMP2 expression. Consequently, treatment with SAHA@LIPO-ANG2 in 5xFAD mice significantly reduced Aβ burden, suppressed neuroinflammation, rescued synaptic loss, and ultimately reversed cognitive deficits.

CONCLUSIONS: Our study not only elucidates a HDAC4-NHE6-pH regulatory axis in AD pathogenesis but also establishes a multifaceted nanotherapeutic strategy for restoring Aβ homeostasis. Our findings may provide therapeutic strategies for treating amyloid-related diseases.},
}

@article {pmid41933395,
year = {2026},
author = {Bayram, E and Carter, DJ and Aslam, S and Forbes, E and Holden, SK},
title = {Sex differences for clinical presentations and co-pathologies in four-repeat tauopathies.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00899-5},
pmid = {41933395},
issn = {2042-6410},
support = {R00AG073453/AG/NIA NIH HHS/United States ; Private donation//University of Colorado/ ; },
abstract = {BACKGROUND: Four-repeat (4R)-tauopathies cause variable clinical profiles leading to clinical misdiagnosis. While sex differences are reported in Alzheimer's disease (AD), Lewy body disease (LBD), and clinically-defined frontotemporal dementia (FTD), little is known in 4R-tauopathies.

METHODS: National Alzheimer's Coordinating Center data were used for pathologically-defined 4R-tauopathies: progressive supranuclear palsy (PSP, n = 175), corticobasal degeneration (CBD, n = 114), argyrophilic grain disease (AGD, n = 230), Other-4R (n = 67). Sex differences for clinical presentation and co-pathologies were assessed adjusting for age and multiple comparisons.

RESULTS: Most common clinical diagnosis was PSP (41%) for PSP; unspecified FTD (36%) for CBD; AD for AGD (57%) and Other-4R groups (48%), without sex differences. Females had less cognitive decline, apathy, motor symptoms; were older at cognitive, behavioral change onset. Males were more likely to demonstrate LBD co-pathology and clinical profile.

CONCLUSION: Both females and males have low clinical diagnostic accuracy for 4R-tauopathies. Females with 4R-tauopathies may experience less severe clinical presentations and less co-pathology.},
}

@article {pmid41933660,
year = {2026},
author = {Wang, Y and Bao, G and Li, H and Li, X and Lv, L},
title = {The Role of Non-Coding RNA-Mediated Autophagy in Alzheimer's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111860},
doi = {10.1016/j.brainresbull.2026.111860},
pmid = {41933660},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and one of the leading causes of dementia, imposing a profound burden on patients, families, and healthcare systems worldwide. Autophagy, an evolutionarily conserved lysosomal degradation pathway critical for maintaining cellular homeostasis, removes damaged organelles and misfolded proteins, thereby preserving metabolic balance and enabling intracellular biomolecule recycling. Growing evidence indicates that dysfunctional autophagy contributes to AD pathogenesis. Concurrently, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of AD pathology, particularly through mechanisms involving autophagy. These ncRNAs not only play a role in disease progression but also represent promising molecular targets for therapeutic intervention via autophagy modulation. This review systematically explores the regulatory networks through which ncRNAs influence autophagy in AD, with the goal of identifying potential therapeutic targets and offering a conceptual framework to guide clinical translation.},
}

@article {pmid41933683,
year = {2026},
author = {Chen, W and Su, F and Kong, H and Wang, Y and Yi, C and Zheng, Y and Fang, Y and Shi, X and Lin, Y and Zhou, J and Zhang, X and Pei, Z},
title = {APOE genotype and astrocyte activity collectively influence AD biomarkers and Aβ burden.},
journal = {Brain research},
volume = {1883},
number = {},
pages = {150283},
doi = {10.1016/j.brainres.2026.150283},
pmid = {41933683},
issn = {1872-6240},
abstract = {BACKGROUND: The apolipoprotein E ε4 (APOE ε4), a well-established genetic risk factor for Alzheimer's disease (AD), is deeply involved in amyloid-β (Aβ) and tau pathology. Blood-based biomarkers (BBMs), including Aβ42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL), offer accessible proxies of AD pathology. Reactive astrocytes, indicated by elevated GFAP, are increasingly recognized as key players in AD progression. However, how astrocyte reactivity interacts with APOE genotype to shape BBMs and Aβ deposition remains unclear.

METHODS: We included 283 participants across the cognitive spectrum including cognitively unimpaired (CU), mild cognitive impairment (MCI), and all-cause dementia (ACD) from Guangzhou health aging and dementia cohort. Primary outcome measures were plasma biomarkers (Aβ42/40 ratio, p-tau181, GFAP, and NfL) and amyloid PET standardized uptake value ratio (SUVR). Participants were stratified by APOE ε4 carrier status and astrocyte activation. Group comparisons, correlation analyses, and sensitivity analyses were performed.

RESULTS: Stage-dependent APOE effects were observed: while modulating Aβ42/40 ratios in both CU and MCI, APOE influenced p-Tau181 only in MCI, exclusively under Ast-. SUVR was significantly higher in APOE ε4 + group at MCI stage, particularly in Ast- cases. Intriguingly, p-Tau/Aβ42 showed strong SUVR correlations across all subgroups except APOE ε4- Ast- group.

DISCUSSION: Our findings indicate that astrocyte reactivity is associated with differences in how APOE ε4 relates to both peripheral BBMs and central Aβ deposition, supporting an interplay between genetic risk and neuroinflammatory states in AD pathogenesis.},
}

@article {pmid41933684,
year = {2026},
author = {Younis, M and Vints, WAJ and Kušleikienė, S and Helsper, S and Himmelreich, U and Česnaitienė, VJ and Masiulis, N and Levin, O and Bautmans, I},
title = {Neural correlates of handgrip strength asymmetry in normal aging and older adults with mild cognitive impairment.},
journal = {Brain research},
volume = {},
number = {},
pages = {150299},
doi = {10.1016/j.brainres.2026.150299},
pmid = {41933684},
issn = {1872-6240},
abstract = {BACKGROUND: Handgrip strength asymmetry (HGS-A) has emerged as a potential non-invasive biomarker reflecting cognitive and neural vulnerability in older adults, yet the neural mechanisms linking asymmetry with cognitive decline remain incompletely characterized. This study aimed to determine the relationships between HGS-A, cognitive function, and regional cortical thickness in healthy older adults and individuals with mild cognitive impairment (MCI).

METHODS: Sixty-eight community-dwelling adults aged 60-85 (42 cognitively healthy, 26 MCI) underwent bilateral handgrip strength assessment using Jamar dynamometry. Cognitive evaluations included global cognition (MoCA) and domain-specific functions (ANAM4 battery). Structural MRI was performed, and cortical thickness was quantified from T1-weighted images within regions affected in MCI and Alzheimer's disease. Associations between HGS-A, cognitive performance, and cortical thickness were examined using partial correlation analyses adjusted for age and sex.

RESULTS: In cognitively healthy participants, greater handgrip strength asymmetry within normal limits (<15%) significantly correlated with higher global cognitive scores (MoCA; r = 0.32, p = 0.043) and increased cortical thickness in the left postcentral gyrus (r = 0.52, p < 0.001; FDR-corrected). Conversely, these relationships were absent in participants with MCI and in those exhibiting high asymmetry levels (≥15%). Domain-specific cognitive tasks showed no significant associations with HGS-A in either group. Exploratory analyses suggested an inverted U-shaped relationship, where both minimal and excessive asymmetry reflect worse cognitive function.

CONCLUSIONS: Handgrip strength asymmetry within normal limits (<15%) is linked to better cognition and cortical integrity, whereas both minimal and excessive asymmetry may reflect reduced cognitive function in older adults.},
}

@article {pmid41933799,
year = {2026},
author = {Huang, Q and Lv, Y and Ye, X and Xia, X and Chen, Y and Wang, X and Tong, F and Yang, W and Bozorov, K and Shevtsov, M and Li, H and Gao, H and Ye, B},
title = {Engineered microglial membrane-coated polydopamine-based nanomedicine for precise treatment of Alzheimer's disease.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114896},
doi = {10.1016/j.jconrel.2026.114896},
pmid = {41933799},
issn = {1873-4995},
abstract = {Multimodal treatment for Alzheimer's disease (AD) is a pivotal option because of its complex pathogenesis. The major challenge of pharmacotherapies is effective drug delivery to the diseased brain and reduction of associated toxicity. Here, we propose a dual-target nanomedicine (PDA@R@M/K) for the management of AD by coating engineered microglial cell membrane (M/K) onto polydopamine (PDA) cores encapsulated with rivastigmine. M/K conferred nanoparticles (NPs) with reduced circulation clearance, pathological blood-brain barrier recognition, and enhanced brain inflammation chemotaxis. PDA cores not only acted as potent ROS scavengers to alleviate neuroinflammation but also piggybacked rivastigmine and implemented responsive release. After applying PDA@R@M/K in preclinical transgenic mouse models, amyloid plaque deposition, neurologic changes, and cognitive decline were largely rescued. These results provide the possibility of directly using NPs as therapeutics rather than merely as nanocarriers, and demonstrate the feasibility of engineered microglia membrane-coated NPs to improve the pharmacokinetics and efficacy of anti-AD drugs.},
}

@article {pmid41933838,
year = {2026},
author = {Zhang, N and Andresen, J and Janzi, S and Glans, I and Samuelsson, J and Nägga, K and Borné, Y and Palmqvist, S and Hansson, O and Sonestedt, E},
title = {Free sugar intake and dementia risk: a Swedish cohort study on dietary sources and dementia subtypes.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101518},
doi = {10.1016/j.tjnut.2026.101518},
pmid = {41933838},
issn = {1541-6100},
abstract = {BACKGROUND: Dementia is a growing public health concern, and while diet is a modifiable potential risk factor, the role of free sugar intake remains unclear. Excess sugar has been linked to metabolic and cardiovascular dysfunction, both associated with cognitive decline, but evidence regarding specific sugar sources is limited.

OBJECTIVE: We aimed to investigate the associations between free sugar intake, its dietary sources, and the risk of all-cause dementia, Alzheimer's disease, and vascular dementia, and to assess potential modification by APOE ε4 status.

METHODS: We included 27,786 participants without dementia at baseline (mean age: 58 years; 61% women) from the Malmö Diet and Cancer Study, a population-based prospective cohort. Dietary intake was assessed using a validated diet history method. Dementia diagnoses were obtained from national registers through and validated by memory clinic physicians. During a median follow-up of 25 years, 3,224 participants (11.6%) were diagnosed with dementia.

RESULTS: Free sugar intake was not significantly associated with all-cause dementia or Alzheimer's disease. However, a U-shaped association was observed for vascular dementia, with moderate intake (10-12.5% of energy) associated with lower risk (HR: 0.70, 95% CI: 0.52-0.95). Sugar-sweetened beverage intake showed no association with dementia risk. High chocolate intake was associated with lower risks of all-cause (HR for Q5 vs Q1: 0.81, 95% CI: 0.72-0.91) and vascular dementia (HR for Q5 vs Q1: 0.68, 95% CI: 0.50-0.92), while high jam/marmalade intake was linked to a lower risk of all-cause dementia (HR: 0.86, 95% CI: 0.77-0.97 for >10 servings/week vs <0.5 servings/week). No significant interactions with APOE ε4 status were observed.

CONCLUSIONS: Free sugar intake was not associated with overall dementia risk, but moderate intake may reduce the risk of vascular dementia. These findings suggest that future dietary guidelines for cognitive health should consider not only sugar quantity but also its food source.},
}

@article {pmid41933844,
year = {2026},
author = {Wang, L and Gao, Y and Lu, J and Jiang, Q and Wang, H and Dong, F and Zhao, Q and Guan, Y and Qi, X and Zuo, C and Yu, J and Jiang, J},
title = {Individual gray-white matter functional connection predicts tau spread and cognitive decline in Alzheimer's disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121904},
doi = {10.1016/j.neuroimage.2026.121904},
pmid = {41933844},
issn = {1095-9572},
abstract = {PURPOSE: Alzheimer's disease is characterized by progressive accumulation of hyperphosphorylated tau protein, which propagates in a prion-like manner along connected neuronal pathways. However, it remains unclear whether functional connectivity between gray and white matter (FCGW) can predict tau spread. This study aimed to determine the association between FCGW and tau deposition and to evaluate its value in predicting longitudinal tau spread.

METHODS: We integrated resting-state fMRI with cross-sectional and longitudinal tau-PET data from two independent cohorts. We assessed baseline associations between FCGW and tau deposition and then constructed an individual-level spreading model to predict longitudinal tau accumulation.

RESULTS: In both cohorts, FCGW showed a positive correlation with tau deposition. Model-simulated white-matter tau deposition was associated with clinical scales and predicted cognitive decline. The spreading model, which incorporated baseline tau-PET and the top 10% of gray and white matter, yielded the highest predictive performance for future tau accumulation.

CONCLUSION: FCGW captures key network pathways underlying tau spread in AD and improves prediction of future tau accumulation. These findings highlight the importance of FCGW in understanding tau propagation and support development of network-targeted therapeutic strategies.},
}

@article {pmid41933850,
year = {2026},
author = {Li, D and He, J and Liu, B and Zhu, L and Yang, Y and Peng, Y and Nie, L and Wang, R},
title = {Multimodal Radiomics of Precisely Segmented Hippocampal Subfields: Iron Deposition and Structural Biomarkers for Early Diagnosis of Alzheimer's Disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121900},
doi = {10.1016/j.neuroimage.2026.121900},
pmid = {41933850},
issn = {1095-9572},
abstract = {Profiling imaging biomarkers of prodromal Alzheimer's disease (AD) against AD dementia may aid earlier diagnosis, yet approaches jointly capturing iron-related pathology and hippocampal subfield heterogeneity remain scarce. We developed a hippocampal-subfield multimodal radiomics framework integrating quantitative susceptibility mapping (QSM) and 3D T1-weighted MRI. A primary cohort of 92 participants (50 prodromal AD, 42 AD dementia) and an independent external cohort of 30 (15/15) were included. Twenty-four hippocampal subfields were segmented on super-resolution T1 images and propagated to co-registered QSM for feature extraction. Radiomic features were condensed into a radiomics score (Rad-score) via a training-only selection pipeline. Using the Rad-score as the sole predictor, a support vector machine (SVM) classifier was trained. On the external cohort, the SVM achieved an area under the receiver operating characteristic curve of 0.85 and an accuracy of 0.83. The predictive signature was dominated by QSM texture features in Cornu Ammonis 1 and the granule cell layer of the dentate gyrus, complemented by T1 first-order heterogeneity. Modality ablation suggested potential-but not definitive-complementarity of multimodal integration. This framework shows promise for AD stage classification and warrants further validation in larger independent cohorts.},
}

@article {pmid41933902,
year = {2026},
author = {Pinkwart, K and Lang, T},
title = {Clustering hinders APP α-secretase processing in the plasma membrane.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.03.061},
pmid = {41933902},
issn = {1542-0086},
abstract = {Alzheimer's disease (AD) is associated with the extracellular accumulation of neurotoxic Aβ-peptides in the brain. Aβ-peptides are produced via an amyloid precursor protein (APP) cleavage pathway that is initiated by the β-secretase. The majority of APP circumvents the amyloidogenic pathway due to α-secretase cleavage at the plasma membrane. In this study, we set out to identify potential mechanisms limiting α-cleavage. We employed isolated cell membranes to study α-secretase cleavage in the absence of APP delivery to the plasma membrane and internalization. We distinguish a readily cleavable and a cleavage-resistant APP pool. The cleavage-resistant and most likely immobile APP pool is organized in clusters and by this could escape the amyloidogenic pathway. In sum, our results identify that α-secretase cleavage at the plasma membrane occurs rapidly though in an incomplete manner due to the presence of cleavage-resistant APP clusters.},
}