@article {pmid42670179,
year = {2026},
author = {Yang, S and Liu, Q and Wang, M and Zhang, Y},
title = {Music and Exercise in Concert: Uncovering Synergistic Mechanisms for Enhancing Brain Health and Cognitive Resilience-A Narrative Review.},
journal = {Brain and behavior},
volume = {16},
number = {9},
pages = {e71735},
pmid = {42670179},
issn = {2162-3279},
support = {23D039//Hubei Provincial Department of Education/ ; },
mesh = {Humans ; *Brain/physiology ; *Exercise/physiology/psychology ; *Cognition/physiology ; Neuronal Plasticity/physiology ; *Music/psychology ; Cognitive Enhancement ; *Resilience, Psychological ; Animals ; },
abstract = {AIM: As the cornerstone of cognition, emotion, and social well-being, brain health faces escalating threats from aging, neurodegenerative diseases, and sedentary lifestyles. Non-pharmacological interventions have attracted growing interest owing to their favorable safety profiles and potential for widespread implementation. This review aims to examine the individual and synergistic effects of music and exercise on brain health.

METHODS: This narrative review integrates literature identified through searches of PubMed and Web of Science using terms related to music, exercise or physical activity, and brain health and offers a concept-driven synthesis of the underlying neurobiological mechanisms and potential combined effects.

FINDINGS: Music modulates neurotransmitters and neural oscillations via reward and emotion networks, while exercise enhances neuroplasticity by improving energy metabolism, neurotrophic signaling, and cerebrovascular function. Their potential synergistic interaction may arise from music's capacity to temporally structure and modulate the neurochemical and metabolic states induced by exercise. Combined interventions may further enhance synaptic plasticity and network integration by mitigating neuroinflammation and oxidative stress. They may offer additional benefits for cognition, mood, and motor control beyond either intervention alone. Dance, a prototypical integration of music and movement, activates multisensory and social networks and has shown potential benefits in Alzheimer's disease, Parkinson's disease, depression, and autism.

CONCLUSION: Music and exercise may engage convergent and potentially interacting mechanisms, including neuroplasticity, metabolic regulation, and neuroinflammatory modulation, forming an integrated framework for brain health. Dance exemplifies this music-movement integration by engaging multisensory and socio-emotional networks, highlighting its translational potential for promoting brain function.},
}

Humans
*Brain/physiology
*Exercise/physiology/psychology
*Cognition/physiology
Neuronal Plasticity/physiology
*Music/psychology
Cognitive Enhancement
*Resilience, Psychological
Animals

@article {pmid42670527,
year = {2026},
author = {Pan, L and Liu, B and Xu, J and Mu, X and Fan, L},
title = {Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {628071},
pmid = {42670527},
issn = {1178-2013},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Extracellular Vesicles/transplantation ; *Mesenchymal Stem Cells/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; },
abstract = {Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.},
}

Humans
*Neurodegenerative Diseases/therapy
*Extracellular Vesicles/transplantation
*Mesenchymal Stem Cells/cytology
*Mesenchymal Stem Cell Transplantation/methods
Animals

@article {pmid42670607,
year = {2026},
author = {Horn, J and Knox, S},
title = {Representation of Alzheimer Disease and Related Dementias in a Statewide Population Genomics Cohort: Early Findings from In Our DNA SC.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000750},
pmid = {42670607},
issn = {1546-4156},
abstract = {Alzheimer Disease and Related Dementias (ADRD) affect more than 125,000 individuals in South Carolina, yet equitable representation in population genomics initiatives remains a concern. We conducted a cross-sectional descriptive analysis of 247 In Our DNA SC participants aged 50 to 89 years with at least 1 ADRD-related diagnosis, identified using ICD-10 codes, to characterize demographic and clinical features and to compare the cohort with statewide ADRD estimates. Most participants were aged 65 years or older (82.2%), female (52.2%), and White (93.1%), while only 5.3% identified as Black. Nearly half had a Charlson Comorbidity Index score of 4 or greater (48.6%), and 49.5% had at least 10 years of longitudinal electronic health record data. Compared with statewide ADRD estimates, Black individuals were substantially underrepresented despite comprising ∼one-third of ADRD cases in South Carolina. These findings highlight the need for continued efforts to improve representation and support equitable, generalizable precision health research.},
}

@article {pmid42670839,
year = {2026},
author = {Zhu, Q and Yu, H},
title = {N-Terminal Chirality and Sequence Variations Modulate the Conformational Landscape of Amyloid-Beta 42.},
journal = {Journal of chemical information and modeling},
volume = {66},
number = {16},
pages = {10156-10167},
doi = {10.1021/acs.jcim.6c01001},
pmid = {42670839},
issn = {1549-960X},
support = {NA//University of Wollongong/ ; CE230100021//Australian Research Council Centre of Excellence in Quantum Biotechnology/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/genetics ; Molecular Dynamics Simulation ; *Peptide Fragments/chemistry/genetics ; Mutation ; Protein Conformation ; Amino Acid Sequence ; Stereoisomerism ; },
abstract = {Amyloid beta (Aβ), one of the hallmark proteins of Alzheimer's disease (AD), aggregates into plaques that are strongly linked to cognitive decline and neuronal death. Reducing its aggregation propensity may provide a strategy to slow the progression of AD. While chirality modulation has emerged as an innovative approach to disrupt this process, research has primarily focused on alterations at the Cα position, often overlooking the impact of the second chiral center, such as the Cβ atom of threonine. Furthermore, the underlying mechanisms governing these chiral effects remain elusive. Given the intrinsically disordered nature of the Aβ peptide, we employed temperature-replica exchange molecular dynamics simulations to explore its rugged conformational landscape. We considered sequence mutations (A2T and A2V), N-terminal chirality inversion of the first six residues (A2V1-6D and WT1-6D), and alteration of the second chiral center (Cβ) of threonine (A2TCβ). By analyzing the effect size and population change induced by these mutations and chiral modulation, we concluded that the modulation at the N-termini is not confined locally but also exerts specific effects on the central hydrophobic core (CHC) region. Inspection of their free energy landscape and representative structures reveals that the protective or pathogenic effects of these variants correlate with their similarity to the wild type ensemble. Beyond these static thermodynamics analyses, a direct connection to phase transitions was made by estimating heat capacity as a function of temperature. Both analyses predict that A2TCβ may exert a pathogenic effect, in contrast to the protective nature of A2T. These findings offer a deeper understanding of the effects of site-specific mutations and chirality and shed light on the development of advanced therapeutic strategies for AD.},
}

*Amyloid beta-Peptides/chemistry/genetics
Molecular Dynamics Simulation
*Peptide Fragments/chemistry/genetics
Mutation
Protein Conformation
Amino Acid Sequence
Stereoisomerism

@article {pmid42670861,
year = {2026},
author = {Yu, A and Ke, W and Shu, H and Xu, Z and Guo, J and Zheng, F and Shen, S and Li, W and Zeng, W and Yang, Y and Qiu, L},
title = {MVGCL: Noise-Robust Multi-Source Similarity Fusion and Type-Aware Dual-Pathway Learning for Drug Repositioning.},
journal = {Journal of chemical information and modeling},
volume = {66},
number = {16},
pages = {10339-10355},
doi = {10.1021/acs.jcim.6c01242},
pmid = {42670861},
issn = {1549-960X},
support = {JCYJ20250604191201002//Science and Technology Foundation of Shenzhen City/ ; A2025105//Guangdong Medical Research Foundation/ ; pdjh2026a114//Special Fund Project for Science and Technology Innovation Strategy of Guangdong Province/ ; CXPJJH124001-2463//Hubei Chen Xiaoping Science and Technology Development Foundation/ ; CXPJJH125004-059//Hubei Chen Xiaoping Science and Technology Development Foundation/ ; },
mesh = {*Drug Repositioning/methods ; *Machine Learning ; Humans ; *Computational Biology/methods ; Representation Machine Learning ; },
abstract = {Drug repositioning can accelerate therapeutic discovery, but computational drug-disease association prediction remains constrained by noisy multisource similarities, heterogeneous biomedical semantics, and sparse supervision. We present MVGCL, a type-aware dual-pathway framework that combines noise-robust multisource similarity fusion with heterogeneous biological network representation learning and aligns the two pathways through a distribution-aware hierarchical contrastive strategy to improve representation consistency under sparse and noisy supervision. Under 10-fold cross-validation protocols consistent with prior work, MVGCL achieves the highest AUC and AUPR on all three benchmark data sets, reaching 0.9538/0.9511 on B-data set, 0.9871/0.9890 on C-data set, and 0.9818/0.9836 on F-data set, with consistent performance across varying negative sampling ratios and entity-wise split settings. Under a leakage-controlled protocol in which GIP kernels were recomputed exclusively from the training DDAs within each fold, MVGCL retained the highest AUC and AUPR among the compared GIP-based models, with AUC values of 0.9029, 0.9422, and 0.9145 on B-data set, C-data set, and F-data set, respectively. Case analyses on Alzheimer's disease and Parkinson's disease further show that MVGCL ranks literature-supported drugs highly and prioritizes biologically plausible candidates for follow-up investigation, supporting its utility for evidence-aware drug repositioning.},
}

*Drug Repositioning/methods
*Machine Learning
Humans
*Computational Biology/methods
Representation Machine Learning

@article {pmid42671006,
year = {2026},
author = {Ayuba, M and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Alhaji Modu, B and Mohd Moklas, MA and Mehat, MZ},
title = {Ficus deltoidea preserves neuronal-glial ultrastructure and attenuates neuroinflammation in an Alzheimer's disease-like rat model.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1028415X.2026.2717205},
pmid = {42671006},
issn = {1476-8305},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) plaques, hyperphosphorylated tau tangles, cognitive decline, neuroinflammation, and neuronal-glial dysfunction, yet effective disease-modifying therapies remain unavailable. Increasing evidence suggests that preservation of neuronal and glial integrity is critical for mitigating disease progression. In the present study, we investigated the neuroprotective effects of Ficus deltoidea Jack (FD) in a D-galactose and aluminum chloride (D-gal/AlCl3)-induced rat model of AD-like neurodegeneration. Adult male Wistar rats were treated with FD (50, 100, and 200 mg/kg) for ten weeks and assessed for cognitive performance, cortical neuronal integrity, hippocampal ultrastructure, and neuroinflammatory signaling. FD treatment significantly improved spatial learning and memory in the Morris water maze without affecting locomotor activity. Histopathological analysis demonstrated dose-dependent preservation of pyramidal neurons in prefrontal cortex and hippocampal layers II (p < 0.0001), III (p < 0.0001), and V (p < 0.0001), with the highest dose of FD producing neuronal viability comparable to donepezil. Importantly, transmission electron microscopy demonstrated that FD markedly preserved the ultrastructural integrity of hippocampal microglia and astrocytes, maintaining mitochondrial morphology, rough endoplasmic reticulum organization, and myelin integrity. Consistent with these structural effects, FD significantly suppressed neuroinflammatory cytokine expression (IL-1β, IL-6, and TNF-α) in the prefrontal cortex. Collectively, this study provides the first integrated ultrastructural and molecular evidence that FD confers multi-level neuroprotection across the cortical-hippocampal axis by preserving neuronal-glial architecture and attenuating neuroinflammation. These findings highlight FD as a promising multi-target natural candidate for mitigating neurodegenerative processes associated with AD.},
}

@article {pmid42671152,
year = {2026},
author = {Otani, K},
title = {From public preferences to clinical tasks in anti-amyloid therapy for Alzheimer's disease.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70128},
pmid = {42671152},
issn = {1440-1819},
abstract = {Tajika and colleagues found that, among Japanese respondents willing to consider lecanemab, the median smallest worthwhile difference exceeded the absolute benefit used in their study scenario. This commentary argues that this expectation-efficacy gap should be translated into concrete clinical tasks across the anti-amyloid care pathway, including expectation assessment, biomarker and eligibility counseling, shared decision-making, treatment monitoring, support for non-initiation or discontinuation, and continuing psychosocial care.},
}

@article {pmid42671246,
year = {2026},
author = {Shvetcov, A and Thomson, S and Graham, ME and Hauger, B and Keller, JE and Smoyer, CJ and Tague, SE and Cho, AN and Imam, FB and Krish, V and , and Taylor, MK and Mahnken, JD and Sullivan, DK and Reed, JH and Burns, JM and Slawson, C and Swerdlow, RH and Wilkins, HM and Finney, CA},
title = {Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71714},
pmid = {42671246},
issn = {1552-5279},
support = {//Dementia Australia Research Foundation/ ; //Neil and Norma Hill Foundation/ ; //Annemarie & Arturo Gandioli-Fumagali Foundation/ ; //Perpetual Foundation John Williams Endowment/ ; //Hillcrest Foundation/ ; //University of Kansas Alzheimer's Disease Research Center/ ; //Paul & Valeria Ainsworth Family/ ; //John & Anne Leece Family/ ; //Australian Government's Medical Research Future Fund/ ; /ALZ/Alzheimer's Association/United States ; //National Health and Medical Research Council/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/genetics/metabolism ; *Apolipoprotein E4/genetics/immunology ; Female ; Proteomics ; Male ; Aged ; Temporal Lobe/immunology ; Prefrontal Cortex/immunology/metabolism ; Genotype ; },
abstract = {INTRODUCTION: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood.

METHODS: Here, we integrate proteomic profiling of plasma (n = 9028), cerebrospinal fluid (n = 1099), dorsolateral prefrontal cortex (n = 720), and superior temporal gyrus (n = 105) to define the immune phenotype associated with APOE ε4.

RESULTS: We identify a conserved, allele dose-dependent pro-inflammatory immune protein signature across peripheral and central tissues independent of AD diagnosis. This signature also emerges in patient-derived cortical organoids prior to amyloid beta and tau pathology, supporting a genotype-driven mechanism. Cross-tissue comparisons reveal shared innate and antiviral responses alongside tissue-specific immune signaling. Notably, a 12-week medical ketogenic diet partially reversed the APOE ε4 immune signature.

DISCUSSION: These findings position immune dysregulation as an early and tractable driver of AD risk in APOE ε4 carriers with direct implications for targeted prevention strategies.},
}

Humans
*Alzheimer Disease/immunology/genetics/metabolism
*Apolipoprotein E4/genetics/immunology
Female
Proteomics
Male
Aged
Temporal Lobe/immunology
Prefrontal Cortex/immunology/metabolism
Genotype

@article {pmid42671334,
year = {2026},
author = {Zhang, W and Wang, S and Gou, X},
title = {Research progress on terpenoids alleviating Alzheimer's disease through the Keap1/Nrf2/ARE pathway by exerting antioxidant effects and promoting mitophagy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480043},
doi = {10.1177/13872877261480043},
pmid = {42671334},
issn = {1875-8908},
abstract = {The exact initiating causes of Alzheimer's disease (AD) remain inconclusive. Meanwhile, the causal sequence and interactions within its pathological network are still poorly understood, which limits the efficacy of single treatment strategies and impedes drug development. Oxidative stress, identified as a central intersection point within this network, drives the deposition of amyloid-β protein, excessive tau phosphorylation, neuroinflammation, and mitochondrial damage, creating a self-perpetuating cycle. Consequently, oxidative stress has become a focal point for multi-target interventions. This review systematically investigates the evidence of terpenoids in cellular and animal models, elucidating their protective effects via a dual antioxidant mechanism. Firstly, terpenoids activate the Keap1/Nrf2/ARE pathway, leading to the upregulation of antioxidant genes and reduced free radical generation. Secondly, they enhance PINK1/Parkin-mediated mitophagy, facilitating the clearance of damaged organelles and preventing the release of reactive oxygen species. The review also delves into the positive feedback regulatory network involving molecules like Nrf2 and key proteins of mitophagy, such as p62/SQSTM1, offering a detailed mechanistic insight into the synergistic effects of terpenoids. This study underscores the significance of natural terpenoids, with their unique regulatory role in oxidative stress, as a promising candidate library for Alzheimer's drug development due to their diverse structures, clear mechanisms, and high safety profile. Additionally, it establishes a theoretical and experimental basis for the development of novel intervention strategies targeting multiple pathways with a single drug.},
}

@article {pmid42671347,
year = {2026},
author = {Shen, B and Zhu, Z and Qing, H and Quan, Z},
title = {Key circuits through which sleep affects memory and their role in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261479999},
doi = {10.1177/13872877261479999},
pmid = {42671347},
issn = {1875-8908},
abstract = {Sleep is a critical physiological process for maintaining the cognitive function of brain, particularly about memory consolidation. This review systematically elaborates on the multiscale regulatory mechanisms of the sleep-wake cycle, with a focus on the neural circuits involved in sleep-dependent memory consolidation, such as the hippocampus-prefrontal-thalamus network, characteristic neural oscillations, and microglia-mediated synaptic changes. Building upon these foundations, the article delves into Alzheimer's disease (AD), providing an in-depth analysis of the complex bidirectional relationship between sleep disturbances and the core pathologies of AD. Early vulnerable brain regions in AD, including the entorhinal cortex, hippocampus, thalamus, and locus coeruleus, coincide precisely with key hubs of the sleep-memory circuitry. Pathological damage in these regions leads to disrupted sleep architecture and impaired memory consolidation, creating a vicious cycle that accelerates memory impairment and cognitive decline. Interventions targeting the sleep-memory circuitry may thus offer a promising new strategy for early intervention in AD.},
}

@article {pmid42671397,
year = {2026},
author = {English, EA and Böken, D and Cotton, MW and Cheetham, MR and Jackson, JS and Meisl, G and Danial, JSH and Matthews, PM and Fancy, NN and Klenerman, D},
title = {Tau Aggregate Imaging and Transcriptomics of Alzheimer's Disease Brain at Different Stages of Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77453},
pmid = {42671397},
issn = {2198-3844},
support = {//UK Medical Research Council/ ; //Alzheimer's Research UK/ ; /ALZS_/Alzheimer's Society/United Kingdom ; /PUK_/Parkinson's UK/United Kingdom ; //Edmond J. Safra Foundation/ ; //UK Dementia Research Institute/ ; //Royal Society/ ; },
abstract = {Tau aggregation plays a critical role in the development and progression of Alzheimer's disease (AD). Tau aggregates of different sizes and shapes are formed, which ultimately lead to the deposition of fibrillar tangles. We used single-molecule techniques to characterize tau aggregates in the middle temporal gyrus and somatosensory cortex in post-mortem brain homogenates at different Braak stages from patients with AD. Total and phosphorylated tau aggregates increased dramatically in late Braak stages. The aggregates showed greater multi-site phosphorylation with increased Braak stage, but there was only a moderate change in the aggregate size distribution. Paired single nuclei transcriptomic analyses provided evidence for greater pro-inflammatory microglial and complement pathway activation with increasing phosphorylated tau aggregate concentration and length. Based on this correlation, we hypothesize a cascade of disease progression in which microglial inflammation induces tau aggregation in neighboring neurons that, in turn, further enhances inflammation and the spread of tau pathology to increase the concentration of small tau aggregates.},
}

@article {pmid42671540,
year = {2026},
author = {Vernooij, MW and Oliveira, TG and Wiest, R and Fox, NC and Frisoni, GB and Barkhof, F},
title = {SWI versus T2*GRE for ARIA-H monitoring: a pragmatic perspective on adoption in clinical practice.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42671540},
issn = {1432-1920},
abstract = {Although radiological severity thresholds for amyloid-related imaging abnormalities with hemosiderin deposition (ARIA-H) were developed using 2-dimensional acquisitions of T2*-weighted gradient-recalled echo (T2*GRE) MRI in pivotal anti-amyloid trials, adoption of well established 3D susceptibility-weighted imaging (SWI) in ARIA-H monitoring in clinical practice represents a reasonable long-term direction for clinical practice. SWI provides documented higher sensitivity and comparable or superior inter-rater reliability compared with conventional T2*GRE for detecting cerebral microbleeds and cortical superficial siderosis, the two key imaging manifestations of ARIA-H. Moreover, SWI is already incorporated into most contemporary dementia MRI protocols, offering important practical and logistical advantages. Available preliminary evidence suggests that the downstream clinical impact of detecting a few additional microbleeds or areas of siderosis may remain modest for most patients. Earlier and more reliable detection could potentially enhance safety by identifying individuals at higher risk of ARIA-H before treatment initiation. The critical requirements are transparency regarding sequence choice and consistency within individual patients over time.},
}

@article {pmid42671740,
year = {2026},
author = {Yang, EZ},
title = {When the Diagnosis Is a Death Sentence: Recovering Hope in Alzheimer's Disease.},
journal = {Journal of general internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11606-026-10763-2},
pmid = {42671740},
issn = {1525-1497},
}

@article {pmid42671814,
year = {2026},
author = {Liu, AJ and Schindler, SE and Whitson, H},
title = {Amyloid-Targeting Treatments in Patients With Non-Alzheimer Disease Copathologies.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.2933},
pmid = {42671814},
issn = {2168-6157},
}

@article {pmid42672905,
year = {2026},
author = {Oliva, PMP and Castro, SG and Manzano, JAH and Ishikawa, H and Tan, MA},
title = {Antiglycation and Amyloid-β Inhibitory Activities of Pandanus odorifer Extracts and Isolated Constituents: In Vitro and Molecular Docking Insights.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {9},
pages = {e71641},
doi = {10.1002/cbdv.71641},
pmid = {42672905},
issn = {1612-1880},
mesh = {*Molecular Docking Simulation ; Antiglycation Agents/chemistry/pharmacology/isolation & purification ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; *Plant Extracts/chemistry/pharmacology/isolation & purification ; Acetylcholinesterase/metabolism ; Humans ; *Antioxidants/chemistry/pharmacology/isolation & purification ; Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; Structure-Activity Relationship ; *Glycation End Products, Advanced/antagonists & inhibitors/metabolism ; Molecular Structure ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder associated with amyloid-β (Aβ) aggregation, advanced glycation end products (AGEs), and oxidative stress. This study investigated the antiglycation, antioxidant, anti-amyloidogenic, and predicted drug-likeness properties of Pandanus odorifer (Forssk.) Kuntze. The methanolic crude extract showed high total flavonoid content (121.7 ± 2.50 mg QE/g), moderate total phenolic content (16.61 ± 1.50 mg GAE/g), and strong AGE inhibition (IC50 = 57.30 µg/mL), with moderate radical scavenging activity. Chromatographic separation yielded syringaresinol (1), dehydrovomifoliol (2), and blumenol C glucoside (3), identified through spectroscopic analysis and comparison with published data. In the Thioflavin T assay, compounds 1-3 reduced Aβ-associated fluorescence, with compound 3 producing the largest reduction (71.20% ± 4.42%) under the tested conditions. Molecular docking suggested interactions with Aβ42 oligomers and AD-related enzymes, particularly acetylcholinesterase and β-secretase, while in silico prediction indicated acceptable drug-likeness without Lipinski violations. Overall, the findings identify P. odorifer as a source of constituents with antiglycation activity and preliminary Aβ-associated ThT responses that warrant confirmation using orthogonal biophysical and biological assays.},
}

*Molecular Docking Simulation
Antiglycation Agents/chemistry/pharmacology/isolation & purification
*Amyloid beta-Peptides/antagonists & inhibitors/metabolism
*Plant Extracts/chemistry/pharmacology/isolation & purification
Acetylcholinesterase/metabolism
Humans
*Antioxidants/chemistry/pharmacology/isolation & purification
Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
Structure-Activity Relationship
*Glycation End Products, Advanced/antagonists & inhibitors/metabolism
Molecular Structure

@article {pmid42673553,
year = {2026},
author = {Sarkis, RA and Yang, HS and Liu, L and Lam, AD and Pavlova, M and Lemus, HN and Kozhemiako, N and Hankerson, A and Amariglio, R and Pennell, PB and Marshall, GA and Purcell, S},
title = {Association Between Alzheimer Pathology, Sleep, and Cognition in Patients With Late-Onset Unexplained Epilepsy.},
journal = {Neurology},
volume = {107},
number = {6},
pages = {e218476},
doi = {10.1212/WNL.0000000000218476},
pmid = {42673553},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/blood/complications/pathology/physiopathology ; *Epilepsy/blood/physiopathology/complications ; Aged ; *tau Proteins/blood ; Electroencephalography ; *Sleep/physiology ; Middle Aged ; *Cognitive Dysfunction/physiopathology/blood ; *Cognition/physiology ; Age of Onset ; },
abstract = {BACKGROUND AND OBJECTIVES: Late-onset unexplained epilepsy (LOUE) has been linked to accelerated cognitive decline. However, the role of neurodegenerative proteins and whether they exert their effects through sleep-related mechanisms remain unexplored in this population. The goal of this study was to investigate the association of plasma p-tau217, a measure of Alzheimer disease (AD) pathology, with cognition in LOUE and its association with sleep.

METHODS: Participants with LOUE, with new-onset unprovoked seizures, age at onset 55 years or older, and absence of cortical lesions on MRI, were prospectively recruited. They underwent cognitive testing which included the extended Preclinical Alzheimer Cognitive Composite (PACC5). A 24-hour EEG was obtained, and sleep manually scored. Measures of sleep macroarchitecture and N2/N3 microarchitecture were extracted including slow oscillation (SO), fast spindle (FS), slow spindle (SS), and spindle-SO coupling measures.

RESULTS: Eighty-five participants enrolled (mean age 71.3 ± 7.1 years; 49% female). The average PACC5 Z score (±SD) was -0.63 ± 1.0. Higher plasma levels of log-transformed p-tau217 (per 1 unit increase) were associated with poorer cognition, PACC5 (β = -0.66; 95% CI -1.19 to -0.13; p = 0.0017), after adjusting for age, sex, and education. The severity of epilepsy modulated this relationship: individuals with both elevated p-tau217 and medication-refractory epilepsy exhibited worse cognitive performance (refractory epilepsy * p-tau217 interaction term β = -1.49; 95% CI -2.94 to -0.05; p = 0.04). Higher plasma p-tau217 levels were associated with reduced spindle-SO coupling. Mediation analysis indicated that approximately 24% of the association between p-tau217 and cognition was accounted for by spindle-SO coupling (95% CI 3%-85%, p = 0.032).

DISCUSSION: In individuals with LOUE, elevated plasma p-tau217 was associated with both cognitive impairment and disrupted sleep microarchitecture, with the most pronounced cognitive deficits observed in individuals with medication refractory epilepsy. These findings support the utility of plasma p-tau217 as a biomarker in this population and underscore the role of sleep processes in the relationship between neurodegenerative pathology and cognition in older adults with epilepsy.},
}

Humans
Female
Male
*Alzheimer Disease/blood/complications/pathology/physiopathology
*Epilepsy/blood/physiopathology/complications
Aged
*tau Proteins/blood
Electroencephalography
*Sleep/physiology
Middle Aged
*Cognitive Dysfunction/physiopathology/blood
*Cognition/physiology
Age of Onset

@article {pmid42673564,
year = {2026},
author = {Shen, M and Lu, M and Sun, K and Zhao, K and Wang, T and Luo, Y and Zhang, Q},
title = {Aligned Electrospun PELA Fibers Promote the Neuronal Orientation and Attenuate Neurotoxicity.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01425},
pmid = {42673564},
issn = {2576-6422},
support = {252300421132//Natural Science Foundation of Henan Province/ ; },
abstract = {Neural regeneration is one of the potential therapeutic approaches for Alzheimer's disease (AD). While aligned electrospun fibers have shown promise in guiding neural regeneration, conventional materials face limitations such as poor hydrophilicity and acidic degradation byproducts. The amphiphilic copolymer poly(lactic-co-glycolic acid)-block-polyethylene glycol (PELA) combines mechanical tunability with enhanced biocompatibility, but its potential as an aligned fibrous membrane for neural regeneration remains unexplored. Here, we fabricated aligned electrospun PELA fibrous membranes (AEF) by modulating the collector rotation speeds. Compared to randomly oriented fibers, AEF exhibited highly ordered fiber alignment, enhanced molecular orientation and crystallinity, improved thermal stability, and increased mechanical anisotropy. When cultured with SH-SY5Y human neuroblastoma cells, AEF effectively directed oriented neural outgrowth and reduced cellular dispersion. In an okadaic acid (OA)-induced neural damage model, AEF significantly attenuated oxidative stress and rescued neuronal proliferation. Moreover, AEF mitigated OA-induced Tau hyperphosphorylation and protein aggregation, while restoring the expression of MAP2 and TUBULIN3. Collectively, these findings demonstrate that aligned electrospun PELA fibers not only provide guidance for neuronal orientation but also exert protective effects against Tau-induced neurotoxicity. This study suggests oriented PELA fibrous membranes as promising candidates for ameliorating neural damage in AD.},
}

@article {pmid42673741,
year = {2026},
author = {August, I and Steiner, S and Oefner, R and Marchetto, MC},
title = {Differential amyloid-beta sensitivity across human and nonhuman primate neurons.},
journal = {Journal of human evolution},
volume = {219},
number = {},
pages = {103888},
doi = {10.1016/j.jhevol.2026.103888},
pmid = {42673741},
issn = {1095-8606},
abstract = {The human brain has undergone a threefold increase in size as well as changes in cytoarchitecture and neurochemical organization since the split with the last common ancestor with chimpanzees and bonobos. These changes have likely promoted increased cognitive flexibility but may also have come at the cost of increased vulnerability to neurodegenerative diseases like Alzheimer's disease (AD). Alzheimer's disease is the most common form of age-dependent dementia, and previous research suggests that humans may be uniquely vulnerable to AD. Primate comparative induced pluripotent stem cell models offer a unique opportunity to study the cellular and molecular mechanisms underlying this vulnerability. Plaques composed of amyloid-beta (aβ) are a hallmark pathology of AD, and while the exact role of aβ in disease pathogenesis remains incompletely understood, it is clear that aβ can have a neurotoxic effect and plays a role in the characteristic loss of neurons and synapses. Here we investigate susceptibility to aβ-induced toxicity in induced pluripotent stem cell-derived neurons from humans-both with and without AD, the two Pan species-a chimpanzee and a bonobo, and a rhesus macaque. To measure toxicity, we looked at cell death, along with other metrics of neuronal health and connectivity (neuritic beading and synaptic puncta density, respectively). We also employed transcriptomic approaches (RNA sequencing) to investigate molecular mechanisms underlying observed species differences. Our findings show that macaque neurons are less sensitive to aβ than human and ape neurons, and RNA sequencing points to molecular mechanisms that may underlie potentially protective responses in both macaque and ape neurons relative to humans. This work highlights the importance of studying AD from a comparative lens and provides insights into variation in susceptibility to AD among primates.},
}

@article {pmid42673747,
year = {2026},
author = {Pyne, IT and Roy, AJ and Boraschi, S and Hajgude, SS and Hall, RA},
title = {Panoramic characterization of proposed ligands for GPR3: oleoylethanolamide as a pharmacological chaperone.},
journal = {Molecular pharmacology},
volume = {108},
number = {8},
pages = {100146},
doi = {10.1016/j.molpha.2026.100146},
pmid = {42673747},
issn = {1521-0111},
abstract = {G protein-coupled receptor 3 (GPR3) is a constitutively active G protein-coupled receptor known to regulate β-amyloid deposition in the brain and metabolism in brown adipose tissue. Although multiple compounds have been proposed to activate GPR3 signaling, it is still considered an orphan receptor. Recently, structural evidence revealed a hydrophobic tunnel in GPR3, suggesting that a lipid may be an endogenous agonist for GPR3. We sought to characterize the reported agonists for GPR3 to determine which might be authentic agonists and found that only the synthetic ligand, diphenyleneiodonium chloride, and the endogenous lipids, oleoylethanolamide (OEA) and oleamide, stimulated cAMP generation in a GPR3-dependent manner. Although treatment of cells with diphenyleneiodonium chloride stimulated rapid cAMP generation, we observed gradual increases in GPR3 activation over multiple hours after OEA treatment. Additionally, we found that chronic stimulation with OEA caused an increase in GPR3 cell surface expression. Coupled with the slow activation kinetics of OEA-stimulated GPR3 signaling, these findings suggest that OEA does not behave strictly as a classical agonist for GPR3. Indeed, we found that the OEA-mediated increase in GPR3 on the cell surface can be blocked by inhibiting receptor forward trafficking through the endoplasmic reticulum and Golgi, which positions OEA as a pharmacological chaperone that increases GPR3 signaling by promoting receptor trafficking to the cell surface. These findings suggest a novel mechanism for the regulation of the constitutively active receptor GPR3, whereby the amount of receptor at the plasma membrane, and therefore, the receptor's signaling activity, can be regulated by lipid binding in the endoplasmic reticulum/Golgi. SIGNIFICANCE STATEMENT: This study proposes a novel mechanism for the regulation of the activity of the G protein-coupled receptor, G protein-coupled receptor 3. This study found that the endogenous lipid oleoylethanolamide functions as a pharmacological chaperone by promoting the accumulation of G protein-coupled receptor 3 at the plasma membrane through increased forward trafficking, thereby inducing increased receptor signaling activity.},
}

@article {pmid42674339,
year = {2026},
author = {Hu, G and Tong, Y and Liu, L and Zhang, Y and Zhang, M},
title = {EEG microstate dynamics across sleep stages in Alzheimer's disease: A pilot study.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112104},
doi = {10.1016/j.brainresbull.2026.112104},
pmid = {42674339},
issn = {1873-2747},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by progressive cognitive decline and brain network dysfunction. EEG microstates offer a sight into rapid network dynamics. However, microstate alterations in AD during waking and different sleep stages remain unexplored.

METHODS: Overnight EEG was recorded from 15 AD patients and 15 healthy controls. Sleep stages (Wake, N1, N2, N3, REM) were manually scored. Microstate analysis extracted temporal parameters and transition probabilities separately for each sleep stage using a common set of grand-mean template maps derived from all stages. Linear mixed models assessed group differences, and correlations examined associations with MMSE.

RESULTS: AD patients showed significantly longer durations compared to HC (Group main effect: F(1,28) = 6.78, p_FDR = 0.042) in mean duration of class A, with the largest difference during wakefulness (p = 0.018, q = 0.046). Mean occurrence of class D was significantly lower in AD (F(1,28) = 5.44, p_FDR = 0.049), with significant reductions during wakefulness and N1. Mean Occurrence of class C showed both a significant Group main effect (F(1,28) = 5.28, p_FDR = 0.049) and a Group × Sleep Stage interaction (F(4112) = 3.31, p_FDR = 0.047) were observed, with AD patients showing lower occurrence during wakefulness and N1. For transition probabilities, AD patients showed significantly increased corrected Class B→A transition (DeltaTM_B→A), but reduced corrected Class D→B transition (DeltaTM_D→B) and raw Class C→D transition (OrgTM_C→D) (all p_FDR < 0.05). Critically, the Group × Sleep Stage interaction for the corrected Class A→D transition (DeltaTM_A→D) reached significance (F(4112) = 6.12, p_FDR = 0.015), with the group difference largest during wakefulness (p = 0.004, q = 0.029). Partial correlations revealed that corrected B→A transition probability negatively correlated with MMSE (r = -0.642, p < 0.001); MeanOccurrence_C (r = 0.487, p = 0.003) and MeanOccurrence_D (r = 0.532, p = 0.001) also showed significant correlations with MMSE.

CONCLUSIONS: This is the first study to report that AD patients exhibit altered microstate parameters and transition probabilities across sleep stages. Present findings suggest that sleep-stage-resolved microstate analysis may offer a new tool for assessing AD.},
}

@article {pmid42674542,
year = {2026},
author = {Mark, RE and Tabak, DM and van den Ende, D and Hellemons, D and Brehmer, Y},
title = {The Famous Faces Test: A Systematic Review of Its Design and Potential for Detecting Early Alzheimer's Disease.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261483940},
doi = {10.1177/07334648261483940},
pmid = {42674542},
issn = {1552-4523},
abstract = {ObjectiveEarly Alzheimer's disease (AD) is currently diagnosed using costly and invasive biomarkers. The Famous Faces Test (FFT) may detect (subtle) cognitive impairment earlier than standard neuropsychological tests. This review aimed to identify methodological variation across FFTs and evaluate their ability to detect early AD.MethodsFollowing PRISMA guidelines, four databases were searched. Studies were included if an FFT was used, participants were older adults or on the AD-continuum, cognitive performance-based data were reported, and the paper was a journal article or dissertation. Extracted information was clustered into stimulus characteristics, performance assessment, and participant characteristics.Results39 of 550 records met the inclusion criteria. Methodological heterogeneity was substantial. FFT performance was predominantly lower in AD-continuum individuals than in controls.ConclusionRecommendations for future studies using an FFT are provided, and evidence supporting its potential clinical sensitivity is reviewed. Longitudinal studies are needed to establish its utility in detecting early AD.},
}

@article {pmid42674964,
year = {2026},
author = {Park, H and Jung, W and You, SH and Lee, H and Kim, B and Hwang, M and Kim, BK and Shin, JH and Suh, SI and Lee, Y and Ryoo, I and Jung, HN},
title = {Ultrafast (0.5-Minute) Deep Learning Based Choroid Plexus Segmentation: Links to Cognitive Impairment and Glymphatic Function.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9614},
pmid = {42674964},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Choroid plexus volume (CPV) may reflect cognitive impairment and glymphatic dysfunction. However, its clinical use is limited by time-consuming segmentation. We developed an ultrafast deep learning method for automated CPV quantification using 3D T1-weighted images (T1WI).

MATERIALS AND METHODS: This retrospective study included 697 patients who underwent brain MRI for cognitive impairment. The model was developed using 3D T1WI from 103 patients as an ensemble of three 2.5D U-Nets in the axial, coronal, and sagittal planes. Imaging validation was performed for 20 patients by comparing manual segmentation, FreeSurfer, and the proposed method. Clinical validation included 574 patients classified as subjective cognitive impairment (SCI), early mild cognitive impairment (MCI), late MCI, or Alzheimer disease (AD). ComBat harmonization was applied to reduce scanner-related effects. Accuracy, processing time, group differences, and correlations with the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index were assessed.

RESULTS: After ComBat harmonization, the deep learning-based model was markedly faster than FreeSurfer (0.4 vs. 188.0 minutes; P<0.001), and its CPV measurements showed no significant difference from manual segmentation (1.89 vs. 1.84 mL; P=1.00). CPV/intracranial volume (ICV)×10³ increased progressively across cognitive stages, from 1.02 in SCI to 1.16 in AD (P=0.004). CPV/ICV measured by the deep learning-based model was negatively correlated with the DTI-ALPS index (ρ=-0.256, P<0.001).

CONCLUSION: An ultrafast deep learning method enables automated CPV quantification and provides clinically relevant CPV/ICV measurements for neurodegenerative disease assessment.},
}

@article {pmid42675027,
year = {2026},
author = {Deaner, N and Daven, M and Naik, AD and Sabbagh, M and Breithaupt, A and Possin, K and Alford, S and Alexander, A and Daniels, A and Dezzutti, L and Bumaschny, VF and , },
title = {A strategic pathway for the ethical development of AI tools in dementia care.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71805},
doi = {10.1002/alz.71805},
pmid = {42675027},
issn = {1552-5279},
support = {//Novo Nordisk, Inc., CommonSpirit, and Eli Lilly & Co/ ; },
mesh = {Humans ; *Dementia/therapy ; *Artificial Intelligence/ethics ; },
abstract = {Artificial intelligence (AI) is rapidly entering dementia clinical practice, offering opportunities across the care continuum. However, cognitive decline creates a unique ethical challenge. This perspective article proposes a strategy to ensure the responsible development and deployment of AI tools for dementia. An interdisciplinary workgroup of the Alzheimer's Association Innovation Roundtable synthesized ethical frameworks, regulatory standards, and empirical evidence to generate expert consensus. The result is a six-step strategic pathway tailored to dementia care: establish ethical foundations, conduct stakeholder engagement, lead a co-design approach, conduct an impact assessment, establish iterative design and feedback loops, and provide education and digital literacy. A practical implementation checklist accompanies the framework. Because responsible progress requires both safety and timely innovation, ethical evaluation must balance the risks of premature deployment against those of harmful delay. Operationalizing ethics throughout the AI lifecycle can ensure that innovation advances autonomy, equity, and safety for people living with dementia.},
}

Humans
*Dementia/therapy
*Artificial Intelligence/ethics

@article {pmid42675112,
year = {2026},
author = {Maas, C and Fang, L and Mathey, E and Jacob, C and Stremel, T and Viering, T and Fliedner, R and Schnieder, M and von Arnim, CAF},
title = {A comprehensive German claims data analysis of care pathways, risk factors and comorbidities among acetylcholinesterase inhibitor initiators in Alzheimer's disease.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42675112},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology/diagnosis ; Germany/epidemiology ; Female ; *Cholinesterase Inhibitors/therapeutic use ; Risk Factors ; Retrospective Studies ; Male ; Comorbidity ; Aged ; Aged, 80 and over ; },
abstract = {Early stages of Alzheimer's Disease (AD), commonly referred to as early AD (eAD), represent a critical phase for timely diagnosis and intervention. However, significant gaps remain in understanding real-world care of individuals initiating first-line treatment such as acetylcholinesterase inhibitors (AChE-I) in Germany. A retrospective study was conducted using the German InGef claims database with a pragmatic proxy approach, identifying de novo AChE-I initiators as individuals suspected of having eAD. Two cohorts were defined: a pre-cohort (2022) capturing eight-years prior to AChE-I initiation, and a post-cohort (2017), analyzing five-years following initiation. Patients were matched 1:1 to controls without AD based on demographic characteristics. Outcomes included comorbidities, risk factors, diagnostics, prescriptions, and survival. The study identified 1,994 (pre-cohort) and 2,051 (post-cohort) AChE-I initiators, and respective controls. Mobility disorders increased significantly (+ 55%) over the eight years preceding treatment. Eight years pre-initiation, 81.9% of initiators exhibited at least one modifiable risk factor compared to 76.2% in controls (p < 0.001). Advanced diagnostic procedures were underutilized (MRI: 39.0%, cerebrospinal fluid analysis: 9.2%, in year -1). Only 78.6% received an AD-specific diagnosis within the first year post-initiation. Extensive use of psycholeptics and psychoanaleptics was observed, with a notable decline in dementia-specific medications post-initiation. Post-initiation, initiators showed higher comorbidity burden (e.g., urinary incontinence: 40.2% vs. 10.7% by year 5) and higher observed, unadjusted mortality (53.3% vs. 21.7%, p < 0.001). This study highlights patterns suggestive of gaps in the management of AChE-I initiators in Germany, including underutilization of guideline-based diagnostics, high comorbidity burden, and higher observed mortality. Improved management strategies and the development of more precise diagnostic coding that reflects disease stages could help to address these issues.},
}

Humans
*Alzheimer Disease/drug therapy/epidemiology/diagnosis
Germany/epidemiology
Female
*Cholinesterase Inhibitors/therapeutic use
Risk Factors
Retrospective Studies
Male
Comorbidity
Aged
Aged, 80 and over

@article {pmid42675211,
year = {2026},
author = {Watanabe, R and Creekmore, BC and Darwich, NF and Smith, CL and Xu, H and Baltazar, A and Salphati, S and Changolkar, L and Hoxha, K and Zhang, B and O'Rourke, CM and Burslem, GM and Lee, VM and Chang, YW and Lee, EB},
title = {Repositioning of polyubiquitin alters the pathologic tau filament structure.},
journal = {Nature structural & molecular biology},
volume = {},
number = {},
pages = {},
pmid = {42675211},
issn = {1545-9985},
abstract = {Structurally diverse tau filaments form proteinaceous aggregates in a heterogeneous group of neurodegenerative diseases called tauopathies. The factors extrinsic to the highly ordered core structure that influence tau filament stability are not well understood. Here, we found that polyubiquitinated tau filaments from Alzheimer disease and vacuolar tauopathy human brain tissue exhibit distinct seeding patterns in mice, in association with differences in tau filament ultrastructure determined by cryo-electron microscopy. Chemical modulation of the polarity of polyubiquitin adjacent to the tau core with the small molecule ubistatin B resulted in the repositioning of poorly structured densities toward positively charged residues on the highly structured core filament, leading to shifting of the protofilament-protofilament interface of certain vacuolar tauopathy tau filaments. These results suggest that the structure of tau filaments that are associated with different seeding activities in vivo can be influenced by post-translational modifications.},
}

@article {pmid42675276,
year = {2026},
author = {Huang, Y and Guo, X and Li, Z and Fan, M},
title = {Generative Brain Priors-Driven Self-Regulated and Clinically-Guided Multimodal Fusion for Early Alzheimer's Disease Diagnosis.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02220-7},
pmid = {42675276},
issn = {2948-2933},
support = {42461053//Innovative Research Group Project of the National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) and mild cognitive impairment (MCI) require accurate early diagnosis to support timely clinical intervention and disease management. Although multimodal neuroimaging with structural MRI, FDG-PET, and AV45-PET has shown promise, existing deep learning methods still face three major challenges: insufficient modeling of pathology-related features across local brain regions and whole-brain connectivity, heterogeneous feature distributions among modalities, and limited use of clinical information for dynamic representation learning. To address these challenges, we propose GBP-SCMF, a multimodal diagnostic framework for AD spectrum classification. The framework first extracts multi-scale features from each imaging modality using parallel modality-specific branches. It then integrates three complementary mechanisms: generative brain-prior enhancement to inject disease-related pathological knowledge into imaging representations, self-regulated multimodal alignment to reduce modality bias and feature redundancy, and clinical-imaging collaborative fusion to embed cognitive measurements as semantic tokens for gated interaction with imaging features. These components are jointly optimized to improve both cross-modal consistency and disease-discriminative representation learning. We evaluated GBP-SCMF on the ADNI dataset for three-class classification among cognitively normal controls, MCI, and AD. The proposed method achieved an overall classification accuracy of 0.9021 and a macro-average area under the receiver operating characteristic curve (AUC) of 0.9514. Ablation studies and attention visualizations further demonstrated the complementary contribution of each component and the biological plausibility of the learned representations. These results suggest that GBP-SCMF provides an effective and interpretable multimodal strategy for computer-aided AD diagnosis.},
}

@article {pmid42675311,
year = {2026},
author = {Crance, S and Hamilton, G and Carlson, C and Garrett, K and Roberg, T},
title = {Building a dementia-capable workforce: Implementation and evaluation of a state-mandated dementia training program for memory care staff.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71813},
doi = {10.1002/alz.71813},
pmid = {42675311},
issn = {1552-5279},
support = {#90ADP10116/ACL/ACL HHS/United States ; },
mesh = {Humans ; *Dementia/therapy ; Arizona ; *Health Personnel/education ; Program Evaluation ; },
abstract = {As dementia prevalence rises, developing a dementia-capable workforce is a national priority. Training requirements vary widely across states, and many memory care staff receive limited dementia education. Although evidence supports dementia training, little is known about translating policy into practice. This paper describes the implementation and evaluation of a statewide mandated dementia training initiative in Arizona. After passage of AZ HB2764 (2024), developed and supported by the Alzheimer's Association Arizona Chapter, an interdisciplinary team at Hospice of the Valley developed a state-approved program including 6 hours of online modules and a 2-hour in-person training. From August to December 2025, 3409 staff across diverse roles completed the program. Knowledge scores improved (79.74%-95.97%), with high satisfaction (4.89/5); 98.53% reported role applicability, and 94.6% reported improved care ability at 3 months. Findings support mandated, statewide dementia training as a feasible policy strategy to strengthen workforce capacity and improve dementia-capable care.},
}

Humans
*Dementia/therapy
Arizona
*Health Personnel/education
Program Evaluation

@article {pmid42675343,
year = {2026},
author = {Gunasekaran, SK and K, HKC and Gobinath, M and Roychowdhury, P and N, MS},
title = {Trehalose's untapped mechanisms in alzheimer's: gut-brain-autophagy signalling beyond the usual targets.},
journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences},
volume = {34},
number = {2},
pages = {},
pmid = {42675343},
issn = {2008-2231},
mesh = {Humans ; *Trehalose/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Brain/metabolism/drug effects ; Signal Transduction/drug effects ; *Autophagy/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Gastrointestinal Microbiome/drug effects ; },
abstract = {BACKGROUND: Trehalose is a promising therapeutic candidate for Alzheimer's disease (AD) that is known to induce autophagy and facilitate misfolded proteins clearance such as amyloid-β and hyperphosphorylated tau. Despite there is emerging evidence that trehalose has a wider range of molecular mechanisms and thus has a greater neuroprotective profile.

OBJECTIVE: To summarize the emerging molecular mechanisms underlying the neuroprotective effects of trehalose beyond classical autophagy and discuss its therapeutic potential in AD.

METHODS: Published evidence from preclinical studies including in-vitro and in-vivo models, along with hypothetical and emerging findings from early clinical investigations was reviewed to evaluate the molecular mechanisms, therapeutic effects, and translational challenges associated with trehalose in AD.

RESULTS: In addition to classical autophagy signalling, recent studies have demonstrated that autophagy can also regulate the stability of neuronal membrane microdomains, prevent lipid bilayers disruption by amyloid proteins, and regulate stress granules dynamics that affect the function of RNA-binding proteins. Other discoveries indicate that interactions with nutrient-sensing pathways and glucose transporter systems that simulate metabolic stress, which may activate protective mechanisms separate from the inhibition of mTOR. Trehalose could also involve in lysosomal-autophagosome fusion and modulate the microglia and astrocytes activation, suggesting an important immunometabolic function. Trehalose often connects to the gut-brain axis and show their effect in gut microbiota composition, microbial metabolite signalling and gut barrier function. These effects can influence systemic inflammation, availability of short-chain fatty acids, bile acid profiles and vagus-mediated gut-to-brain communication, all of which can influence neuroinflammation networks in AD.

CONCLUSION: Although promising results have been reported, primarily from preclinical studies, with early human investigations now beginning to emerge, opportunities remain to address, such as poor oral bioavailability, penetration into the brain and long-term safety in elderly patients. Mechanistic dissection in multi-omics approaches, microbiome-stratified models and early-phase clinical testing are the areas that need to be targeted in future research. A broader understanding of the mechanisms of action of trehalose provides a good chance to reimagine its therapeutic implications and develop novel approaches to AD.},
}

Humans
*Trehalose/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism
Animals
*Brain/metabolism/drug effects
Signal Transduction/drug effects
*Autophagy/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Gastrointestinal Microbiome/drug effects

@article {pmid42675347,
year = {2026},
author = {Xu, M and Gao, Y and Ou, P and Yang, H and Wang, J and Liu, W and Shu, N and Sun, Y and Fu, L and Glodzik, L and Butler, TA and Chaing, GC and Li, Y and Wang, Y and Zhou, L and Ma, G},
title = {Female vulnerability to microvascular transport dysfunction emerges early across the Alzheimer's disease continuum.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71811},
doi = {10.1002/alz.71811},
pmid = {42675347},
issn = {1552-5279},
support = {2022ZD0213300//Brain Science and Brain-like Intelligence Technology - National Science and Technology Major Project/ ; 82271953//National Natural Science Foundation of China/ ; U25A20136//National Natural Science Foundation of China/ ; R01 AG057848-02/AG/NIA NIH HHS/United States ; R01AG077576-01A/AG/NIA NIH HHS/United States ; R01NS104364-02/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Female ; *Alzheimer Disease/physiopathology/diagnostic imaging ; *Cerebrovascular Circulation/physiology ; Aged ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; Male ; Magnetic Resonance Imaging ; Biomarkers/blood ; Aged, 80 and over ; *Brain/blood supply/diagnostic imaging ; *Microvessels/physiopathology ; Sex Characteristics ; Hippocampus/pathology ; },
abstract = {INTRODUCTION: We tested whether quantitative transport mapping (QTM)-derived perfusion velocity would detect earlier and more sex-specific microvascular alterations than cerebral blood flow (CBF) across the Alzheimer's disease (AD) continuum.

METHODS: In 182 participants (cognitively normal = 53, subjective cognitive decline [SCD] = 48, mild cognitive impairment [MCI] = 31, AD = 50), seven-delay arterial spin labeling was used to derive CBF and QTM velocity. Age/sex-adjusted models assessed diagnostic and sex effects, associations with plasma biomarkers and Mini-Mental State Examination (MMSE), and mediation of the hippocampal volume-cognition relationship.

RESULTS: QTM velocity was reduced already in SCD, including the hippocampus, whereas CBF declined mainly in MCI/AD. Sex × Diagnosis interactions were significant for QTM in gray and white matter, but not for CBF. QTM, especially in females, was inversely associated with plasma NfL/GFAP, related to MMSE, and parietal QTM partially mediated the hippocampal volume-MMSE association.

DISCUSSION: QTM is a non-invasive biomarker more sensitive than CBF to early, female-biased microvascular transport dysfunction in AD.},
}

Humans
Female
*Alzheimer Disease/physiopathology/diagnostic imaging
*Cerebrovascular Circulation/physiology
Aged
*Cognitive Dysfunction/physiopathology/diagnostic imaging
Male
Magnetic Resonance Imaging
Biomarkers/blood
Aged, 80 and over
*Brain/blood supply/diagnostic imaging
*Microvessels/physiopathology
Sex Characteristics
Hippocampus/pathology

@article {pmid42675511,
year = {2026},
author = {Schwarz, C and Frenzel, S and Ittermann, T and Grittner, U and Wortha, SM and Brzoska, T and Grabe, HJ and Flöel, A and Ihler, F},
title = {Association of self-reported hearing loss and tinnitus with brain structure and cognitive function: a population-based cross-sectional analysis from the Study of Health in Pomerania (SHIP).},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42675511},
issn = {1758-9193},
mesh = {Humans ; *Tinnitus/epidemiology/diagnostic imaging/psychology ; Female ; Male ; *Hearing Loss/epidemiology/diagnostic imaging/psychology ; Cross-Sectional Studies ; *Brain/diagnostic imaging/pathology ; Aged ; Aged, 80 and over ; Germany/epidemiology ; Middle Aged ; Magnetic Resonance Imaging ; Self Report ; Adult ; *Cognition/physiology ; Young Adult ; Neuropsychological Tests ; Cohort Studies ; },
abstract = {BACKGROUND: Hearing loss has been reported as a major, potentially modifiable risk factor for dementia and often co-occurs with tinnitus. Both conditions are prevalent and have been linked to brain health and cognitive decline. However, evidence from studies containing the whole age span of adults remains limited. Therefore, this study investigated associations of hearing loss and tinnitus with brain structure and cognitive performance in a large population-based cohort from northeastern Germany.

METHODS: Data from the baseline investigation of 4,420 participants (age 20-84 years) for the SHIP-TREND cohort was analysed. Thereof, 4,400 completed a self-assessment for hearing and 3,937 for tinnitus. Cognitive performance was assessed by tests on verbal memory and executive function. T1-weighted magnetic resonance imaging yielded data on global and regional volumes and cortical thickness for 2,144 participants. Multiple linear regression and mediation analyses were conducted, adjusted for age, sex, and further risk factors for dementia.

RESULTS: A total of 1,455 participants reported hearing loss, 679 thereof a clinically relevant degree while 874 participants reported tinnitus. Hearing loss was associated with worse memory performance and unfavourable brain measures, particularly along the central auditory pathway and in regions implicated in cognitive function and Alzheimer's Disease. Notably, white matter hypointensity volume partially mediated (8.8%) the association of self-reported hearing loss with immediate recall performance. Self-reported hearing loss was associated with tinnitus (odds ratio 7.5 [95%CI 6.0 to 9.3]; p < 0.001), but no relevant combined effects on cognitive performance or brain measures were observed, and tinnitus alone was not associated with cognition or adverse brain measures.

CONCLUSIONS: This large cohort study not only confirmed independent associations of self-reported hearing loss with memory performance and structural brain measures but also suggested a pathophysiologic link between hearing loss and cerebrovascular disease. Our findings support an association between hearing loss, but not tinnitus, and cognitive decline as well as dementia-related brain changes, highlighting hearing loss as a potentially important target for early prevention strategies.},
}

Humans
*Tinnitus/epidemiology/diagnostic imaging/psychology
Female
Male
*Hearing Loss/epidemiology/diagnostic imaging/psychology
Cross-Sectional Studies
*Brain/diagnostic imaging/pathology
Aged
Aged, 80 and over
Germany/epidemiology
Middle Aged
Magnetic Resonance Imaging
Self Report
Adult
*Cognition/physiology
Young Adult
Neuropsychological Tests
Cohort Studies

@article {pmid42675683,
year = {2026},
author = {Wu, HY and Wang, XS and Yang, M and Cai, J},
title = {The global research of artificial intelligence on Alzheimer disease: A 25-year bibliometric analysis.},
journal = {Medicine},
volume = {105},
number = {35},
pages = {e50370},
doi = {10.1097/MD.0000000000050370},
pmid = {42675683},
issn = {1536-5964},
mesh = {*Alzheimer Disease/diagnosis ; *Bibliometrics ; Humans ; *Artificial Intelligence/trends ; *Biomedical Research ; },
abstract = {BACKGROUND: With the increasing global prevalence of Alzheimer disease (AD), there has been heightened attention on the onset and progression of AD. Studies indicate that artificial intelligence (AI) has demonstrated potential in the early prediction and diagnosis of AD. However, current research still falls short in terms of data diversity and the application of personalized models.

OBJECTIVE: This manuscript utilizes bibliometric methods to explore the application trends and emerging frontiers of AI in AD research.

METHODS: In the Web of Science Core Collection, we gathered documents from 1999 to 2023 focusing on the application of AI in AD. CiteSpace and VOSviewer were utilized to conduct a thorough analysis of various aspects, including countries, institutions, authors, journals, and keywords.

RESULTS: A total of 5347 articles were selected for this study. The United States of America leads this field. The University of London, Harvard University, the University of North Carolina, and the University of California are the top 4 institutions by publication volume. Daoqiang Zhang is identified as the most influential scholar in this field. NeuroImage is regarded as the most influential journal in this field. The keyword co-occurrence analysis indicates that this study focuses on the application of machine learning and deep learning (DL) in predicting and diagnosing AD. Research trends show an increasing preference for using DL in combination with multimodal data for AD classification and early diagnosis.

CONCLUSIONS: AI is accelerating AD research through DL and multimodal imaging, driving progress in early diagnosis and biomarker discovery. However, challenges remain, including limited data diversity and a lack of model interpretability. Future efforts should focus on developing robust, generalizable, and clinically interpretable models by integrating diverse and longitudinal data to enable personalized diagnosis and treatment.},
}

*Alzheimer Disease/diagnosis
*Bibliometrics
Humans
*Artificial Intelligence/trends
*Biomedical Research

@article {pmid42675877,
year = {2026},
author = {Vinod, P and Arampady, C and Sen, S and Janardhanan, M and Narayanan Kota, L and Ganesh, S and Jayasankar, P and Shankarappa, B and Paul, P and Buddha Nayok, S and J, N and Teotia, V and Manideepika, T and Viswanath, B and Mahadevan, J and Sivakumar, PT and Bharath, S and Varghese, M and Jain, S and Purushottam, M},
title = {Clinical correlates of APOE ε4 homozygosity in Alzheimer's dementia: findings from an Indian cohort.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/17582024.2026.2723525},
pmid = {42675877},
issn = {1758-2032},
abstract = {AIM: The apolipoprotein E ε4 (APOE ε4) allele is a well-established genetic risk factor for Alzheimer's disease (AD), with a gene-dose effect, but its prevalence and clinical correlates in remain underexplored in South Asians. We examined APOE ε4 homozygosity and its clinical correlates in Indian cohort.

PATIENTS AND METHODS: We analyzed APOE genotype data from 393 patients with AD and 850 age-matched healthy controls from India. Variables included family history of dementia, age at onset, behavioral and psychological symptoms of dementia (BPSD), comorbidities (Diabetes and Hypertension), and severity on the Hindi Mental Status Examination (HMSE) and Clinical Dementia Rating (CDR) scale.

RESULTS: APOE ε4 allele frequency was higher in patients with AD (25%) than controls (9%); homozygosity was also more frequent among patients (5% vs 1%; X[2] = 103.48, p < 0.001). Homozygosity was associated with family history of dementia, [Odds Ratio (OR) 4.03, 95% CI 1.46-11.10, p = 0.007], consistent on Firth analysis, but not with age at onset, duration, severity, BPSD, or comorbidities.

CONCLUSION: In this Indian cohort, APOE ε4 homozygosity reflects increased susceptibility and familial aggregation of AD but does not confer a more severe or distinct phenotype, suggesting ancestry- specific expression of APOE ε4 gene-dose effects.},
}

@article {pmid42676120,
year = {2026},
author = {Liu, J and Chen, J and Wyatt-Johnson, SK and Chen, J and Liu, Z and Wu, H and Feng, L and Brutkiewicz, RR and Wang, N},
title = {Quantifying the Diamagnetic and Paramagnetic Components of Beta-Amyloid Plaques Using Decomposed Quantitative Susceptibility Mapping in Mouse Models of Alzheimer's Disease.},
journal = {NMR in biomedicine},
volume = {39},
number = {10},
pages = {e70383},
doi = {10.1002/nbm.70383},
pmid = {42676120},
issn = {1099-1492},
support = {R01 NS125020/NH/NIH HHS/United States ; //Ralph W. and Grace M. Showalter Research Award/ ; //UT Rising STARs award/ ; },
mesh = {Animals ; *Alzheimer Disease/diagnostic imaging/pathology ; *Plaque, Amyloid/pathology/diagnostic imaging ; Disease Models, Animal ; *Magnetic Resonance Imaging ; Mice ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Brain/pathology/diagnostic imaging ; },
abstract = {High-resolution quantitative susceptibility mapping (QSM) combined with susceptibility source decomposition provides a powerful approach for investigating the magnetic susceptibility alterations in Alzheimer's disease (AD). In this study, ex vivo three-dimensional multi-echo gradient-echo (mGRE) images of 5xFAD and A p p SAA mouse brains were acquired at 30 μ m isotropic resolution using a 9.4 T MRI scanner. QSM was reconstructed and decomposed into diamagnetic component susceptibility (DCS) and paramagnetic component susceptibility (PCS). Individual amyloid-beta (A β) plaques were automatically detected and their susceptibility properties were quantitatively characterized. DCS and PCS revealed subvoxel mixtures of diamagnetic and paramagnetic components. Compared with conventional QSM, DCS exhibited clearer plaque visualization and higher plaque detection sensitivity. Histological analysis revealed the coexistence of A β aggregates and ferritin in both mouse models, with most plaques measuring less than 70 μ m in diameter. To assess the impact of spatial resolution on plaque visualization and susceptibility quantification, the acquired k-space data were downsampled to isotropic resolutions of 45, 60, and 90 μ m. As spatial resolution became coarser, plaque visibility degraded progressively, resulting in reductions in both the number of detectable plaques and the estimated plaque burden. Whole-cortex plaque loading decreased from 8.9% at 30 μ m to 3.1% at 90 μ m in 5xFAD and from 6.5% to 2.6% in A p p SAA mice. In both models, detected plaques exhibited predominantly diamagnetic susceptibility, with the diamagnetic component accounting for approximately 80% of the total absolute susceptibility. These findings demonstrate that high-resolution susceptibility mapping combined with source decomposition enables plaque-level characterization of diamagnetic and paramagnetic contributions and provides complementary biomarkers for assessing A β pathology and associated iron dysregulation in preclinical mouse models of AD.},
}

Animals
*Alzheimer Disease/diagnostic imaging/pathology
*Plaque, Amyloid/pathology/diagnostic imaging
Disease Models, Animal
*Magnetic Resonance Imaging
Mice
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
Brain/pathology/diagnostic imaging

@article {pmid42676148,
year = {2026},
author = {Xu, C and Liang, H and Chen, Y and Wang, X and Selvan, GT and Wang, K and Zhu, Q and Xing, Y and Dou, K and Yu, F and Lu, J},
title = {Near-Infrared Imaging of Senescence-Associated β-Galactosidase Enables Discovery of a Glycerol-3-Phosphate Dehydrogenase 2-Regulated Neuroprotective Pathway in Alzheimer's Disease.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {},
doi = {10.1021/acssensors.6c02748},
pmid = {42676148},
issn = {2379-3694},
support = {22204037//National Natural Science Foundation of China/ ; 826YXQN0943//Natural Science Foundation of Hainan Province/ ; NHXXRCXM202319//Natural Science Foundation of Hainan Province/ ; RZ2500002159//Hainan Medical University/ ; XSTS2025018//Hainan Medical University/ ; XSTS2025120//Hainan Medical University/ ; XSTS2026067//Hainan Medical University/ ; },
abstract = {Neuronal senescence is increasingly recognized as a contributor to Alzheimer's disease (AD), yet the molecular mechanisms underlying its progression remain incompletely understood. Herein, we introduce XCH-sen, a β-galactosidase (β-Gal)-responsive near-infrared fluorescent probe designed for imaging senescence-associated β-Gal activity in living cells and animals. Utilizing XCH-sen, we identified glycerol-3-phosphate dehydrogenase 2 (GPD2) as a previously unrecognized regulator of neuronal senescence. The deficiency of GPD2 significantly increased β-Gal activity and accelerated neuronal senescence, which was consistent with the results of SA-β-Gal staining. Mechanistically, loss of GPD2 disrupts mitochondrial redox homeostasis, leading to oxidative stress, mitochondrial dysfunction, impaired autophagic flux, and inflammatory activation, which collectively drive activation of the P16/P21/P53 pathway and cell-cycle arrest. In vivo, GPD2 deficiency exacerbates cognitive impairment, neuroinflammation, Aβ accumulation, and neuronal damage in AD models. Together, this work identifies GPD2 as a metabolic regulator of neuronal senescence and demonstrates the utility of molecular imaging in uncovering mechanisms underlying the progression of neurodegenerative diseases.},
}

@article {pmid42676198,
year = {2026},
author = {Shirolapov, IV and Zakharov, AV and Kurmaev, DP and Bulgakova, SV},
title = {[Molecular and systemic mechanisms of cognitive impairment associated with coronavirus infection].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {8},
pages = {40-50},
doi = {10.17116/jnevro202612608140},
pmid = {42676198},
issn = {1997-7298},
mesh = {Humans ; *COVID-19/complications/physiopathology/metabolism ; *Cognitive Dysfunction/etiology/virology/physiopathology/metabolism ; SARS-CoV-2 ; Post-Acute COVID-19 Syndrome ; Blood-Brain Barrier ; Neuroinflammatory Diseases ; },
abstract = {Cognitive dysfunction represents a prevalent and long-lasting non-respiratory symptom following a protracted course of coronavirus infection, yet its molecular basis remains inadequately characterized. This review aims to present a comprehensive and systematic examination of the pathogenic mechanisms underlying cognitive impairment associated with COVID-19 and to consolidate current evidence on the critical processes linking SARS-CoV-2 infection to long-term neurological outcomes. Evidence indicates that cognitive deficits resulting from COVID-19 arise from a multifaceted interplay, including the virus's direct neurotropic effects, the emergence of neuroinflammation characterized by microglial and astrogliosis activation, disruption of the blood-brain barrier, and cerebrovascular complications. Additionally, systemic neuroendocrine alterations - including dysfunctions of the autonomic nervous system, hypothalamic-pituitary-adrenal axis, and monoamine metabolism - as well as diminished glymphatic clearance, are significant in the pathogenesis and are intricately associated with neuropsychiatric symptoms, thereby perpetuating the pathological processes. The notable molecular similarities with the early stages of neurodegenerative diseases suggest a potential risk for long-term acceleration of neurodegenerative processes in individuals experiencing post-COVID syndrome. Future research should focus on developing integrative diagnostic algorithms that combine biomarkers representative of various pathogenic processes with advanced neuroimaging techniques, organizing longitudinal studies to assess the time course of cognitive disorders, and formulating personalized therapeutic strategies to address key components of the identified pathogenic mechanisms.},
}

Humans
*COVID-19/complications/physiopathology/metabolism
*Cognitive Dysfunction/etiology/virology/physiopathology/metabolism
SARS-CoV-2
Post-Acute COVID-19 Syndrome
Blood-Brain Barrier
Neuroinflammatory Diseases

@article {pmid42676200,
year = {2026},
author = {Gileva, EA and Kovalenko, EA and Makhnovich, EV and Osinovskaya, NA and Bogolepova, AN},
title = {[Current perspectives on non-pharmacological approaches to cognitive impairment].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {8},
pages = {59-65},
doi = {10.17116/jnevro202612608159},
pmid = {42676200},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; Cognitive Training ; Cognitive Enhancement ; },
abstract = {Cognitive impairment (CI) is increasingly recognized as a significant public health issue. Despite extensive research into its causes, mechanisms, and risk factors, along with advancements in pharmacological treatments for associated conditions, preventing or slowing the progression of cognitive decline often cannot be achieved through medication alone. Consequently, non-pharmacological strategies are also employed to support cognitive health in patients with cognitive disorders. This literature review explores the most effective non-drug therapies for cognitive impairment, as well as potential combinations of these approaches.},
}

Humans
*Cognitive Dysfunction/therapy
Cognitive Training
Cognitive Enhancement

@article {pmid42676313,
year = {2026},
author = {Sahli, C and Zhu, H and Kenry, },
title = {Colorimetric gold nanosensors for monitoring protein aggregation: implications for Alzheimer's disease.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc02973f},
pmid = {42676313},
issn = {1364-548X},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide. It remains a major public health challenge due to the lack of early diagnostic tools and effective disease-modifying therapies. Molecularly, AD is characterized by extracellular amyloid-β (Aβ) plaques and intracellular Tau tangles, as well as soluble oligomers that are likely the neurotoxic species. However, the transient and heterogeneous nature of these oligomers makes them difficult to detect using conventional biosensing approaches. Nanomaterial-based colorimetric biosensors have emerged as promising platforms for detecting protein aggregates and discovering aggregation inhibitors. Specifically, the localized surface plasmon resonance properties of metallic nanomaterials can enable rapid, label-free, and visually detectable colorimetric sensing of molecular interactions. These features can be leveraged to monitor protein aggregation processes in real time and achieve high-throughput screening of aggregation inhibitors, which may collectively enable early detection and timely intervention of AD progression. This Review Article presents the design and engineering of gold-nanomaterial-based colorimetric biosensors for monitoring protein aggregation and highlights the current challenges and emerging opportunities for applying these nanosensors to combat AD.},
}

@article {pmid42676462,
year = {2026},
author = {Noh, MY and Sung, W and Kim, H and Son, B and Kim, YE and Choi, YY and Holtzman, DM and Kim, SH},
title = {Lecanemab in symptomatic PSEN1 p.Met233Val early-onset Alzheimer's disease: Neuroimaging safety, regional amyloid-PET dynamics, and longitudinal plasma biomarkers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70468},
pmid = {42676462},
issn = {2352-8729},
abstract = {INTRODUCTION: The presenilin 1 (PSEN1) p.Met233Val variant is a Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU)-eligible autosomal-dominant Alzheimer's disease (ADAD) variant for which lecanemab response data are unavailable.

METHODS: A 34-year-old symptomatic PSEN1 p.Met233Val carrier (APOE ε3/ε3) was prospectively followed through 26 lecanemab infusions over 12 months, with serial magnetic resonance imaging (MRI), amyloid positron emission tomography (PET), and plasma biomarkers.

RESULTS: No amyloid-related imaging abnormalities occurred. Composite Centiloid increased modestly (+7.2), masking regional divergence: basal ganglia (-24.5) and medial temporal cortex (-22.1) declined, whereas posterior cortical regions accrued amyloid. Plasma amyloid beta (Aβ) 42/40 rose to 122% by T22, with concurrent decreases in phosphorylated tau at threonine 217 (p-tau217), p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Global Clinical Dementia Rating (CDR) score remained 0.5; caregiver reports noted improvements in spasticity, dystonia, and affective features.

DISCUSSION: Lecanemab demonstrated neuroimaging safety and evidence of biological target engagement in this symptomatic PSEN1 p.Met233Val ADAD carrier. These longitudinal neuroimaging and plasma biomarker findings may help inform interpretation of treatment responses in genetically defined ADAD.},
}

@article {pmid42676474,
year = {2026},
author = {Yan Liang, T and Cui, X and Adeyosoye, M and Okino Sawada, L and Cabrerizo, M and Cid, REC and Barreto, A and Rishe, N and Loewenstein, DA and Duara, R and Adjouadi, M},
title = {Machine learning for the prediction of amyloid PET positivity using plasma biomarkers, cognition, APOE genotype, and structural imaging.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1905974},
pmid = {42676474},
issn = {1662-4548},
abstract = {PURPOSE: Machine learning to enable precise, non-invasive detection of cerebral amyloid-beta (Aβ) pathology by integrating cognitive assessments, plasma biomarkers, and structural neuroimaging.

METHODS: We developed an explainable multimodal machine-learning framework to predict amyloid PET visual read status using plasma biomarkers, cognitive assessments, APOE genotype, demographic variables, and structural MRI measurements. The development cohort consisted of 170 participants from the 1Florida Alzheimer's Disease Research Center (ADRC) and 129 participants from the ADNI4 cohort. Machine-learning pipelines were evaluated using combinations of five classifiers and multiple feature-selection approaches with Bayesian hyperparameter optimization and stratified five-fold cross-validation. Model interpretability was assessed using SHapley Additive exPlanations (SHAP).

RESULTS: Ensemble methods consistently outperformed linear and distance-based classifiers. The optimal pipeline, XGBoost with mutual-information feature selection, achieved a mean AUC of 0.891 ± 0.048 and a recall of 0.84. SHAP analyses identified the plasma p-tau217/Aβ42 ratio as the most influential predictor, followed by plasma p-tau217, p-tau181, MMSE, and APOE ε4 status. Structural MRI variables provided complementary predictive information. ADNI4 evaluation yielded a mean AUC of 0.545, while training on ADRC and testing on ADNI4 achieved an AUC of 0.636 and an overall accuracy of 63%. Importantly, plasma p-tau217/Aβ42 and p-tau217 remained the dominant predictors across cohorts.

CONCLUSION: Multimodal machine learning can predict amyloid PET status while providing biologically interpretable explanations. Plasma tau and amyloid-related biomarkers carried the strongest predictive signal, while cognition, APOE genotype, and MRI refined classification decisions. External validation highlighted the challenges of cohort heterogeneity and domain shift but demonstrated preservation of biologically meaningful biomarker relationships.},
}

@article {pmid42676482,
year = {2026},
author = {Ren, X and Jin, X and Li, L and Li, F},
title = {Direct toll-like receptor 4 inhibition in Alzheimer's disease models: a focused scoping review of inflammatory, amyloid-handling, and functional outcomes.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1889254},
pmid = {42676482},
issn = {1663-4365},
abstract = {OBJECTIVE: This focused scoping review evaluated whether direct toll-like receptor 4 (TLR4) inhibition, antagonism, or genetic suppression in Alzheimer's disease (AD)-related models was associated with concordant inflammatory, amyloid-β (Aβ)-handling, and functional outcomes.

METHODS: Original AD- or Aβ-related animal, cellular, and ex vivo studies were eligible when they directly inhibited, antagonized, or genetically suppressed TLR4 signaling using pharmacological approaches, including TAK-242/CLI-095/resatorvid, IAXO-101, RSLA, or related TLR4-targeting strategies, or genetic approaches such as TLR4 siRNA, knockdown, knockout, or loss-of-function mutation. Evidence was synthesized using a three-layer framework comprising inflammatory activation, Aβ handling, and neuronal, synaptic, or behavioral consequences.

RESULTS: Direct TLR4 suppression generally attenuated target-proximal inflammatory activation, including microglial activation, pro-inflammatory mediator expression, NF-κB signaling, NLRP3 inflammasome activation, and reactive microglial phenotypes. In contrast, amyloid-related and functional outcomes were heterogeneous. Some studies reported reduced Aβ pathology, enhanced phagocytosis, synaptic protection, or cognitive improvement, whereas others showed impaired amyloid clearance, increased Aβ deposition, or worsened memory-related outcomes. APOE genotype, sex, treatment window, model system, Aβ species, and intervention type appeared to modify the direction of downstream effects.

CONCLUSION: Toll-like receptor 4 suppression relatively consistently attenuated inflammatory readouts, whereas amyloid-related and functional outcomes remained heterogeneous, supporting an exploratory, hypothesis-generating model of context-dependent inflammatory-amyloid-functional dissociation rather than a uniform therapeutic benefit.},
}

@article {pmid42676530,
year = {2026},
author = {Şimşekçi, U and Cesaretli, Y},
title = {From pathology to network failure: a Question-Model-Outcome framework for interpreting animal models of AD-related and dementia-relevant mechanisms.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1882211},
pmid = {42676530},
issn = {1663-4365},
abstract = {Animal studies remain indispensable for research on Alzheimer's disease (AD), vascular cognitive impairment, and other dementia-relevant mechanisms. Their value, however, is not that they reproduce human late-life dementia in miniature. A mouse line, vascular manipulation, or mixed-pathology preparation can make one aspect of the problem experimentally visible while not capturing the long preclinical course, clinical heterogeneity, and everyday functional consequences that define the human syndrome. This review therefore treats animal models as instruments for bounded inference. Drawing on translational, mechanistic, and methodological literature, we ask which biological question is posed, which outcome can legitimately answer it, and where the claim should be drawn back. The Question-Model-Outcome framework is developed around five recurrent problems: the loose relation between lesion burden and functional severity; vascular influences on proteinopathy and network injury; stage-dependent immune and glial responses; the narrow construct validity of many behavioral assays; and the interpretation of reported improvement after intervention. We argue that translational value arises when model biology, disease stage, and outcome level are aligned. In that role, animal studies can sharpen mechanistic reasoning and discipline clinical extrapolation without being treated as generic substitutes for human AD-related dementia.},
}

@article {pmid42676531,
year = {2026},
author = {Li, Y and Liu, S and Lan, J},
title = {P2X7 receptor-dependent microglia-astrocyte coupling in Alzheimer's disease: from eATP sensing to synaptic and proteostatic failure.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1915244},
pmid = {42676531},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is characterized not only by amyloid-β and tau pathology but also by progressive failure of multicellular homeostasis. The P2X7 receptor (P2X7R), a low-affinity ATP-gated ion channel preferentially activated in extracellular ATP-rich pathological microenvironments, is well positioned to translate local tissue stress into sustained glial dysfunction. Although P2X7R has traditionally been studied as a microglial inflammasome-associated receptor, its broader significance may lie in coupling microglial activation to astrocytic loss of homeostatic support. In this review, we propose an integrative model in which P2X7R functions as a high-threshold inter-glial transducer through five interconnected axes: extracellular ATP amplification, cytokine relay, extracellular vesicle exchange, convergent synaptic modulation and circuit destabilization, and a coordinated clearance-to-retention switch. Microglial P2X7R activation promotes cytokine and reactive oxygen species production, vesicle and mitochondrial release, inflammatory reprogramming, and impaired phagocytic and lysosomal competence. Astrocytic P2X7R may reinforce this environment through feed-forward ATP release, altered gliotransmission, reactive transformation, extracellular vesicle shedding, and disrupted autophagic and lysosomal processing. We further situate this reciprocal loop within the amyloid plaque niche, where dystrophic neurites, stressed synapses, and reactive glia may create a spatially restricted P2X7R-sensitive ATP microdomain. The resulting cross-glial amplification is proposed to connect neuroinflammation with synaptic destabilization and defective proteostasis. This framework also suggests that brain-penetrant and pharmacologically selective P2X7R antagonists could complement protein-targeted therapies, particularly when guided by functional biomarkers of receptor activity. However, the proposed coupling architecture remains an integrative and testable hypothesis because much of the supporting evidence derives from non-AD models, in vitro studies, or correlative human tissue analyses. Cell-type-specific, temporally resolved studies are therefore required to establish whether P2X7R-dependent microglia-astrocyte coupling causally drives AD progression.},
}

@article {pmid42676548,
year = {2026},
author = {Moses, S and Phulambrikar, T and Dosi, T},
title = {From Mouth to Mind: Unraveling the Oral Microbiome's Role in Orofacial Pain and Neurodegeneration.},
journal = {Journal of clinical practice and research},
volume = {48},
number = {4},
pages = {356-367},
pmid = {42676548},
issn = {2980-2156},
abstract = {The human oral cavity hosts a diverse and dynamic microbiome comprising more than 700 microbial species, which plays a crucial role in maintaining oral and systemic health. Oral dysbiosis, defined as disruption of this microbial balance, has been increasingly implicated not only in periodontal disease but also in the pathogenesis of orofacial pain and neurodegenerative diseases. Key pathogens, such as Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum, have been proposed to release virulence factors, including lipopolysaccharides and gingipains, which may activate immune pathways and nociceptors, thereby driving peripheral sensitization and neuroinflammation. These organisms have also been suggested to breach mucosal and vascular barriers, enter the systemic circulation, and, in some cases, access the central nervous system. Evidence has linked oral pathogens to Alzheimer's disease, Parkinson's disease, autism spectrum disorder, and multiple sclerosis. Notably, P. gingivalis and its gingipains have been identified in postmortem brain tissue from patients with Alzheimer's disease, with proposed roles in neuroinflammation and amyloid plaque formation. Salivary microbial alterations in burning mouth syndrome and temporomandibular disorders further highlight the influence of the oral microbiome on neuropathic pain. Therefore, the oral-gut-brain axis represents a novel and promising area of investigation, offering potential diagnostic biomarkers and targeted microbial therapies for the management of chronic orofacial pain and neurological disorders.},
}

@article {pmid42676569,
year = {2026},
author = {Khan, MA and Sher, N},
title = {Comment on "The Diagnostic Performance of the AlzoSure Predict Assay and Its Association With Alzheimer's Disease Biomarkers and Imaging Findings".},
journal = {Health science reports},
volume = {9},
number = {9},
pages = {e73152},
pmid = {42676569},
issn = {2398-8835},
}

@article {pmid42676641,
year = {2026},
author = {Inoue, T and Nakamura, T and Senba, L and Narumoto, J},
title = {Comparison of Gaze Behavior During a Visual Search Task in a Virtual Reality Environment Between Individuals With Alzheimer's Disease and Healthy Older Adults.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e113761},
pmid = {42676641},
issn = {2168-8184},
abstract = {INTRODUCTION: Decline in spatial attention is a core feature of Alzheimer's disease (AD) that directly impairs everyday visual search behavior, such as locating items during shopping. Japan's rapidly aging population has led to a growing prevalence of dementia, with AD being the most common subtype. The use of virtual reality (VR) enables standardized cognitive assessment in ecologically valid settings.

METHODS: A total of 25 individuals with AD and 30 healthy controls (HC) aged 65 years or older performed a visual search task presented via a head-mounted display (HMD; VIVE Pro Eye, HTC Corporation, Taoyuan, Taiwan) showing a VR simulation of a supermarket beverage section captured with a 360° camera. Participants were instructed to locate a lemon tea product within 30 seconds. Eye movements were recorded binocularly at 120 Hz. The viewing field was divided into a 48×48 grid; fixation duration and proportion in the central region (columns 20-27, rows 24-33) were extracted and compared between groups using independent samples t-tests. The chi-square test of independence was used to compare the rate of successful target identification.

RESULTS: Compared with HC, the AD group showed significantly longer central fixation duration (11.63 s vs. 6.66 s, p = .009) and a higher central fixation proportion (38.55% vs. 22.06%, p = .009). None of the AD participants identified the target within the time limit, compared with 15 of 30 (50%) HC participants (χ²(1) = 17.19, p < .001, φ = -0.559).

CONCLUSION: Individuals with AD demonstrated a restricted gaze pattern characterized by central fixation bias during VR-based visual search, reflecting impaired exploratory eye movements and narrowed visual search range. These findings suggest that VR-based gaze analysis may serve as a useful tool for evaluating functional visual cognition in AD and that consideration of these gaze characteristics may inform the design of more accessible retail environments and support daily functioning and social participation.},
}

@article {pmid42676723,
year = {2026},
author = {Zhao, B and Wei, M and Shang, S and Gao, L and Wei, S and Dang, L and Liu, J and Chen, C and Li, Y and Wang, J and Gao, F and Qu, Q},
title = {Acute total sleep deprivation transiently increases plasma total tau but not plasma P-tau181 in healthy adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1904137},
pmid = {42676723},
issn = {1663-4365},
abstract = {BACKGROUND: Sleep deprivation is a modifiable risk factor for Alzheimer's disease (AD). Plasma amyloid-β (Aβ) and phosphorylated tau (P-tau) are closely related to cerebral AD pathology and serve as peripheral biomarkers. Our previous work showed that acute sleep deprivation elevated plasma Aβ40 in healthy adults. Here we conducted an exploratory analysis to examine the effects of sleep deprivation and subsequent recovery on plasma total tau (T-tau) and P-tau181 levels.

METHODS: Twenty healthy adults underwent 24 h of total sleep deprivation followed by daytime naps and a full night of recovery. Venous blood was drawn at 12 predefined time points. Plasma T-tau and P-tau181 were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTS: Plasma T-tau increased by 35.09% (P = 0.018) after 24 h of sleep deprivation, and decreased by 37.78% (P = 0.005) after sleep recovery. The rise in T-tau was positively correlated with wakefulness duration (β = 0.629, P < 0.001). In contrast, no significant changes in plasma P-tau181 were detected with sleep deprivation or recovery under the present experimental conditions.

CONCLUSION: Under an experimental protocol of 24-h sleep deprivation followed by recovery sleep, transient elevation of plasma T-tau (but not P-tau181) was observed in healthy young adults in this exploratory study. These findings indicate that conditions involving short-term sleep loss are associated with fluctuations in a nonspecific plasma marker of neuronal activity.},
}

@article {pmid42676794,
year = {2026},
author = {Cui, X and Wei, Z and Wang, Q and Du, S and Lin, Z and Chen, Z and Zhang, J and Li, C and Tang, L and Dai, X and He, W},
title = {Astragalus polysaccharide alleviates neuropathology and cognitive deficits by modulating gut microbiota and neuroinflammation in an Alzheimer's disease model.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1830927},
pmid = {42676794},
issn = {1663-9812},
abstract = {BACKGROUND: Emerging evidence indicates that the neuroprotective effects of Astragalus polysaccharides (APS), an extract compound and bioactive constituent derived from traditional Chinese herbs, may be relevant to an effective prescription for delaying progression of Alzheimer's disease (AD), yet the underlying mechanisms remain to be fully elucidated. This study aimed to investigate the therapeutic efficacy of APS in alleviating cognitive impairment and neuropathology in 5×FAD transgenic mice, with a specific focus on the regulatory role of the gut-brain axis.

METHODS: Male 5×FAD mice were orally administered APS (200 mg/kg/day) for 60 days. General observations were conducted to assess the in vivo tolerance of APS. Cognitive function was evaluated using the Morris water maze (MWM). Neuropathological assessments included immunofluorescence and Western blotting for amyloid-β (Aβ) deposition, synaptic proteins, and neuroinflammatory markers. Gut microbiota composition and metabolic profiles were analyzed via 16S rRNA gene sequencing and targeted metabolomics. Furthermore, fecal microbiota transplantation (FMT) was performed to verify the causal contribution of gut microbiota to the observed therapeutic effects.

RESULTS: APS administration was well-tolerated throughout the study period, with no overt toxic effects observed. Moreover, APS administration significantly ameliorated spatial learning and memory deficits in 5×FAD mice. Mechanistically, APS treatment reduced Aβ plaque burden, restored synaptic protein expression (PSD-95 and Syntaxin), and attenuated microglia-mediated neuroinflammation by suppressing pro-inflammatory cytokines (IL-6, TNF-α) and upregulating TREM2. Microbiome analysis revealed that APS reshaped gut microbial diversity and composition, enriching beneficial taxa such as Lactobacillus. Metabolomics indicated a partial restoration of amino acid metabolism. Notably, FMT from APS-treated donors successfully reproduced the cognitive improvements and anti-inflammatory effects in recipient mice.

CONCLUSION: These findings demonstrate that APS alleviates cognitive deficits and AD-like pathology, partially through remodeling gut microbiota and modulating the gut-brain axis. APS represents a promising natural compound-based therapeutic candidate for managing cognitive decline associated with Alzheimer's disease.},
}

@article {pmid42677017,
year = {2026},
author = {Gyebi, GA and Onesi, OO and Sabiu, S},
title = {Machine Learning-Driven Bioprospecting of Cholinergic Medicinal Plants for Putative Leads Against Butyrylcholinesterase Towards Alzheimer's Care.},
journal = {Biochemistry research international},
volume = {2026},
number = {},
pages = {4503245},
pmid = {42677017},
issn = {2090-2247},
abstract = {Butyrylcholinesterase (BChE) plays a key role in preserving appropriate cholinergic neurotransmission that is essentially altered in the brains of advanced Alzheimer's disease (AD), hence a therapeutic target. This study employed a machine learning (ML) bioactivity predictive model to explore the chemical space of potential BChE inhibitors. A cheminformatics pipeline was explored to create a ML model for BChE inhibition using structural insights complemented with a comprehensive variance importance plot (VIP) and correlation matrix analysis. Specifically, a compiled library of 2179 secondary metabolites (SMs) from 50 Nigerian medicinal plants with reported cholinergic activity was investigated using the ML model. After which, molecular modelling was used to further screen the active SMs (827). The final predicted models demonstrated significant robustness, with a correlation coefficient of 0.8981. Molecular docking investigation of the 827 SMs identified the top five candidates based on their scores: three triterpenoids (adipedatol, lupenone and β-amyrin), one steroid (9 (11)-dehydroergosterol benzoate) and one flavonoid (tiliroside). These leads exhibited favourable ADMET properties and promising safety profiles. Among these five, lupenone (-48.78 kcal/mol), β-amyrin (-49.19 kcal/mol) and adipedatol (-48.87 kcal/mol), from Peltophorum pterocarpum, Bryophyllum pinnatum and Alchornea laxiflora, respectively, were the most promising leads with significant binding free energy compared to decamethonium (-17.64 kcal/mol) and more favourable van der Waals, electrostatics and nonpolar solvation energetics. Furthermore, the binding of these leads resulted in optimised interaction profiles that preserved the structural integrity of the BChE and aligned well with desirable drug-like characteristics. These findings position the leads as promising candidates for therapeutic applications targeting BChE for AD management, subject to further in vitro and in vivo validation investigations.},
}

@article {pmid42677111,
year = {2026},
author = {Şen, A and Eroğlu Güneş, C and Dursun, EN and Kurar, E and Kutlu, S},
title = {Investigation of neuroprotective and antiapoptotic effects of rosmarinic acid in an in vitro Alzheimer's disease model.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {8},
pages = {1241-1248},
pmid = {42677111},
issn = {2008-3866},
abstract = {OBJECTIVES: Rosmarinic acid (RA) exhibits anti-oxidant, anti-aging, and anti-inflammatory properties. This study aimed to investigate the effects of RA on amyloid beta (Aβ), phosphorylated tau (p-tau), α-synuclein (α-syn), Abelson tyrosine kinase (Abl), and apoptotic markers in an in vitro Alzheimer's disease (AD) model.

MATERIALS AND METHODS: SH-SY5Y cells were differentiated into cholinergic neurons by all-trans retinoic acid (ATRA). CCK-8 assay was performed to determine the concentrations of Aβ, RA, and Aβ+RA on differentiated cells (D-cholinergic neurons). Then, control (D), D+Aβ, pretreatment (D+Aβ+RA), and D+RA groups were formed. Gene expression levels of apoptotic biomarkers were evaluated using qRT-PCR. Aβ, α-syn, Abl, p-tau, caspase-7 (CASP7), BAX, and cytochrome c (CYCS) protein levels were determined by ELISA.

RESULTS: CCK-8 assay showed that RA (0.5-5 µM) was non-toxic to differentiated cells, and the IC₄₀ of Aβ₁₋₄₂ was 20 µM. Pretreatment with 1.5 µM RA protected cells from Aβ-induced toxicity. Gene expression analysis revealed that apoptotic markers (BAX, BLC2, CYCS, CASP3, CASP7, FAS, FADD) were significantly increased in the D+Aβ group compared to the control, whereas their levels were markedly reduced in the D+Aβ+RA group relative to the D+Aβ group. ELISA results corroborated qRT-PCR findings for CASP7, BAX, and CYCS. Additionally, RA decreased Aβ, α-syn, and p-tau protein levels, while Abl levels increased only in the D+RA group.

CONCLUSION: RA exhibits neuroprotective and antiapoptotic effects by modulating apoptotic markers and reducing pathological proteins in an in vitro AD model.},
}

@article {pmid42677148,
year = {2026},
author = {Doyon, V and Janelle, F and Sean, M and Vanderweyen, D and Côté, S and Huck, J and Tétreault, P and Lepage, JF and Gutierrez, J and Bocti, C and Fülöp, T and Pichet-Binette, A and Whittingstall, K},
title = {A vascular component to the selective vulnerability of the medial temporal lobe to tau pathology.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag301},
pmid = {42677148},
issn = {2632-1297},
abstract = {The medial temporal lobe is widely recognized as an early site of pathological tau deposition, a central feature in the development of cognitive symptoms. As of now, the biological mechanisms underlying this selective vulnerability of the medial temporal lobe are not yet understood. Here, we tested whether alterations in medial temporal lobe arterial structure are associated with early tau accumulation and cognitive decline. We first applied a novel imaging methodology (super-selective arterial spin labelling) to map vascular supply to the medial temporal lobe. Next, we cross-sectionally investigated the relationship between medial temporal lobe artery diameters and tau burden, derived from magnetic resonance angiography and positron emission tomography imaging, in 151 cognitively unimpaired individuals (mean age: 67.6 years old). Finally, we examined whether artery diameter was correlated with the rate of cognitive decline in a separate cohort of 43 individuals (mean age: 74.2 years old). We found that the blood supply to the medial temporal lobe depended more on arteries from the anterior circulation than the posterior circulation. Individuals with small anterior choroidal artery diameters tended to show higher medial temporal lobe tau burden (r = -0.26, P = 0.001) and faster rates of cognitive decline (r = -0.40, P = 0.012). These results remained significant after adjusting for potential confounding factors such as amyloid burden. Our results show that anterior choroidal artery diameter may be an amyloid-independent determinant of tau pathology and cognitive decline. This suggests that the selective vulnerability of the medial temporal lobe may emerge from subpar perfusion from the anterior circulation.},
}

@article {pmid42677190,
year = {2026},
author = {Li, J and Ji, C and Wang, J and Xiao, J and Li, H and Xie, X and Zhi, N and Song, Y and Cao, W and Wang, L and Geng, J and Ren, R and Wang, G},
title = {Elevated endogenous glucagon-like peptide-1 as a novel Alzheimer's disease biomarker associated with neuroinflammation and Aβ pathology.},
journal = {General psychiatry},
volume = {39},
number = {5},
pages = {e70052},
pmid = {42677190},
issn = {2517-729X},
abstract = {BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disorder, is pathologically defined by the accumulation of amyloid-β (Aβ) plaques, hyperphosphorylated tau tangles and sustained neuroinflammation. Glucagon-like peptide-1 (GLP-1), originally characterised as an incretin hormone, is also expressed endogenously in the brain. Although GLP-1 receptor agonists (GLP-1RAs) have demonstrated compelling neuroprotective effects in preclinical AD models, their efficacy in human clinical trials has, thus far, been inconsistent and limited. Moreover, the physiological role and dynamics of endogenous GLP-1 during AD progression remain poorly understood, with studies reporting conflicting findings across different patient cohorts.

AIMS: This study aimed to characterise serum GLP-1 levels across the Alzheimer's disease cognitive continuum and to examine their associations with neuroinflammation, Aβ pathology, tau pathology, brain atrophy and cognitive decline.

METHODS: We analysed two independent cohorts (Renji: n = 123; SheMountain: n = 127), including participants with cognitive unimpairment, mild cognitive impairment and AD dementia. Serum biomarkers (GLP-1, glial fibrillary acidic protein [GFAP], Aβ40, Aβ42 and tau phosphorylated at threonine 217 [pTau217]) were quantified, along with APOE genotyping, neuropsychological assessments, brain magnetic resonance imaging and Aβ-PET imaging. Postmortem brain tissue GLP-1 expression was analysed in the prefrontal cortex (PFC) and hippocampus (HP). Statistical analyses included partial correlations, mediation analysis and machine learning models.

RESULTS: GLP-1 levels were significantly elevated in both brain tissue and serum of patients with AD compared to controls, with concentrations increasing progressively from cognitively normal individuals through mild cognitive impairment (MCI) to AD dementia. Serum GLP-1 negatively correlated with Montreal Cognitive Assessment (MoCA) cognitive performance and positively correlated with GFAP, pTau217 and brain amyloid burden. Serial mediation analysis suggested that GLP-1 and GFAP were statistically positioned along the association between amyloid burden and tau pathology. Machine learning models combining GLP-1 with other biomarkers achieved diagnostic performance (area under the curve = 0.896).

CONCLUSIONS: The elevation of endogenous GLP-1 in Alzheimer's disease likely represents a compensatory yet ultimately insufficient response to the underlying pathology. It functions as a multidimensional biomarker, reflecting the integrated neuroinflammatory burden, amyloid deposition and clinical disease severity, and may have potential utility in diagnostic applications.},
}

@article {pmid42677229,
year = {2026},
author = {Tarbiat, S and Bal, T and Gülmez, D},
title = {Profiling arbutin as a potent cholinesterase and GSK-3β inhibitor and evaluating its cytotoxicity in SH-SY5Y cells for Alzheimer's disease therapy.},
journal = {Turkish journal of biology = Turk biyoloji dergisi},
volume = {50},
number = {4},
pages = {286-295},
pmid = {42677229},
issn = {1303-6092},
abstract = {BACKGROUND/AIM: Alzheimer's disease (AD) is a neurodegenerative disorder linked to cognitive decline and memory loss, marked by hyperphosphorylated tau tangles and decreased acetylcholine levels, which are affected by acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. Glycogen synthase kinase-3 beta (GSK-3β) also plays a role in AD through abnormal activation. In this study, the potential of β-arbutin to inhibit cholinesterases and GSK-3β was investigated, utilizing in vitro assays, cytotoxicity analysis, and molecular docking simulations to explore its therapeutic implications.

MATERIALS AND METHODS: Ellman's technique was used to test the inhibitory effects of arbutin on cholinesterase enzymes. An ATP-Glo luminescent assay kit was used to evaluate the inhibitory effects and inhibition kinetics of arbutin on GSK-3β. A Cell Titer-Glo 2.0 assay kit was used to assess the cytotoxicity of arbutin in SH-SY5Y cells.

RESULTS: β-Arbutin exhibited significant inhibitory effects on AChE, BuChE, and GSK-3β, with IC50 values of 0.6, 4, and 1.23 μM, respectively. The inhibition kinetics of GSK-3β with respect to ATP was competitive but with respect to the substrate (GS-2) was noncompetitive. We further found that β-arbutin, when applied alone to SH-SY5Y cells, does not affect cell viability and can ensure the sustainability of cell viability and health. Docking scores were -7.980, -6.726, and -6.115 kcal/mol for GSK-3β, AChE, and BuChE, respectively.

CONCLUSION: Our research demonstrates that arbutin is a modulator of cholinesterase and GSK-3β and may be beneficial as a multitarget-directed therapeutic natural compound for AD.},
}

@article {pmid42677254,
year = {2026},
author = {Dönmez, MO and Şener, A and Karaman Ersoy, Ş and Marzi, M and Şener, G},
title = {L-theanine attenuates AlCl3-induced cognitive dysfunction and neurotoxicity in rats: a behavioral and biochemical study.},
journal = {Turkish journal of medical sciences},
volume = {56},
number = {4},
pages = {1308-1319},
pmid = {42677254},
issn = {1303-6165},
mesh = {Animals ; *Glutamates/pharmacology ; Aluminum Chloride/toxicity ; Male ; Rats, Wistar ; Rats ; *Cognitive Dysfunction/chemically induced/drug therapy ; Lipid Peroxidation/drug effects ; Aluminum Compounds ; Disease Models, Animal ; *Alzheimer Disease/chemically induced/drug therapy ; Brain/drug effects/metabolism ; *Neurotoxicity Syndromes/drug therapy/etiology ; Glutathione/metabolism ; Oxidative Stress/drug effects ; Chlorides ; Acetylcholinesterase/metabolism ; Maze Learning/drug effects ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND/AIM: The effects of L-theanine (LTN), a natural compound found in tea leaves, on biochemical parameters and cognitive functions were investigated in an aluminum chloride (AlCl3)-induced Alzheimer's disease-like experimental model.

MATERIALS AND METHODS: A total of 32 male Wistar rats were allocated into four groups: control, AlCl3-induced AD-like group, LTN-treated AD-like group, and donepezil-treated AD-like group. Donepezil was used as a reference drug. For the induction of AlCl3-induced neurotoxicity, AlCl3 was administered by gavage at a dose of 25 mg/kg/day during the 1st week and 150 mg/kg/day for the subsequent 3 weeks. LTN was administered orally at a dose of 100 mg/kg. Spatial memory was assessed using the Morris water maze and the novel object recognition test. Brain tissues were collected to analyze acetylcholinesterase, catalase, and myeloperoxidase activities, as well as amyloid beta (Aβ), lipid peroxidation, glutathione, and nitric oxide levels.

RESULTS: LTN reversed AlCl3-induced cognitive deficits. Moreover, the elevations in acetylcholinesterase and myeloperoxidase activities, as well as increased Aβ levels in the brain tissues of AlCl3-treated rats, were significantly reduced following LTN treatment. The increases in lipid peroxidation and nitric oxide observed in the AlCl3 group were suppressed by LTN treatment, while decreased antioxidant defenses, namely reduced glutathione levels and catalase activity, were restored.

CONCLUSION: The findings demonstrate that AlCl3 exposure impairs cholinergic function, induces oxidative damage, and leads to cognitive dysfunction, whereas LTN treatment effectively mitigates these effects, suggesting potential neuroprotective benefits against aluminum-induced neurotoxicity.},
}

Animals
*Glutamates/pharmacology
Aluminum Chloride/toxicity
Male
Rats, Wistar
Rats
*Cognitive Dysfunction/chemically induced/drug therapy
Lipid Peroxidation/drug effects
Aluminum Compounds
Disease Models, Animal
*Alzheimer Disease/chemically induced/drug therapy
Brain/drug effects/metabolism
*Neurotoxicity Syndromes/drug therapy/etiology
Glutathione/metabolism
Oxidative Stress/drug effects
Chlorides
Acetylcholinesterase/metabolism
Maze Learning/drug effects
Neuroprotective Agents/pharmacology

@article {pmid42677302,
year = {2026},
author = {Patel, D and Rakowiecki, K and Lazarov, O},
title = {Amyloid precursor protein dosage normalization rescues neurogenesis and Alzheimer's Disease phenotypes associated with Down Syndrome.},
journal = {Medical research archives},
volume = {14},
number = {6},
pages = {},
pmid = {42677302},
issn = {2375-1916},
abstract = {Down Syndrome (DS) is the most abundant genetic form of mental retardation. It is caused by the triplication of partial or complete human chromosome 21 (HSA21). The molecular mechanisms of DS are not fully understood. Amyloid precursor protein (APP) resides on HSA21 and is triplicated in DS. While it is not thought to be a part of the "Down syndrome Critical Region", APP plays a role in developmental and post-natal neurogenesis and synaptic plasticity, thus, its triplication may affect cortical development in DS. Further, mutations in APP cause familial Alzheimer's disease (AD). However, whether APP overdose is sufficient or required for the development of Alzheimer's disease in DS is not fully elucidated. Here, we addressed the role of APP overdose in neuronal development and AD pathology. Using DS patient-derived induced pluripotent stem cells in which one copy of APP was silenced using CRISPR-Cas9, we examined developmenta neurogenesis, AD-related pathology and the expression levels of genes on HSA21 that are implicated in DS, neurodegeneration and inflammation. Amyloid precursor protein triplication, in DS induced pluripotent stem cells, led to reduced stem cell proliferation, enhanced differentiation into neurons, increased amyloid pathology, and altered protein levels of selected genes on HSA21. Correction of APP gene dosage rescued the altered neurogenesis phenotype and reduced pathological amyloidogenic processing. These data highlight APP dosage as a key regulator of neuronal maturation and AD pathology in DS, suggesting therapeutic value in targeting APP expression to mitigate neurodevelopmental and neurodegenerative features of the disorder.},
}

@article {pmid42677332,
year = {2026},
author = {Lahiri, D},
title = {The Need for a Fast-track Pathway to Streamline Disease-modifying Treatments in Early Alzheimer's Disease.},
journal = {Canadian geriatrics journal : CGJ},
volume = {29},
number = {3},
pages = {209-210},
pmid = {42677332},
issn = {1925-8348},
}

@article {pmid42677463,
year = {2026},
author = {Denkinger, MN and Brum, WS and Leuzy, A and Singh, A and Marques, TM and Ghisays, V and Protas, H and Su, Y and Atri, A and Beach, TG and Serrano, GE and Bhatt, K and Carlson, CM and Hoffmann, K and Reiman, EM and Ashton, NJ},
title = {Brain-derived plasma p-tau217 shows enhanced dynamic range for Alzheimer's disease neuropathological change.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71773},
doi = {10.1002/alz.71773},
pmid = {42677463},
issn = {1552-5279},
support = {U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30AG072980/AG/NIA NIH HHS/United States ; 05700//Arizona Department of Health Services/ ; 4001 0011 05-901//Arizona Biomedical Research Commission/ ; 1001//Arizona Biomedical Research Commission/ ; CTR040636//Michael J. Fox Foundation for Parkinson's Research/ ; //Arizona Department of Health Services and Gates Ventures/ ; },
mesh = {Humans ; *tau Proteins/blood/metabolism ; *Alzheimer Disease/pathology/blood ; Female ; Biomarkers/blood ; Amyloid beta-Peptides/blood ; Male ; *Brain/pathology/metabolism ; Phosphorylation ; Aged ; Peptide Fragments/blood ; Aged, 80 and over ; Positron-Emission Tomography ; },
abstract = {INTRODUCTION: Plasma phosphorylated tau (p-tau), particularly p-tau217, is a highly specific biomarker of Alzheimer's disease (AD) pathology. However, plasma p-tau217 can be elevated in rare non-AD conditions. Brain-derived (BD) p-tau217 may reduce these off-target effects, but its performance against neuropathology has not been evaluated.

METHODS: We compared p-tau217, BD p-tau217, their amyloid beta 42 (Aβ42) ratios, BD p-tau217/p-tau217, and BD p-tau217/BD tau in end-of-life plasma from 288 neuropathologically characterized participants using a fully automated immunoassay. Biomarkers were assessed against National Institute on Aging-Alzheimer's Association (NIA-AA) classification, Thal phase, Braak stage, cognitive decline, and tau-PET (positron emission tomography).

RESULTS: All markers tracked neuropathological severity, with BD p-tau217 having larger fold-changes than p-tau217 but BD p-tau217/Aβ42 enhancing this further. BD p-tau217/BD tau achieved the highest area under the curve (AUC) for distinguishing Intermediate/High from Not/Low AD neuropathological change (ADNC) (0.89 vs 0.82 for p-tau217). Although BD p-tau217/p-tau217 showed smaller fold-changes, it had the strongest association with continuous tangle burden in AD (R[2] = 0.68) and best predicted Clinical Dementia Rating Sum of Boxes (CDR-SB decline) (R[2] = 0.26).

DISCUSSION: BD p-tau217 and BD-based ratios enhance dynamic range and prognostic performance while maintaining diagnostic accuracy, supporting further clinical evaluation.},
}

Humans
*tau Proteins/blood/metabolism
*Alzheimer Disease/pathology/blood
Female
Biomarkers/blood
Amyloid beta-Peptides/blood
Male
*Brain/pathology/metabolism
Phosphorylation
Aged
Peptide Fragments/blood
Aged, 80 and over
Positron-Emission Tomography

@article {pmid42677560,
year = {2026},
author = {Powell, WC and Yan, N and Tse, E and Melo, AA and Vasquez, JA and Southworth, DR and Gestwicki, JE},
title = {Cofactor-Free Tau Filaments Are Dynamic and Undergo Structural Evolution Driven by Thermodynamic Control.},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {33},
pages = {35386-35398},
doi = {10.1021/jacs.6c04928},
pmid = {42677560},
issn = {1520-5126},
support = {NA//BrightFocus Foundation/ ; NA//Tau Consortium/ ; NS059690//National Institutes of Health (NIH)/ ; },
mesh = {*tau Proteins/chemistry/metabolism ; *Thermodynamics ; Humans ; },
abstract = {Tau filaments are a hallmark of neurodegenerative tauopathies, such as Alzheimer's disease (AD). Structural studies have revealed that patient-derived tau fibrils adopt distinct folds in different tauopathies; however, it is unclear what forces guide this process. To explore this question, we investigated the assembly of a tau fragment containing four disease-associated phospho-mimetics (termed Tau(297-407)-4D) in vitro. Under cofactor-free and quiescent conditions, Tau(297-407)-4D forms fibrils with a core structure that partially resembles the AD fold after about 7 days. Strikingly, we noticed that this filament behaves as a hydrogel and evolves into two new polymorphs as it ages over the next 35 days. Thus, tau fibrils formed under cofactor-free conditions are dynamic, exhibiting substantial nonequilibrium behavior. To probe what types of perturbations might stabilize these structures, we applied mechanical agitation, which drove the filaments toward thermodynamic equilibrium in a mechanism consistent with Ostwald ripening into solid-phase, micrometer-sized particles. Likewise, the addition of polyanionic cofactors to preformed Tau(297-407)-4D fibrils significantly stabilized them, as judged by solubility equilibria and chemical denaturation experiments. A subset of the polyanions also remodeled the fibril structure and tuned the extent of fibril-fibril interactions (i.e., "clumping"). We conclude that environmental factors, such as mechanical stress and/or polyanions, play an important role in promoting the thermodynamic stability of otherwise dynamic tau fibrils. We speculate that, in patients, such factors might contribute to the maturation of disease-specific conformers.},
}

*tau Proteins/chemistry/metabolism
*Thermodynamics
Humans

@article {pmid42677635,
year = {2026},
author = {Huang, Q and Fu, J and Zhang, L and Yao, J and Cao, H and Zheng, L and Zhao, C and Xiao, J},
title = {Identification of Cysl-2 as a Compensatory Factor in Vitamin B12-Mediated Protection in a Mitochondrial Aβ Toxicity Model.},
journal = {Journal of agricultural and food chemistry},
volume = {74},
number = {33},
pages = {26389-26400},
doi = {10.1021/acs.jafc.6c07935},
pmid = {42677635},
issn = {1520-5118},
support = {RYC2020-030365-I//Fundaci?n Ram?n Areces/ ; IJC2020-046055-I//Ministerio de Ciencia, Innovaci?n y Universidades/ ; ED431F2022/01//Xunta de Galicia/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Mitochondria/metabolism/genetics/drug effects ; *Vitamin B 12/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Amyloid beta-Peptides/metabolism/genetics/toxicity ; *Alzheimer Disease/metabolism/genetics ; Humans ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a highly sophisticated disease associated with mitochondrial deterioration, which potentiates proteotoxic stress and accelerates neuronal decline. Vitamin B12 (B12), an essential cofactor in one-carbon metabolism and cellular homeostasis, plays a pivotal role in modulating neurodegenerative pathology. Here, we established a mitochondrial-associated AD model by using Caenorhabditis elegans (C. elegans) expressing Aβ combining with the mtDNA deletion uaDf5, and evaluated the effect of B12 as a metabolic modulator of neurodegenerative stress. We observed that mitochondrial dysfunction markedly exacerbated Aβ phenotypes, while B12 mitigated paralysis and cellular deficits. Integrated transcriptomics and proteomics revealed a compensatory mechanism activated by B12 under mitochondrial stress, predominantly engaging one-carbon and transsulfuration pathways. Functional analyses uncovered that metr-1 and cysl-2 are required for B12-mediated protection, and multiomics corroborated this rescue axis. This study indicates that cysl-2 is an essential mediator and reveals a B12-driven adaptive response, which provides mechanistic insight into nutrition-based neuroprotection in AD.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics
*Mitochondria/metabolism/genetics/drug effects
*Vitamin B 12/metabolism
*Caenorhabditis elegans Proteins/metabolism/genetics
*Amyloid beta-Peptides/metabolism/genetics/toxicity
*Alzheimer Disease/metabolism/genetics
Humans
Disease Models, Animal

@article {pmid42677779,
year = {2026},
author = {Ali, A and Arif, M and Ashraf, U and Elahi, S and Mustafa, A and Yasir, MB and Sarfraz, W and Ansari, AU and Masood, HMY and Shabbir, MA and Abdullah, A and Sharma, MK},
title = {CSF Tau and Amyloid Biomarkers in Cognitive Impairment Across the ALS-FTD Spectrum: A Systematic Narrative Review and Evidence Map.},
journal = {Brain and behavior},
volume = {16},
number = {9},
pages = {e71740},
doi = {10.1002/brb3.71740},
pmid = {42677779},
issn = {2162-3279},
mesh = {Humans ; *tau Proteins/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/complications ; Biomarkers/cerebrospinal fluid ; *Frontotemporal Dementia/cerebrospinal fluid/complications ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/etiology ; },
abstract = {INTRODUCTION: Cognitive impairment is an important non-motor manifestation of amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (ALS-FTD) spectrum. Cerebrospinal fluid (CSF) tau and amyloid biomarkers may reflect nonspecific neurodegenerative injury, concomitant Alzheimer disease (AD) pathology, or distinct cognitive phenotypes. However, available evidence remains limited, fragmented, and methodologically heterogeneous.

METHODS: This systematic narrative review and semi-quantitative evidence map was conducted according to PRISMA 2020 recommendations. PubMed, Scopus, Web of Science, and Google Scholar were searched from database inception through May 2026. Eligible observational studies reported cognition-specific associations between CSF tau, amyloid, or related neurodegenerative biomarkers and cognitive outcomes in ALS-spectrum populations. Two reviewers independently screened studies, extracted quantitative effect estimates, and assessed risk of bias using the Newcastle-Ottawa Scale. Cross-study consistency was summarized using an exploratory semi-quantitative evidence-coding framework.

RESULTS: Four observational studies comprising 638 ALS-spectrum participants fulfilled the eligibility criteria. Total tau and p-tau181 showed the most reproducible associations with cognition. Total tau correlated with ECAS total (r = -0.398, P < 0.001) and ALS-specific cognition (r = -0.403, P < 0.001), while adjusted multicenter analyses demonstrated associations between p-tau181 and ECAS total (β = -0.03, p = 0.006) and memory performance (β = -0.04, p = 0.003). Both biomarkers received ++ evidence-map coding. Amyloid findings were more heterogeneous; lower Aβ42/Aβ40 was associated with poorer memory performance (β = 0.20, p = 0.044), but continuous amyloid-cognition associations were not consistently replicated across cohorts (± evidence). Broader CSF protein-ratio findings remained exploratory. Clinical, cognitive, assay, and analytical heterogeneity precluded meta-analysis.

CONCLUSIONS: The available evidence, although limited and heterogeneous, suggests that total tau may primarily reflect broader neurodegenerative injury, whereas p-tau181 and Aβ42/Aβ40 may be more informative for selected cognitive phenotypes or possible AD co-pathology. These biomarkers should remain research tools until larger, standardized, longitudinal multicenter studies establish their pathological specificity, predictive value, and clinical utility.},
}

Humans
*tau Proteins/cerebrospinal fluid
*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/complications
Biomarkers/cerebrospinal fluid
*Frontotemporal Dementia/cerebrospinal fluid/complications
*Amyloid beta-Peptides/cerebrospinal fluid
*Cognitive Dysfunction/cerebrospinal fluid/etiology

@article {pmid42677830,
year = {2026},
author = {Markovich, SW and Frey, BL and Scalf, M and Smith, LM},
title = {Metal Oxides Catalyze Formation of Dehydroamino Acids by Phosphate β-Elimination Under Physiological Conditions.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e9805066},
doi = {10.1002/anie.9805066},
pmid = {42677830},
issn = {1521-3773},
support = {R35GM126914/NH/NIH HHS/United States ; },
abstract = {The dehydroamino acids (DHAAs) dehydroalanine and dehydrobutyrine are formed in proteins posttranslationally from serine and threonine, respectively. They contain an electrophilic alkene, which reacts readily with nucleophiles by Michael addition, giving rise to a variety of chemical modifications as well as protein crosslinks. Recent work has shown DHAAs and their modifications to be highly prevalent in protein aggregates isolated from brains of Alzheimer's Disease (AD) patients. As there is no human enzyme known to catalyze the formation of DHAAs, this raised the question of how they are produced. We show here that metal oxides, particularly the iron oxides goethite and hematite, efficiently catalyze the formation of DHAAs in model phosphopeptides in vitro under physiologically relevant conditions. Iron oxides are known to accumulate in the human brain with age, and this deposition is enhanced in neurodegenerative disorders like AD. The DHAA formation by heterogeneous catalysis reported here provides a previously unknown mechanism linking iron deposition to protein crosslinking in AD and potentially other neurodegenerative diseases where iron accumulation and protein aggregation co-occur.},
}

@article {pmid42677870,
year = {2026},
author = {Lv, Q and Huang, S and Li, Y and Li, Y},
title = {Oxidative Stress: The Role of Aluminum Ions in Copper Homeostasis Within the Neurons.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70412},
pmid = {42677870},
issn = {1099-1263},
support = {YDZJ202401043ZYTS//Jilin Province Science and Technology Development Plan/ ; },
abstract = {Aluminum (Al) and copper (Cu) homeostasis is critical for neuronal health. Disruption of their balance contributes to oxidative stress, mitochondrial dysfunction, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Existing studies have reported a positive correlation between aluminum and copper concentrations in specific neuronal models. Such homeostatic imbalance may contribute to the activation of pathways related to apoptosis or cuproptosis through mechanisms including oxidative stress, mitochondrial dysfunction, and glutathione depletion. Aluminum-copper dysregulation is considered to potentially play a significant role in certain neurodegenerative disease studies, suggesting that targeted regulation of trace elements may hold potential therapeutic value. However, the specific mechanisms by which maintaining aluminum-copper homeostasis prevents neurodegenerative diseases remain incompletely understood, and further interventional studies focusing on trace elements are urgently needed to validate the causal relationships and clinical application prospects.},
}

@article {pmid42678350,
year = {2026},
author = {Nabizadeh, F and Mohamadi, H and , },
title = {GWAS of Tau-Neurodegeneration Mismatch Identifies New Risk Loci for Susceptibility to Tau.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71125},
doi = {10.1002/cns.71125},
pmid = {42678350},
issn = {1755-5949},
mesh = {Humans ; *Genome-Wide Association Study/methods ; *tau Proteins/genetics/metabolism ; *Genetic Predisposition to Disease/genetics ; Polymorphism, Single Nucleotide/genetics ; Female ; *Alzheimer Disease/genetics/diagnostic imaging ; Male ; Aged ; Aged, 80 and over ; Genetic Loci/genetics ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: In Alzheimer's disease (AD), neurodegeneration is primarily attributed to the accumulation of tau neurofibrillary tangles. However, the distribution patterns of both tau pathology and neurodegeneration vary across different brain regions and among individuals. Moreover, multiple factors may influence the relationship between tau burden and neurodegenerative processes. Identifying the genetic architecture associated with deviation in the tau-neurodegeneration relationship can provide deeper mechanistic insights and guide the development of precision medicine strategies.

METHODS: Here, I perform a genome-wide association study (GWAS) of cortical tau and thickness quantified by positron emission tomography (PET) and magnetic resonance imaging (MRI) in 794 participants from two cohorts of Alzheimer's disease Neuroimaging Initiative (ADNI) and A4.

RESULTS: A GWAS was identified between the Tau/Neurodegeneration residual and two novel loci on chromosomes 7 and 14, with two SNPs (rs9323573 and rs9784993) exceeding the genome-wide significance threshold (p ≤ 5 × 10[-8]). SNP rs9323573 is located in STXBP6 on chromosome 14, while rs9784993 is in AKAP9 on chromosome 7, both of which were directly genotyped. The minor allele G of both SNPs (rs9323573, MAF = 0.221, p = 2.60 × 10[-8]; rs9784993, MAF = 0.197, p = 4.92 × 10[-8]) was associated with lower Tau/Neurodegeneration residuals, indicating higher-than-expected neurodegeneration given tau levels.

CONCLUSION: GWAS of tau-related neurodegeneration identified two novel genetic variants in the loci AKAP9 and STXBP6 leading to higher than expected regional neurodegeneration given the tau level. Identifying genetic factors involved in tau-neurodegeneration mismatch may improve our understanding regarding the potential mechanistic downstream leading to susceptibility or resilience to tau pathology.},
}

Humans
*Genome-Wide Association Study/methods
*tau Proteins/genetics/metabolism
*Genetic Predisposition to Disease/genetics
Polymorphism, Single Nucleotide/genetics
Female
*Alzheimer Disease/genetics/diagnostic imaging
Male
Aged
Aged, 80 and over
Genetic Loci/genetics
Magnetic Resonance Imaging
Positron-Emission Tomography

@article {pmid42667649,
year = {2026},
author = {O'Neil, LM and Qureshi, HA and Lindemann, L and Cvancara, DJ and Lehmann, AE and Jafari, A},
title = {Cognitive Dysfunction in Chronic Rhinosinusitis: A Scoping Review.},
journal = {International forum of allergy & rhinology},
volume = {},
number = {},
pages = {},
doi = {10.1002/alr.70262},
pmid = {42667649},
issn = {2042-6984},
abstract = {BACKGROUND: Cognitive dysfunction is increasingly recognized as an extra-nasal manifestation of chronic rhinosinusitis (CRS). This scoping review characterizes the primary evidence on cognition in adult CRS, covering measures, treatment response, and incident dementia.

METHODS: We searched EMBASE, PubMed/MEDLINE, Web of Science, the Cochrane Library, CINAHL, and Global Index Medicus through May 2026 using a MeSH and free-text strategy. Inclusion criteria include primary studies of adult CRS with a formal clinical diagnosis (AAO-HNS, EPOS or ICD-coded) reporting at least one validated cognitive measure or recognized cognitive impairment. Two reviewers screened independently. Animal studies, reviews, conference abstracts, and non-CRS populations were excluded. PRISMA-ScR reporting was performed; heterogeneity precluded meta-analysis.

RESULTS: Twenty-four primary studies met inclusion criteria. Adults with CRS perform worse than controls on subjective (Cognitive Failures Questionnaire [CFQ], Neuro-QoL) and objective (Montreal Cognitive Assessment [MoCA], Automated Neuropsychological Assessment Metrics [ANAM], eye movement assessment, P300) cognitive instruments. Deficits correlate with disease-specific QoL severity (SNOT-22, Rhinosinusitis Disability Index [RSDI]). Cognitive measures improve after medical therapy or endoscopic sinus surgery. Two resting-state fMRI analyses identified altered orbitofrontal-precuneus connectivity scaling with sinonasal inflammation. Dementia results are mixed: a UK Biobank analysis (7176 CRS cases among 364,945 participants) reported increased Alzheimer disease risk (HR 1.33), while two Korean cohorts and a 2025 meta-analysis found no association.

CONCLUSION: Adults with CRS show measurable cognitive dysfunction that may improve with treatment, with a plausible neuroinflammatory pathophysiology. Whether this translates to incident dementia is contested. Outcome heterogeneity limits synthesis; therefore, development of a CRS-specific cognitive measurement set is recommended.},
}

@article {pmid42667812,
year = {2026},
author = {Rodriguez-Lopez, A and Acero, G and Díaz, G and Gevorkian, G},
title = {Altered peripheral immune cell profiles in Tg-SwDI mice compared with wild-type controls.},
journal = {Journal of neuroimmunology},
volume = {421},
number = {},
pages = {579079},
doi = {10.1016/j.jneuroim.2026.579079},
pmid = {42667812},
issn = {1872-8421},
abstract = {Sporadic Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder characterized by numerous pathological processes occurring both in the brain and in the periphery, including chronic local or systemic inflammation, cerebrovascular impairment, oxidative stress, mitochondrial dysfunction, amyloidosis, synaptic and neuronal network dysfunction, metabolic syndrome, and disrupted cell signaling pathways. Although these mechanisms have been extensively studied, the contribution of the peripheral immune system to the etiology and progression of AD remains poorly understood. Emerging evidence suggests that pathological events in the brain, such as amyloid and phosphorylated tau accumulation, neurodegeneration, and neuroinflammation, may trigger systemic immune responses that alter the distribution and function of peripheral immune cells. However, available findings remain inconsistent. In the present study, we examined age-dependent alterations in peripheral blood immune cell populations in Tg-SwDI mice, a transgenic model of AD. We documented for the first time that transgenic mice exhibited increased proportions of neutrophils and an elevated neutrophil-to-lymphocyte ratio (NLR), along with reduced percentages of T lymphocytes compared with wild-type controls. Furthermore, significant differences in T-cell subpopulations were observed between Tg-SwDI and wild-type animals. Our findings are partially consistent with reported clinical observations in patients with AD. Because no single transgenic mouse model fully recapitulates the complex pathology of AD, and many therapeutic approaches successful in preclinical models have failed in clinical trials, a detailed characterization of disease-related alterations in each model is essential for selecting the most appropriate model to investigate specific mechanisms or therapeutic approaches.},
}

@article {pmid42667825,
year = {2026},
author = {Giriprakash, PP and Caldwell, JZK and Doty, RL and Cordes, D and Cieri, F},
title = {From function to structure: Cortical thickness correlates of olfactory dysfunction across cognitively normal, mild cognitive impairment and Parkinson's disease.},
journal = {Journal of the neurological sciences},
volume = {490},
number = {},
pages = {126151},
doi = {10.1016/j.jns.2026.126151},
pmid = {42667825},
issn = {1878-5883},
abstract = {Decreased olfactory function occurs in over half of individuals aged 65-80 years, and in 62-80% of those over 80 years of age. Hyposmia is an early symptom and a potential marker for a number of neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD), and can predict the conversion from Mild Cognitive Impairment (MCI) to AD. Building on our previously published resting-state fMRI findings on olfactory network functional connectivity [10], this study examined the same 74 participants categorized as Cognitively Normal (CN), MCI, or PD with cognitive impairment (PD-CogImp) using the Brief Smell Identification Test (B-SIT®). Automated measurements of cortical thickness (CT) and volume for 34 bilateral cortical regions were obtained using FreeSurfer v7.3.2. A moderation analysis based on multiple linear regression was performed to investigate the relationship between B-SIT® scores and cortical measures, controlling for age, education, sex, APOE genotype, and estimated total intracranial volume (eTIV). A significant interaction effect of clinical diagnosis on the olfaction-cortical thickness relationship was identified in 3 out of 68 regions of interest (ROIs): the cuneus bilaterally and the right pericalcarine gyrus, all showing large effect sizes (η[2] > 0.14). CN individuals showed a significant positive association between B-SIT® and CT in these regions, whereas MCI and PD-CogImp groups showed a negative trend. Cortical volume models yielded no significant findings after correction for multiple comparisons. These results highlight distinct diagnostic group-specific patterns in the olfaction-brain structure relationship, with implications for understanding early pathological aging and neurodegeneration.},
}

@article {pmid42667832,
year = {2026},
author = {Etafo, EO and Dutta, D and Bhattarai, S and Gendelman, HE and Gorantla, S},
title = {Does HIV-1 infection drive Alzheimer's disease pathobiology?.},
journal = {Neuroscience and biobehavioral reviews},
volume = {190},
number = {},
pages = {106932},
doi = {10.1016/j.neubiorev.2026.106932},
pmid = {42667832},
issn = {1873-7528},
abstract = {Lifelong antiretroviral therapy extends the lifespan of individuals with human immunodeficiency virus (HIV). However, HIV-associated neurocognitive disorders (HAND) remain with age-linked comorbidities. Despite viral suppression, the co-development of Alzheimer's disease (AD) remains a concern. Both HAND and AD share key mechanisms, including chronic neuroinflammation, glial dysfunction, and progressive neurodegeneration. Microglial activation is a key contributor that generates persistent proinflammatory neurotoxins, promoting amyloid-β aggregation, disrupting clearance, and accelerating neurodegeneration. Persistent viral reservoirs and low-level viral protein expression disrupt glial homeostasis, enhancing oxidative stress, tau hyperphosphorylation, and synaptic damage in the brain. This review highlights the intersections between both disorders and discusses emerging rodent models to investigate convergent pathways with the goal of improving therapeutic strategies to preserve cognitive health.},
}

@article {pmid42667878,
year = {2026},
author = {Gomes Dos Santos, J and de Andrade, LP and Cassemiliano, G and Santos, VRDS and Farche, ACS and Carnavale, BF and Pedroso, RV and Takahashi, ACM},
title = {Effects of circle dance (CircleCare) on the physical and mental health of women caregivers of older adults with Alzheimer's disease: a randomized controlled study.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {73},
number = {},
pages = {104315},
doi = {10.1016/j.gerinurse.2026.104315},
pmid = {42667878},
issn = {1528-3984},
abstract = {Dancing can be an alternative to traditional intervention programs for caregivers. This study aims to examine the effects of the Brazilian Circle Dance Program (CircleCare) on the physical and mental health of family caregivers of older adults with Alzheimer's disease (AD). Twenty-five caregivers over the age of 50 were randomized into an Intervention Group (IG, n = 13, CircleCare, 60 min, 2x/week for 12 weeks) and a Control Group (CG, n = 12, without intervention). Physical health was assessed using measures of functional mobility, walking speed, and lower limb strength. Mental health was assessed using measures of cognition, caregiver burden, perceived stress, depressive symptoms, and quality of life. Frailty was assessed using the frailty phenotype. The Statistical analysis was performed using two-way repeated-measures ANOVA (significance level 5%). Only the IG shows improvements in functional mobility (p < 0.001), burden (p = 0.001), stress level (p = 0.045) and contribution to a transition from pre-frail to non-frail. However, CircleCare was not sufficient to induce applied responses concerning walking speed, lower limb strength, cognition and quality of life. CircleCare can be considered as an intervention option for caregivers of older people with AD, especially middle-aged and older women, as it was effective in improving functional mobility, burden, stress level and contributed to the transition from pre-frailty to non-frailty. TRIAL REGISTRATION: ClinicalTrials.gov Number NCT03081533. Registered 2 March 2017, https://clinicaltrials.gov/study/NCT03081533.},
}

@article {pmid42667923,
year = {2026},
author = {Macedo, AC and Trudel, L and Hosseini, SA and Bezgin, G and Quispialaya-Socualaya, K and Therriault, J and Rahmouni, N and Tissot, C and Woo, MS and Limberger, C and Machado, LS and Souza, DG and Oliva-Lopez, D and Mitchell, S and Chan, T and Hall, B and Aumont, É and Servaes, S and Gonçalves, MP and Bernardes Real, AP and Klostranec, J and Vitali, P and Provost, K and Pascoal, TA and Zimmer, ER and Soucy, JP and Rosa-Neto, P and , },
title = {Differential associations of tau extent and load with brain metabolic and cognitive dysfunction in Alzheimer's disease.},
journal = {EBioMedicine},
volume = {131},
number = {},
pages = {106460},
doi = {10.1016/j.ebiom.2026.106460},
pmid = {42667923},
issn = {2352-3964},
abstract = {BACKGROUND: Reduced [[18]F]Fluorodeoxyglucose ([[18]F]FDG)-PET uptake is a core imaging feature of Alzheimer's disease (AD). While tau load correlates with this metabolic signature, it remains unclear whether the spatial extent of tauopathy (SEOT) more accurately explains brain glucose hypometabolic patterns. Here, we compared SEOT versus tau load to determine their ability to predict brain hypometabolic signatures in AD.

METHODS: We performed a cross-sectional study of amyloid-β positive participants from ADNI (n = 150) and an atypical AD subset from the McGill University Research Centre for Studies in Ageing (MCSA; n = 44). Participants underwent [[18]F]AV1451 or [[18]F]MK6240 tau-PET and [[18]F]FDG-PET. Tau load was indexed with regional SUVR, and SEOT with the proportion of abnormal voxels. Linear regressions related temporal and whole-cortex tau-PET load or SEOT to [[18]F]FDG-PET. We also compared the accuracy of tau-PET metrics for identifying AD-like hypometabolism. Spearman correlations assessed SEOT/tau load-FDG associations at regional and network levels. Partial Least Squares (PLS) regression investigated whether distributed tau load and SEOT predicted [[18]F]FDG-PET signatures. Structural equation modelling and hierarchical linear models assessed associations between tau metrics and cognition dependent and independent of [[18]F]FDG-PET.

FINDINGS: Whole-cortex SEOT best predicted decreased signal in the [[18]F]FDG-PET AD-meta-ROI. SEOT also performed better in classifying AD-related brain hypometabolism. Across regions and networks, SEOT performed similarly or better than tau load in predicting metabolic dysfunction. Voxelwise analyses suggested complementary predictive value of SEOT and tau load, each capturing slightly distinct spatial associations with [[18]F]FDG-PET. PLS demonstrated partially non-redundant contributions from tau load and SEOT. Cortical SEOT showed the strongest predictive value for cognition.

INTERPRETATION: SEOT provides complementary, independent, and often stronger predictive value than tau load for brain metabolism, particularly for network-level dysfunction. SEOT may improve diagnostic characterisation and prediction of cognitive impairment beyond [[18]F]FDG-PET.

FUNDING: TRIAD is supported by the Weston Brain Institute, Canadian Institutes of Health Research, Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé, and the Colin J Adair Charitable Foundation. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and the Canadian Institutes of Health Research.},
}

@article {pmid42667935,
year = {2026},
author = {Banerjee, S and Wang, KZQ and DeChellis-Marks, MR and Ross, MR and Oury, NH and Chu, CT},
title = {The PINK1-VCP-p47 pathway protects against tau-induced dendritic shrinkage in cortical neurons through interaction with STIP1.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107592},
doi = {10.1016/j.nbd.2026.107592},
pmid = {42667935},
issn = {1095-953X},
abstract = {Microtubule associated protein tau (tau) contributes to the pathogenesis of AD and some forms of Frontotemporal Lobar Dementia wherein dendritic simplification is strongly related to cognitive dysfunction. Loss of function mutations in PTEN-induced kinase 1 (PINK1) cause recessive early-onset Parkinson's disease with dementia, and reduced wild-type PINK1 expression is observed in Alzheimer's disease (AD). We previously found that PINK1 interacts with valosin-containing protein (VCP) and promotes phosphorylation of the VCP co-factor NSFL1C (p47). This study was designed to test the hypothesis that PINK1 rescues tau-induced dendritic simplification through the VCP-p47 pathway, and to define neuroprotective mechanisms downstream of p47 phosphorylation. Mouse primary cortical neurons were transfected with 2N4R-Tau and plasmids encoding components of the PINK1-VCP-p47 signaling pathway and the impact on Tau-mediated dendritic injury was assessed. Immunoprecipitation-mass spectrometry, immunoblotting, RNAi and Sholl analysis were performed to define downstream mechanisms of neuroprotection. Tau-induced dendritic shortening and simplification was fully rescued by co-expression of PINK1, VCP, p47 or the p47-S176D phosphomimic (p47D), but not by the non-phosphorylatable p47-S176A (p47A) variant. Pathway analysis showed enhanced interactions of p47D with proteins in the Rho-GTPase pathway. Immunoprecipitation confirmed that STIP1 interacts with p47D to a significantly higher degree than p47A. Overexpression of STIP1 rescued tau-mediated dendritic simplification. Moreover, STIP1 siRNA impaired the neuroprotective effects of both PINK1 and p47D, indicating an essential role in the PINK1-p47D neuroprotection pathway. The current study highlights a novel PINK1-(phospho)p47-STIP1 signaling axis that promotes dendritic complexity and protects against tau-induced neurodegeneration in cortical neurons.},
}

@article {pmid42667939,
year = {2026},
author = {Zhang, B and Li, Y and Qiao, X and Zhang, B and Liu, X and Li, X and Liu, Z and Li, Z and Wang, G and Wang, Y and Yang, X},
title = {Semi-synthesis and activity study of α-mangostin ether derivatives bearing N-heterocyclic side chains as multitarget-directed ligands against AD.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130758},
doi = {10.1016/j.bmcl.2026.130758},
pmid = {42667939},
issn = {1464-3405},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with intricate pathogenic factors. Multi-target drug design offers a promising approach to address AD's complex pathogenesis. α-Mangostin (α-M), a natural product with multifunctional anti-AD potential, is limited by poor aqueous solubility and bioavailability. This work employed regioselective Williamson O-alkylation to semi-synthesize three novel α-M alkylamine derivatives (1-3), enabling tunable mono- and disubstitution. In silico predictions demonstrated that disubstituted compounds 2 and 3 exhibited markedly improved blood-brain barrier permeability and oral bioavailability. While experimental results showed that monosubstitution optimally balanced intrinsic antioxidant activity with target binding. Compound 1 displayed potent AChE inhibition (IC50 = 0.11 μM) with high selectivity (SI = 59.27), effectively inhibited both self-induced and AChE-induced Aβ aggregation (53.8% and 57.3%, respectively), and exhibited excellent antioxidant capacity (·OH IC50 = 0.19 μM). Meanwhile, disubstitution achieved superior BuChE inhibition by occupying both sides of the expanded active site pocket. Furthermore, 1 significantly reduced ROS levels by ~48% in C. elegans. These results highlight the potential of tunable α-M derivatives as promising anti-AD candidates.},
}

@article {pmid42668040,
year = {2026},
author = {Sima, J and Wu, J and Zhao, Z and Du, L and Zhang, J},
title = {Assessing the agreement between self- and proxy-reported responses for measuring health-related quality of life in people with dementia using the Alzheimer's Disease Five Dimensions instrument.},
journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jval.2026.06.028},
pmid = {42668040},
issn = {1524-4733},
}

@article {pmid42668129,
year = {2026},
author = {Chen, X and Jiang, W and Wang, L and Han, B and Yu, D and Li, G and Sun, J and Liu, X and Xie, Y and Zhangx, G},
title = {Analytical validation and clinical performance of a chemiluminescence immunoassay panel for plasma biomarkers in Alzheimer's disease: a preliminary study.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121300},
doi = {10.1016/j.cca.2026.121300},
pmid = {42668129},
issn = {1873-3492},
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a growing global health challenge, highlighting the urgent need for reliable and minimally invasive diagnostic tools. This study aimed to develop and comprehensively validate an automated chemiluminescence immunoassay (CLIA) for the simultaneous quantification of six core plasma AD biomarkers: Aβ1-40, Aβ1-42, p-Tau181, p-Tau217, GFAP and NfL.

METHODS: A fully automated CLIA platform (Shine i2910, Vazyme, China) was utilized for biomarker detection. A total of 87 plasma samples from hospitalized patients with confirmed diagnosis at Beijing Tiantan Hospital were stratified into three cohorts: AD, Other Dementia (OD), and Mild Cognitive Impairment (MCI). The analytical performance of the assay, including precision, accuracy, linearity, and detection limits, was validated in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines (EP15-A3, EP09-A3, EP06-A2, EP17-A2).

RESULTS: This CLIA panel achieved robust analytical metrics, with within-run coefficient of variation (CV) < 3%, between-run CV < 5%, relative bias < ±10%, and linear correlation coefficient (R[2]) > 0.99 for all six biomarkers, along with sub-picogram level detection sensitivity. Clinical sample analysis revealed that AD patients had significantly higher plasma concentrations of p-Tau181 and p-Tau217, along with a significantly reduced Aβ1-42/Aβ1-40, compared with OD and MCI patients (p < 0.05). GFAP and NfL concentrations were significantly elevated in both AD and OD patients relative to the MCI patients (p < 0.05), with no significant difference between AD and OD patients. Receiver operating characteristic (ROC) curve analysis demonstrated an area under the curve (AUC) > 0.7 for all biomarkers, supporting auxiliary differential diagnosis of AD and demonstrating the assay's clinical discriminatory ability.

CONCLUSION: The developed fully automated CLIA platform enables rapid, high-performance quantification of six core plasma AD biomarkers with satisfactory analytical performance. As a single-center exploratory study without matched healthy controls, this study only provides analytical validation and preliminary clinical discriminatory evidence. It offers a cost-effective, minimally invasive alternative for auxiliary AD screening under clinical research conditions, while large multi-center cohorts are required to verify its real-world large-scale screening value.},
}

@article {pmid42668271,
year = {2026},
author = {Cabasino, C and Enrico, P and Bottaro, F and De Santis, D and Cagnoli, C and Garbelli, R and Bongarzone, I and Torrente, Y and Delvecchio, G and Brambilla, P},
title = {Spatial lipidomics of the human brain: systematic review of current state and future perspectives.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42668271},
issn = {1476-5578},
support = {HLS-DA, PNC-E3-2022-23683266- CUP: C43C22001630001 / MI-0117//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca corrente 2025//Ministero della Salute (Ministry of Health, Italy)/ ; RF-2019-12371066//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca corrente 2025//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca corrente 2025//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca corrente 2025//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca corrente 2025//Ministero della Salute (Ministry of Health, Italy)/ ; 'Dipartimenti di Eccellenza' Programme 2023-27//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 'Dipartimenti di Eccellenza' Programme 2023-27//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; },
abstract = {BACKGROUND: Lipids represent a significant component of the human brain, exerting crucial functions in both physiological and pathological conditions. Mapping brain lipids distribution is an emerging area of research, with mass spectrometry imaging allowing the detection of lipid species and their localization within tissue sections. However, comprehensive spatial mapping of lipids in the human brain remains to be achieved. This systematic review addresses this gap by critically synthesizing the available literature in the field.

METHODS: A bibliographic search on PubMed, Scopus and Web of Science for original articles employing mass spectrometry imaging to analyze lipids and their distribution in the human brain was performed. The included articles were grouped according to the clinical characteristics of the studied populations, including healthy subjects and selected neurological and psychiatric disorders. Studies on human brain tissue from tumoral specimens, animals, or in vitro models such as organoids were excluded to maintain focus on translational findings directly applicable to human neurological and psychiatric diseases.

RESULTS: Following the inclusion criteria, 34 articles were selected. Alzheimer's disease, schizophrenia and multiple sclerosis were the most frequently investigated conditions, alongside studies in healthy subjects describing lipid distribution under physiological conditions. We observed considerable heterogeneity across studies in terms of research questions and methodological approaches. Nevertheless, our critical synthesis allowed us to identify both consistencies and discrepancies in experimental strategies and in the lipid signatures reported.

CONCLUSIONS: Studying lipids by mass spectrometry imaging enables the identification of spatially defined profiles in distinct brain areas, providing valuable insights into both human neurobiology and brain disorders' pathophysiology. In this context, spatial information is crucial for linking lipid alterations to specific structures or lesions, thereby supporting translational applications. Finally, we identified key methodological issues that must be addressed to advance this emerging field.},
}

@article {pmid42668333,
year = {2026},
author = {Kalra, P and Chaturvedi, D and Kumar, A and Grewal, AK and Khan, H and Singh, V and Singh, TG and Singh, T and Ahmad, SF and Attia, SM},
title = {AMBMP Hydrochloride Reverses STZ-Induced Alzheimer-Type Dementia Associated with Wnt/β-catenin/TLR4 Signaling.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42668333},
issn = {1559-1174},
support = {ORF-2026-748//King Saud University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Toll-Like Receptor 4/physiology/agonists ; Streptozocin/toxicity ; Male ; Mice ; *Wnt Signaling Pathway/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Donepezil/therapeutic use/pharmacology ; Disease Models, Animal ; Maze Learning/drug effects ; beta Catenin/physiology ; Acetylcholinesterase/metabolism ; Palmitic Acid/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with progressive cognitive decline and neuronal loss. This study investigated the neuroprotective effects of AMBMP Hydrochloride, a Wnt/β-catenin agonist, in a streptozotocin (STZ)-induced mice model of AD, elucidating the interplay between dysregulated Wnt/β-catenin signaling and Toll-Like Receptor 4 (TLR4)-mediated inflammation, with Palmitic acid used as a TLR4 pathway modulator. Mice received bilateral intracerebroventricular (i.c.v.) injections of STZ (3 mg/kg) on Day 1 and Day 3, followed by administration of Donepezil (3 mg/kg)/ AMBMP Hydrochloride (5 mg/kg and 10 mg/kg)/Palmitic acid (TLR4 agonist, 20 mg/kg) via the intraperitoneal (i.p.) route from Day 4 to Day 22. STZ-treated mice exhibited significant cognitive dysfunction, characterized by impaired performance in the Morris Water Maze (MWM) task along with increase in acetylcholinesterase (AChE) activity, oxidative stress (thiobarbituric acid reactive substances; TBARS), neuroinflammation [tumor necrosis factor alpha (TNF-α)/Interleukin-6 (IL-6)/Interleukin-1 beta (IL-1β) and nuclear factor kappa B (NF-κB)] and decreased reduced glutathione (GSH) levels. However, AMBMP Hydrochloride significantly improved behavioral and biochemical alterations possibly through modulation of Wnt/β-catenin signaling and attenuation of TLR4-mediated inflammation. Interestingly, Palmitic acid co-treatment was found to counteract these protective effects, further pointing to a role of TLR4 in the pharmacological effect of AMBMP Hydrochloride. In summary, we confirmed that AMBMP Hydrochloride exhibits potent neuroprotective effects associated with modulating Wnt/β-catenin/TLR4 signaling, offering a promising therapeutic approach against Alzheimer-Type Dementia. Future studies should delve deeper into the molecular mechanisms and translational promise of AMBMP hydrochloride, paving the way for its development as a potential candidate for AD management.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced
*Toll-Like Receptor 4/physiology/agonists
Streptozocin/toxicity
Male
Mice
*Wnt Signaling Pathway/drug effects
*Neuroprotective Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects
Donepezil/therapeutic use/pharmacology
Disease Models, Animal
Maze Learning/drug effects
beta Catenin/physiology
Acetylcholinesterase/metabolism
Palmitic Acid/pharmacology

@article {pmid42668348,
year = {2026},
author = {Han, Z and Chen, H and Yao, Y and Bo, X and Ni, X and Liu, H and Bai, M and Li, T and Bao, L and Zhang, D and Dong, W},
title = {Promoting Effect of (+)-Borneol on Alzheimer's Disease Treatment in APP Transgenic Zebrafish and Its Blood-Brain Barrier Permeation Mechanism.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42668348},
issn = {1559-1182},
mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism/pathology ; Zebrafish/genetics ; Animals, Genetically Modified ; *Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; *Camphanes/pharmacology/therapeutic use ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/pathology/metabolism/drug effects ; },
abstract = {(+)-Borneol (Bor) has been shown to enhance drug penetration across the blood-brain barrier (BBB); yet its mechanisms of action and adjuvant effects on Alzheimer's disease (AD) drugs remain insufficiently investigated. This study systematically explored the adjuvant effects of Bor and its underlying mechanisms by employing AB wild-type zebrafish and APP transgenic zebrafish models. Results demonstrated that Bor at concentrations of 0.05 mM or lower exhibited no toxicity toward AB wild-type zebrafish, whereas 0.01 and 0.05 mM Bor significantly increased the expression of green fluorescent protein (GFP) in the zebrafish brain. Genetic analyses revealed that Bor downregulated genes encoding tight junction proteins and P-glycoprotein (P-gp). Drug treatment experiments showed that Bor enhanced the efficacy of AD therapeutic agents, including Zhenbaopill (ZBP, a traditional medicinal preparation) and the synthetic drug 8e. Specifically, Bor ameliorated AD-related behavioral impairments, inhibited cerebral apoptosis, restored the expression of AD-associated genes, normalized the activities of acetylcholine (ACh)-related enzymes, and downregulated both the mRNA and protein levels of Claudin 5. In summary, Bor enhances BBB permeability by regulating the expression of genes encoding BBB-related proteins, thereby increasing the brain concentration and bioavailability of AD drugs with anticholinesterase activity. An appropriate dose of Bor may thus contribute to enhancing the therapeutic efficacy of AD drugs.},
}

Animals
*Blood-Brain Barrier/drug effects/metabolism/pathology
Zebrafish/genetics
Animals, Genetically Modified
*Alzheimer Disease/drug therapy/genetics/pathology/metabolism
*Camphanes/pharmacology/therapeutic use
*Amyloid beta-Protein Precursor/genetics/metabolism
Brain/pathology/metabolism/drug effects

@article {pmid42668476,
year = {2026},
author = {Wu, B and Wu, J and Zhu, L and Li, A and Fu, Y and Lei, Z and Wu, D and Peng, W and Xie, L},
title = {Intranasal L-DOPA/TPP-engineered extracellular vesicles deliver icariin to ameliorate mitochondrial dysfunction with associated sphingolipid remodeling in Alzheimer's disease models.},
journal = {Materials today. Bio},
volume = {40},
number = {},
pages = {103563},
pmid = {42668476},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD) is associated with mitochondrial dysfunction, oxidative stress, and disrupted lipid homeostasis, but the therapeutic translation of mitochondrial-protective agents remains limited by inefficient brain delivery, insufficient neuronal selectivity, and poor subcellular precision. Here, we developed an intranasal extracellular vesicle formulation (L-DOPA/TPP-EV-ICA) by loading icariin (ICA) into mesenchymal stem cell-derived extracellular vesicles and post-inserting DSPE-PEG-Levodopa and TPP-PEG-PE to enhance nasal environment, neuronal association, and mitochondria-associated intracellular enrichment. The engineered vesicles retained EV-like morphology, showed measurable ICA encapsulation, and maintained colloidal stability under the tested storage and simulated nasal conditions. In a human nasal epithelial Transwell model, L-DOPA/TPP-EV-ICA showed greater neuronal uptake than unmodified EVs without detectable disruption of epithelial barrier integrity and exhibited preferential colocalization with mitochondria-associated structures after cellular internalization. In Aβ-injured neuronal cells, L-DOPA/TPP-EV-ICA treatment reduced mitochondrial oxidative stress and mPTP opening, improved membrane potential, and enhanced ATP production and redox-related parameters. Following intranasal administration, the engineered formulation generated stronger and more persistent brain-associated fluorescence and showed preferential association with NeuN-positive cells. In APP/PS1 mice, treatment improved cognitive performance, and attenuated histopathological and mitochondrial abnormalities. Integrated proteomic, metabolomic analyses, and protein-level analyses further identified treatment-associated alterations in sphingolipid-related pathways. These findings support L-DOPA/TPP-EV-ICA as a promising preclinical intranasal EV platform for improving mitochondrial function and modulating sphingolipid-associated alterations in AD-related models.},
}

@article {pmid42668611,
year = {2026},
author = {Gao, F and Luo, G and Liu, B and Qiu, X and Bai, J and Wang, R},
title = {Comparative effectiveness of multiple interventions for Alzheimer's disease on ABC syndromes and QoL: A Bayesian network meta-analysis.},
journal = {iScience},
volume = {29},
number = {9},
pages = {117250},
pmid = {42668611},
issn = {2589-0042},
abstract = {Evidence comparing directly pharmacological and non-pharmacological treatments for Alzheimer's disease (AD) is scarce. The ABC symptoms-activities of daily living (ADLs) (A), behavioral and psychological symptoms (BPSs) (B), cognitive function (C), and quality of life (QoL)-are critical for diagnosing and assessing treatment effects in AD. This study aims to evaluate five interventions for AD: pharmacological therapy (PT), photobiomodulation (PBM), cognitive therapy (CT), exercise therapy (ET), and repetitive transcranial magnetic stimulation (rTMS) using a Bayesian network meta-analysis approach. Among 6,450 records screened, 91 randomized controlled trials (RCTs) involving 12,242 participants met the inclusion criteria. PBM and rTMS showed significant benefits for cognitive function in AD patients. PT and CT showed notable effectiveness in enhancing activities of daily living. For QoL, CT and ET were identified as more favorable outcomes. Collectively, each intervention exerts unique merits targeting ABC symptoms and QoL, implying combined pharmacological and non-pharmacological regimens could optimize therapeutic gains for AD management.},
}

@article {pmid42669066,
year = {2026},
author = {Cosarderelioglu, C and Kreimer, S and Plaza-Rodriguez, AI and Iglesias, PA and Talbot, CC and Siragy, HM and Ubaida-Mohien, C and Grodstein, F and Ferrucci, L and Bennett, DA and Walston, J and Abadir, P},
title = {Higher Frontal Cortex Angiotensin Type 2 Receptor-Interacting Protein (ATIP) Levels Are Associated With a Lower Amyloid-Beta Burden in Postmortem Brains of Older Adults With Alzheimer's Disease.},
journal = {Aging cell},
volume = {25},
number = {9},
pages = {e70686},
pmid = {42669066},
issn = {1474-9726},
support = {//Bright Focus Foundation Research Award/ ; P30AG021334//National Institute on Aging of the National Institutes of Health (NIH)/ ; R01AG046441//NIH/ ; K24AG088484/AG/NIA NIH HHS/United States ; //Nathan W. and Margaret T. Shock Aging Research Foundation, Nathan Shock Scholar in Aging/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Aged ; Male ; Female ; *Frontal Lobe/metabolism/pathology ; Aged, 80 and over ; Receptor, Angiotensin, Type 2/metabolism ; Autopsy ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation. Dysregulation of the brain renin-angiotensin system, particularly hyperactivation of the angiotensin II type-1 receptor, contributes to AD pathogenesis. In contrast, activation of the angiotensin II type-2 receptor (AT2R) has been linked to neuroprotection and reduced Aβ accumulation. However, the underlying mechanisms of AT2R-related Aβ reduction and the role of AT2R-interacting protein (ATIP), also known as AT2R-binding protein, remain unclear. We aimed to explore the relationship between ATIP and Aβ and tau pathologies as well as brain AT2R protein levels in older adults with AD. Using TOMAHAQ, a method that enables precise examination of numerous peptides across various samples in a single mass spectrometry analysis, we identified a specific human tryptic peptide that enables ATIP quantification. We applied this method to postmortem frontal-cortex samples to measure ATIP levels. Sixty individuals with AD were included, half of whom were users of angiotensin receptor blockers (ARBs). The ATIP peptide was quantifiable in 12 participants. Among these individuals, higher ATIP levels were associated with lower Aβ burden in the frontal-cortex and across multiple brain regions. This association remained significant after adjustment for age and ARB use. In contrast, ATIP levels were not significantly associated with AT2R, which was quantified using TOMAHAQ. This suggests that the relationship between ATIP and Aβ burden may not depend on differences in AT2R abundance. Although causality cannot be established, these findings may suggest a potential protective role for ATIP in AD that warrants further investigation.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Aged
Male
Female
*Frontal Lobe/metabolism/pathology
Aged, 80 and over
Receptor, Angiotensin, Type 2/metabolism
Autopsy
*Brain/metabolism

@article {pmid42669099,
year = {2026},
author = {Alonge, P and Baiamonte, L and Gerardi, G and Torrente, A and Lo Mauro, E and Veronese, N and Labate, A and Monastero, R},
title = {APOE in subjective cognitive decline: a systematic review and meta-analysis.},
journal = {Journal of neurology},
volume = {273},
number = {9},
pages = {},
pmid = {42669099},
issn = {1432-1459},
mesh = {Humans ; *Cognitive Dysfunction/genetics ; *Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly conceptualised as a biological and clinical continuum that includes Subjective cognitive decline (SCD), mild cognitive impairment (MCI), and overt dementia. We conducted a systematic review and meta-analysis to assess the prevalence of APOE ε4 allele in individuals with SCD.

METHODS/AIMS: Main databases were searched to identify studies published up to 15 April 2026, plus citation checking. Eligible studies included participants with SCD defined according to standardized criteria, with available APOE genotype data. Application of SCD-plus criteria was also recorded.

RESULTS: Of 474 screened records, 49 studies were included in the quantitative synthesis. The pooled prevalence of APOE ε4 allele carriers was 28.3% (95% CI 25.1-31.8%) in SCD, 41.0% (95% CI 35.3-46.8%) in MCI, and 22.0% (95% CI 18.6-25.9%) in cognitively normal (CN) individuals. Multivariate analysis showed that the odds of being an APOE ε4 allele carrier were significantly higher in SCD compared to HC (OR = 1.28, 95% CI 1.12-1.46, p <0.001) and higher in MCI compared to SCD (OR = 1.48, 95% CI 1.23-1.76, p <0.0001). Meta-regression analyses indicated that age and education contributed to heterogeneity in SCD cohorts, while sex distribution did not. Sensitivity analyses restricted to SCD-plus studies confirmed the robustness of these findings.

CONCLUSION: The prevalence of APOE ε4 allele in SCD falls between that observed in CN and MCI populations, supporting its role as an intermediate stage in the AD continuum. However, substantial heterogeneity persists, highlighting the need for more accurate stratification approaches integrating genetic and clinical markers.},
}

Humans
*Cognitive Dysfunction/genetics
*Apolipoprotein E4/genetics

@article {pmid42669137,
year = {2026},
author = {Xu, B and Li, X and Dong, S and Zhang, Z and Jin, D and Li, G and Wang, J},
title = {Modulating the Gut-Microbiota-Brain Axis in Alzheimer's Disease: Therapeutic Potential of Nutritional and Metabolic Factors.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71117},
pmid = {42669137},
issn = {1755-5949},
mesh = {Humans ; *Alzheimer Disease/metabolism/diet therapy/microbiology/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation/methods ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia among the elderly, characterized by a gradual decline in memory and cognitive function. The growing body of evidence highlighting the interaction between the gut microbiota and the central nervous system has positioned the gut microbiota as a key area of research in AD pathogenesis.

METHODS: This review critically evaluates the preclinical evidence and clinical trial outcomes, complemented by mechanistic studies and Mendelian randomization analyses, to assess the therapeutic potential of nutritional interventions targeting the gut-microbiota-brain axis in AD.

RESULTS: Dietary components and patterns regulate the composition and function of the gut microbiota, which in turn influence brain function through the gut-microbiota-brain axis via chemical/metabolic, immune-mediated, and neural pathways. Specific nutrients, microbial metabolites, and dietary patterns have been shown to exert either protective or detrimental effects on AD pathology and cognitive function. Emerging strategies, including precision nutrition, fecal microbiota transplantation, and next-generation microbiome-based therapies, offer new avenues for AD prevention and treatment.

CONCLUSIONS: Nutritional interventions targeting the gut-microbiota-brain axis represent a promising approach for the comprehensive prevention and management of AD. Further mechanistic and clinical studies are warranted to translate these findings into effective therapeutic strategies.},
}

Humans
*Alzheimer Disease/metabolism/diet therapy/microbiology/therapy
*Gastrointestinal Microbiome/physiology
Animals
*Brain/metabolism
*Brain-Gut Axis/physiology
Fecal Microbiota Transplantation/methods

@article {pmid42669176,
year = {2026},
author = {Forsyth, F and Diaz, A and Andersson, V and Haraldsen, IH and Gove, D},
title = {Ethical considerations of fluid biomarker use in alzheimer's disease - a rapid review.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/13607863.2026.2719938},
pmid = {42669176},
issn = {1364-6915},
abstract = {OBJECTIVE: Alzheimer's disease (AD) care has been reshaped by the integration of fluid biomarkers. This review addressed the question "What are the ethical considerations of fluid biomarker use in eligibility assessments for treatment in AD and mild cognitive impairment?"

METHODS: A rapid review following established guidelines was performed. Relevant data were identified and organised within the four pillars of biomedical ethics. Results were reported in line with the PRISMA checklist.

RESULTS: Searches identified 10,611 records; 34 were included following screening. Narrative synthesis suggests there are a greater number of ethical risks over benefits within the current clinical context. However, interpretation is subjective and empirical data is lacking.

CONCLUSIONS: Multiple ethical concerns surround the use of fluid biomarkers in AD treatment decisions, and there is limited empirical evidence to substantiate claims about benefits and harms. Uncertainty in biomarker performance, particularly in underrepresented groups, raises risks to non-maleficence, autonomy, and justice and complicates clinical decision making.},
}

@article {pmid42669622,
year = {2026},
author = {Sun, W and Yang, B and Zheng, H and Wang, Q and Shi, Y and Wang, G and Yin, W and Wang, H and Qi, X and Yao, Y and Wang, J and Cui, S and Cui, K and Mao, J and Xia, Y and Deng, J and Zhao, S and Wang, Z and Liu, F and Yi, M and Ding, J and Le, W and Li, X and Yuan, J and Wan, Y and Zheng, J},
title = {Extracellular matrix remodeling upregulates hippocampal neurogenic niche stiffness and impairs neurogenesis in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71784},
doi = {10.1002/alz.71784},
pmid = {42669622},
issn = {1552-5279},
support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology-National Science and Technology/ ; BMU2022YJ003//Peking University Talent Startup Fund supported by the Fundamental Research Funds for the Central Universities/ ; PKU2026PKULCXQ003//Clinical Medicine Plus X - Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities/ ; 2024300CC0020//Scientific Project of Beijing Life Science Academy/ ; 2023000CB0010//Scientific Project of Beijing Life Science Academy/ ; 2023000CA0060//Scientific Project of Beijing Life Science Academy/ ; HBCAD2024-03//Opening Project of Hubei Key Laboratory of Cognitive and Affective Disorders/ ; LGL-2614-02//Lingang Laboratory/ ; 2024302RPIB03//Supporting Project for Principle Investigators of Beijing Life Science Academy/ ; 82671849//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/physiopathology ; *Extracellular Matrix/metabolism ; *Neurogenesis/physiology ; Mice ; Humans ; *Hippocampus/metabolism/pathology ; YAP-Signaling Proteins ; Male ; Mice, Transgenic ; Disease Models, Animal ; *Dentate Gyrus/metabolism ; Up-Regulation ; },
abstract = {INTRODUCTION: Preserving adult hippocampal neurogenesis alleviates cognitive deficits in Alzheimer's disease (AD), yet how biophysical alterations in such as stiffness in the neurogenic niche regulate neurogenesis remains unclear.

METHODS: Stiffness in the hippocampal dentate gyrus subgranular cell zone (SGZ) of 5×FAD mice was measured using atomic force microscopy. Extracellular matrix (ECM) components in mice and AD patients were profiled through proteomics. Hydrogels were supplemented in the SGZ to upregulate local stiffness in wildtype mice, while glycosaminoglycanases was injected to downregulated stiffness in 5×FAD mice. Gene expression in the neurogenic lineage was analyzed through single nucleus sequencing. Conditional knockdown or overexpression of mechanosensors and/or Yes-associated protein 1 (YAP1) were achieved using viral vectors.

RESULTS: We found SGZ stiffening occured early in 3-month 5×FAD mice, associating with ECM remodeling and neurogenesis impairment. Upregulation of tissue stiffness in the SGZ of wild-type mice via supplementing high-density hydrogel suppressed neurogenesis, whereas downregulaion of the niche stiffness in AD mice using hyaluronidase-1 (HAase1) and other glycosaminoglycanases preserved neurogenesis. Single-nucleus transcriptomics reveals that the HAase1 treatment reshaped transcriptome of the neural stem cells (NSCs) lineage. Specifically, we found that the integrin-YAP1 mechanotransduction axis played important roles in the stiffness-induced neurogenesis deficits. Conditional knockdown of both integrin β1 and YAP in the NSC lineage mitigated stiffness-induced deficits. Consistently, the association of ECM remodeling and neurogenesis impairments were also observed in post mortem AD patients.

DISCUSSION: ECM stiffness plays as a critical regulator of hippocampal neurogenesis, providing potential targets for pro-neurogenic therapeutics of AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/physiopathology
*Extracellular Matrix/metabolism
*Neurogenesis/physiology
Mice
Humans
*Hippocampus/metabolism/pathology
YAP-Signaling Proteins
Male
Mice, Transgenic
Disease Models, Animal
*Dentate Gyrus/metabolism
Up-Regulation

@article {pmid42669630,
year = {2026},
author = {Lan, G and Liao, W and Jiang, M and Zhu, J and Ran, W and Gonzalez-Ortiz, F and Fan, X and Yang, H and Shi, D and Zhang, L and Li, A and Cai, Y and Sun, P and He, Z and Zhou, X and Yang, J and Zhu, Y and Li, M and Huang, W and Liu, B and Wang, Y and Ma, X and Ma, R and Zhang, Y and Huang, C and Liu, Z and Wang, Q and Zhou, L and Xie, F and Han, Y and Liang, Z and Chen, X and Dong, M and Cheng, G and Wang, L and Luo, B and Wang, YJ and Chen, X and , and Xin, J and Peng, G and Guo, T},
title = {Longitudinal plasma phosphorylated tau217 classification and the association with Alzheimer's disease progression.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71783},
doi = {10.1002/alz.71783},
pmid = {42669630},
issn = {1552-5279},
support = {2022ZD0211603//National Science and Technology Innovation/ ; 82301380//National Natural Science Foundation of China/ ; 82422027//National Natural Science Foundation of China/ ; U24A20340//National Natural Science Foundation of China/ ; 2023YFC3605400//National Key Research and Development Program of China/ ; //Guangdong Basic and Applied Basic Science Foundation/ ; 2023B1515020113//Distinguished Young Scholars/ ; B2402020//Shenzhen Medical Research Fund/ ; A2403016//Shenzhen Medical Research Fund/ ; S241101004//Shenzhen Bay Laboratory/ ; ADB510200//Lingang Laboratory/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; *tau Proteins/blood/classification ; *Disease Progression ; Female ; Positron-Emission Tomography ; Phosphorylation ; Longitudinal Studies ; Male ; Amyloid beta-Peptides/metabolism ; Aged ; Biomarkers/blood ; Brain/diagnostic imaging ; Cohort Studies ; },
abstract = {INTRODUCTION: Longitudinal diagnostic and prognostic validity of plasma phosphorylated tau217 (p-tau217) in Alzheimer's disease (AD) remains uncertain.

METHODS: In this multi-cohort study of 2117 individuals, we established baseline plasma p-tau217 thresholds for amyloid-β-positron emission tomography (Aβ-PET) and assessed their longitudinal classification stability and prognostic relevance for AD-related outcomes.

RESULTS: Baseline-defined cutoffs achieved high and sustained accuracy (86%-95%) for Aβ-PET positivity over up to 5 years of follow-up. Longitudinally, most p-tau217-positive individuals remained stable (93%-98%), whereas the intermediate zone group progressed more to positive (44%-78%) than p-tau217-negative individuals (4%-21%). Participants with stable-positive and progress-to-positive p-tau217 profiles more frequently exhibited Aβ abnormalities (90%-100% and 64%-96%, respectively) and experienced accelerated tau accumulation, hippocampal atrophy, and incident dementia compared to those with a stable-negative p-tau217 profile.

DISCUSSION: These findings support the high stability and Aβ-PET classification performance of longitudinal plasma p-tau217 monitoring in AD, providing a scalable tool for risk stratification and disease monitoring.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/pathology
*tau Proteins/blood/classification
*Disease Progression
Female
Positron-Emission Tomography
Phosphorylation
Longitudinal Studies
Male
Amyloid beta-Peptides/metabolism
Aged
Biomarkers/blood
Brain/diagnostic imaging
Cohort Studies

@article {pmid42669708,
year = {2026},
author = {Boggess, SC and Gandhi, V and Tsai, MC and Marzette, E and Teyssier, N and Chou, JY and Hu, X and Cramer, A and Yadanar, L and Shroff, K and Jeong, CG and Eidenschenk, C and Hanson, JE and Tian, R and Kampmann, M},
title = {A massively parallel CRISPR-based screening platform for modifiers of neuronal depolarization.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42669708},
issn = {2041-1723},
support = {U54 NS123746//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; EDUC2-12730//California Institute for Regenerative Medicine (CIRM)/ ; 23AARF-1027616/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Neurons/metabolism/physiology ; Induced Pluripotent Stem Cells/cytology/metabolism ; *CRISPR-Cas Systems ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Calcium/metabolism ; },
abstract = {Understanding the complex interplay between gene expression and neuronal activity is crucial for unraveling the molecular mechanisms underlying cognitive function and neurological disorders. Here, we developed pooled screens using CRISPR interference (CRISPRi) and the fluorescent calcium integrator CaMPARI2 to evaluate genetic modifiers of neuronal depolarization. Using this screening method, we evaluated 1343 genes for their effect on depolarization in a human iPSC-derived neuron model, revealing potential links to neurodegenerative and neurodevelopmental disorders. These genes include known regulators of neuronal excitability, such as TARPs and ion channels, as well as genes associated with autism spectrum disorder and Alzheimer's disease not previously described to affect neuronal depolarization. This CRISPRi-based screening platform offers a versatile tool to uncover molecular mechanisms controlling neuronal function in health and disease.},
}

Humans
*Neurons/metabolism/physiology
Induced Pluripotent Stem Cells/cytology/metabolism
*CRISPR-Cas Systems
*Clustered Regularly Interspaced Short Palindromic Repeats
Calcium/metabolism

@article {pmid42669797,
year = {2026},
author = {Zhang, Q and Cai, X and Zhao, Y and Ren, X and Yan, D},
title = {Depressive symptoms and low cognitive performance in Chinese older adults: A severity-graded epidemiological analysis and a BARNN-inspired prospective risk-prediction framework with strict participant-level temporal validation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261482053},
doi = {10.1177/13872877261482053},
pmid = {42669797},
issn = {1875-8908},
abstract = {BackgroundLate-life depression is robustly associated with subsequent cognitive impairment, yet the dose-response gradient and temporally validated, uncertainty-aware prediction tools remain understudied in Chinese older adults.ObjectiveTo characterize the severity-graded epidemiological association between depressive symptoms and low cognitive performance, and to develop and validate a prospective risk-prediction framework with explicit uncertainty estimation.MethodsWe analyzed 31,570 observations from 12,494 participants aged ≥45 years in the China Health and Retirement Longitudinal Study (2011-2020). Depressive symptoms were measured with the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10); low cognitive performance was defined as total cognition score < 10. Layer 1 reported severity-graded prevalence and adjusted odds ratios. Layer 2 implemented a BARNN-inspired prospective state-transition predictor via a diverse tree ensemble, yielding predictive probability and epistemic uncertainty. Both layers used strict participant-level temporal validation.ResultsClinically significant depressive symptoms (CESD-10 ≥ 10) were associated with twofold higher odds of low cognitive performance (OR = 2.07, 95% CI 1.97-2.18), with a monotonic dose-response gradient across severity tiers (20.8% to 46.0%, p < 0.001). In prospective validation, the ensemble achieved comparable discrimination (AUC-ROC 0.838 versus 0.839 for logistic regression, P = 0.85) but superior calibration (Brier score 0.099 versus 0.126), plus per-sample uncertainty estimates and an explicit algorithmic deferral tier. The frozen four-tier rule produced a steep risk gradient (Low 5.8%, Moderate 24.9%, High 63.0%; OR high versus low=27.8).ConclusionsDepressive symptom severity shows a robust graded association with low cognitive performance in Chinese older adults. The framework supports reliable ordinal risk stratification with algorithmic deferral, providing a transferable template for population-level cognitive monitoring.},
}

@article {pmid42669799,
year = {2026},
author = {Mulligan, MD and Wang, R and Yang, Q and Beiser, AS and Maillard, P and Satizabal, C and Ghosh, S and Tanner, J and Johnson, KA and DeCarli, C and Tracy, RP and Levy, D and Benjamin, EJ and El Fakhri, G and Vasan, RS and Seshadri, S and McGrath, ER},
title = {Mid-life candidate vascular plasma biomarkers are associated with MRI markers of vascular brain injury and amyloid- and tau-PET in cognitively healthy adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480733},
doi = {10.1177/13872877261480733},
pmid = {42669799},
issn = {1875-8908},
abstract = {BackgroundIdentifying candidate biomarkers for preclinical dementia could improve our understanding of underlying biological pathways leading to vascular brain injury (VBI) and neurodegeneration.ObjectiveTo identify plasma protein markers of MRI markers of VBI and amyloid- and tau-PET burden in cognitively healthy adults.Methods125 plasma proteins were measured in dementia-free Framingham third Generation cohort participants between 2002-2005 (mean age 46 [SD 8]) with available MRI brain (n = 1039), [11]C-Pittsburgh Compound-B (PiB)- (n = 279), and/or [18]F-Flortaucipir (FTP)-PET (n = 239) performed ∼13-15 years after blood sampling. Outcomes included white matter hyperintensities, peak width of skeletonized mean diffusivity, and free water); precuneus-, posterior cingulate- and frontal, lateral and retrosplenial cortices-Aβ deposition; and global- and entorhinal cortex-tau.ResultsGrowth differentiation factor-15 (GDF-15) was associated with increased VBI (p ≤ 0.02), while soluble receptor for advanced glycation end products (sRAGE) and insulin-like growth factor 1 (IGF-1) were associated with reduced VBI (p ≤ 0.04). Plasma tau, renin, and ApoB were associated with increased Aβ deposition (p ≤ 0.02), while sRAGE was associated with reduced Aβ deposition in all regions (p ≤ 0.03). Brain natriuretic peptide (NT-proBNP) and purine nucleoside phosphorylase (PNP) were associated with increased tau deposition (p ≤ 0.02), while low density lipoprotein cholesterol (LDL-C) and GDF-15 were associated with reduced tau deposition (p ≤ 0.04).ConclusionsCandidate vascular plasma proteins measured in dementia-free, asymptomatic adults at late mid-life were associated with subsequent neuroimaging markers of VBI and tau and amyloid deposition. Our findings highlight potential novel candidate vascular biomarkers for preclinical dementia but will require validation.},
}

@article {pmid42669807,
year = {2026},
author = {Ruiz-García, Á and Díaz-Benito, B and Muñoz-García, M},
title = {A hippocampal vascular-glymphatic model of brain maintenance and cognitive resilience in Alzheimer's disease and post-stroke dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483191},
doi = {10.1177/13872877261483191},
pmid = {42669807},
issn = {1875-8908},
abstract = {Individuals with comparable burdens of brain pathology often follow markedly different cognitive trajectories. This heterogeneity is captured by three partly dissociable constructs-brain reserve, cognitive reserve, and brain maintenance-here grouped under the superordinate term cognitive resilience. Cognitive reserve has traditionally been indexed by education, occupational complexity, and lifelong cognitive engagement, yet its biological substrates remain incompletely defined. We propose that hippocampal vascular supply and perivascular (glymphatic) and meningeal lymphatic clearance, modulated by blood-brain barrier integrity and neuroinflammatory tone, constitute one biological substrate of resilience. We make its conceptual placement explicit: these processes operate predominantly as substrates of brain maintenance (efficient clearance limiting amyloid-β and tau accumulation) and brain reserve (a redundant hippocampal arterial supply buffering partial vascular compromise), rather than of cognitive reserve sensu stricto. We hypothesize, as an inference requiring direct testing rather than an established mechanism, that vascular architecture and clearance capacity are mechanistically coupled through perfusion and arterial pulsatility, rather than acting as independent parallel contributors. Preserved blood-brain barrier integrity and a regulated neuroinflammatory tone are proposed to sustain this axis, whereas their disruption, through astrocytic aquaporin-4 mislocalization, microglial activation, and barrier breakdown, accelerates cognitive decline. We additionally outline one speculative pathway by which cerebral perfusion may contribute directly to cognitive reserve. Consistent with a Hypothesis article, the model is framed as a small set of constrained, falsifiable predictions-distinguishing established, inferred, and speculative links-and as a research roadmap for Alzheimer's disease and post-stroke dementia, identifying modifiable targets (cerebral perfusion, sleep, vascular risk control) and reframing cognitive resilience as biologically grounded and potentially actionable.},
}

@article {pmid42669911,
year = {2026},
author = {Demirbas, ZS and Naharci, MI},
title = {Antiplatelet use in all-cause dementia and dementia subtypes among older adults: a population-based retrospective study.},
journal = {Croatian medical journal},
volume = {67},
number = {4},
pages = {297-305},
pmid = {42669911},
issn = {1332-8166},
mesh = {Humans ; Female ; Retrospective Studies ; Male ; Aged ; *Platelet Aggregation Inhibitors/therapeutic use ; *Dementia/drug therapy/classification ; Aged, 80 and over ; Aspirin/therapeutic use ; Risk Factors ; Clopidogrel/therapeutic use ; },
abstract = {AIM: To evaluate the appropriateness of antiplatelet use across dementia subtypes in older adults and to identify factors associated with inappropriate antiplatelet use.

METHODS: This population-based retrospective study enrolled adults aged ?65 years with dementia evaluated at a tertiary geriatric outpatient clinic at Gulhane Training and Research Hospital between 2016 and 2025. Antiplatelet (aspirin or clopidogrel) use was categorized as appropriate use, underuse, overuse, or appropriate non-use according to the 2021-2024 European Society of Cardiology guidelines. Multivariable logistic regression analyses were performed to identify the factors associated with inappropriate antiplatelet use.

RESULTS: Among 683 older adults with dementia, 40.7% received antiplatelet therapy. Antiplatelet underuse and overuse were observed in 16.8% and 16.1% of the participants, respectively. Underuse was most prevalent in vascular dementia (38.9%), whereas overuse was most prevalent in Alzheimer disease (20.2%) and frontotemporal dementia (19.0%). In multivariable analyses, antiplatelet overuse was independently associated with diabetes mellitus (odds ratio [OR] 4.31; 95% confidence interval [CI] 1.66-11.16) and inversely associated with current smoking (OR 0.06; 95% CI 0.06-0.67). Antiplatelet underuse was independently associated with female sex (OR 4.44; 95% CI 1.52-12.92).

CONCLUSIONS: Our findings highlight the gaps between guideline recommendations and real-world practice and support the need for individualized dementia-sensitive antiplatelet treatment strategies.},
}

Humans
Female
Retrospective Studies
Male
Aged
*Platelet Aggregation Inhibitors/therapeutic use
*Dementia/drug therapy/classification
Aged, 80 and over
Aspirin/therapeutic use
Risk Factors
Clopidogrel/therapeutic use

@article {pmid42669955,
year = {2026},
author = {Lauritzen, M and Dienel, G},
title = {EXPRESS: Brain energy metabolism and metabolic water in ageing, Alzheimer's, and other neurological diseases.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261486145},
doi = {10.1177/0271678X261486145},
pmid = {42669955},
issn = {1559-7016},
abstract = {BACKGROUND/HYPOTHESIS: Glucose oxidation is the brain's main way of producing the energy needed for neuronal signaling and essential maintenance tasks. When the brain cannot produce or use energy efficiently, neurons become less functional and more vulnerable. Although ageing is thought to affect brain metabolism, precise measurements of oxidative glucose use are still limited.

METHODS/RESULTS: This review brings together current evidence on how brain energy metabolism changes during healthy ageing, dementia, and major neurological disorders, using absolute measurements of oxygen consumption. Overall, the data show that oxidative glucose metabolism stays stable in healthy brain ageing. In contrast, it drops by up to ~40% in Alzheimer's disease, more with greater disease severity, and by ~ 25% in multiple sclerosis and hydrocephalus. These declines reduce the amount of ATP available for both signaling and basic cellular functions, which are essential for perception and cognition. Metabolic water production is proportionately reduced when CMRO2 decreases in diseased brain, and its secretion into interstitial fluid is diminished.

CONCLUSION/INTERPRETATION: In disease, lower oxidative metabolic activity reduces metabolic water production, which may in turn affect brain fluid dynamics, including processes involved in neuroprotection and waste clearance.},
}

@article {pmid42670072,
year = {2026},
author = {Sura, S and Okwuofu, EO and Ramakrishnappa, S and Jagadeesan, S and Binti Masrudin, SS and Mohd Moklas, MA and Dandala, KCR and Judson, JP and Mohd Nor, NH},
title = {Structural and Ultrastructural Neuropathological Changes in Alzheimer's Disease: Biomarkers, Current Insights and Emerging Perspectives.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050468141260805043246},
pmid = {42670072},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) involves progressive brain changes at both the structural and ultrastructural levels, which begin long before patients present with clinical symptoms. These changes relate to the complex processes of amyloid-β deposition, tau accumulation, synaptic damage, glial activation, impaired vascular function, and disruption of large-scale brain networks. Understanding these neurobiological changes is essential for improving diagnosis, biomarker development, and targeted therapy. We conducted a search across PubMed, Scopus, and Web of Science using the terms "Alzheimer's disease," "brain structure," "ultrastructure," "cryo-electron microscopy," and "neuroimaging." We limited our review to peer-reviewed papers published in English. Recent developments in cryo-electron microscopy, super-resolution imaging, in situ cryo-electron tomography, and correlative microscopy have revealed the molecular and subcellular features of amyloid plaques and tau filaments, as well as the associated cellular pathology of AD. These investigations refine current pathophysiological models and improve understanding of molecular-level changes in the brain. Improvements in structural and molecular imaging provide potential new biomarkers and therapeutic targets in AD. Advances in imaging and structural neuroscience could support earlier disease detection and improve clinical outcomes. These advances are helping to connect molecular pathology with structural brain remodelling and may support more precise biomarker interpretation and therapeutic development.},
}

@article {pmid42670073,
year = {2026},
author = {Ma, J and Wei, Z and Rong, C and He, W and Wang, X and Zhao, D},
title = {The Relationship Between Biomarkers in Blood and Urine and Alzheimer's Disease and Sleep Disorders (Long Sleep): A Mendelian Randomization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050466562260804080255},
pmid = {42670073},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a neurological condition that increases in severity from a gradual start. Previous studies have found an association between long sleep (LS) and AD. To slow its progression, it is important to recognize biomarkers associated with the early stages of both AD and LS.

METHODS: This study aimed to use two-sample Mendelian Randomization (MR) to identify blood and urine biomarkers associated with AD and LS. Thirty-five biomarkers from blood and urine were included as exposures in the MR analysis, while AD and LS were considered the outcomes. The AD dataset included 39,106 patients and 46,828 controls from Europe. Data on sleep duration were obtained from a GWAS in 34,184 cases and 305,742 controls of European ancestry. This study included 35 blood and urine biomarkers across 355,891 participants, including 318,953 white British, 23,582 non-white British, 6,019 African, and 7,338 South Asian participants from the UK Biobank.

RESULTS: Cystatin C, CRP, and Non-Albumin protein showed genetic association with AD and LS. The genetic association results after Bonferroni's correction are significant for Non-Albumin Protein in AD and LS.

DISCUSSION: This study provides further insight into the genetic associations and relationships among AD, LS, and other biomarkers; it also presents several potential candidates for AD and LS diagnosis and treatment. The opposing roles of C-reactive Protein, Cystatin C, and Non-Albumin protein in AD and LS warrant a greater exploration of their differential functions at various ages and in specific brain microenvironments in future studies.

CONCLUSION: This study provides a theoretical basis for the diagnosis and treatment of AD and LS. More experiments are needed in the future to verify this prediction.},
}

@article {pmid42666354,
year = {2026},
author = {Xiao, P and Wang, Y and Li, J and Li, W},
title = {Retinal neurovascular coupling dysfunction and plasma metabolomic features as biomarkers of Alzheimer's disease: an integrated diagnostic model.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1892148},
pmid = {42666354},
issn = {1662-4548},
abstract = {OBJECTIVE: To explore features associated with impaired retinal neurovascular coupling among individuals diagnosed with Alzheimer's disease (AD) and its association with alterations in plasma metabolomics, and to establish an integrated diagnostic model for evaluating its possible significance regarding early-stage identification of AD.

METHODS: We prospectively enrolled 85 AD patients, 82 subjects with mild cognitive impairment (MCI), and 83 cognitively normal controls. Retinal vessel density, foveal avascular zone (FAZ) parameters, choriocapillaris flow deficits (CCFDs), ganglion cell layer thickness, and neurovascular coupling index (NVCI) were quantified using optical coherence tomography angiography (OCTA). Untargeted plasma metabolomics was performed via ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Differential metabolites and pathways were identified, followed by correlation, regression, and receiver operating characteristic (ROC) analyses.

RESULTS: Compared with controls, the AD group showed reduced superficial vascular plexus perfusion density (-7.1%, P < 0.001), enlarged FAZ area (+16.1%, P < 0.001), increased CCFDs (+28.3%, P < 0.001), decreased ganglion cell layer thickness (-18.3%, P < 0.001), and lower NVCI (-12.7%, P < 0.001). Values in the MCI group were intermediate. In metabolomic profiling, AD patients had lower leucine (-17.0%, P < 0.001) and phosphatidylcholine PC(16:0/20:4) (-19.4%, P < 0.001), but higher ceramide d18:1/24:1 (+33.6%, P < 0.001) and ceramide/sphingomyelin ratio (+22.2%, P < 0.001). NVCI positively correlated with leucine (r = 0.205, q = 0.0011) and negatively with ceramide d18:1/24:1 (r = -0.139, q = 0.0280). An integrated model combining FAZ area, CCFDs, NVCI, leucine, ceramide d18:1/24:1, and PC(16:0/20:4) discriminated AD from controls with an AUC of 0.908 (95% CI: 0.865-0.952), 83.5% sensitivity, and 88.0% specificity. For predicting MCI-to-AD progression, the AUC was 0.744 (95% CI: 0.669-0.819), with 57.6% sensitivity and 85.4% specificity.

CONCLUSION: Retinal neurovascular coupling dysfunction was significantly associated with systemic metabolic disturbances (branched-chain amino acid deficiency and ceramide accumulation) in patients with AD. The OCTA-metabolomics integrated model offers excellent diagnostic performance, supporting its potential for non-invasive early AD detection and risk assessment.},
}

@article {pmid42666359,
year = {2026},
author = {Ma, Y and Li, X and Chen, H and Fan, R},
title = {Exercise alone or combined with functional foods in aging and age-related diseases: targeting DNA damage, repair pathways, and genome integrity.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1772217},
pmid = {42666359},
issn = {1663-4365},
abstract = {Aging is fundamentally associated with the gradual accumulation of DNA damage, which is instrumental in the initiation and advancement of age-associated pathologies, including neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. Recent studies indicate that lifestyle modifications-especially the consumption of functional foods and participation in consistent physical exercise-can influence cellular and molecular processes related to DNA repair, reduction of oxidative stress, and maintenance of genomic integrity. This review consolidates contemporary research regarding how particular bioactive compounds (e.g., polyphenols, omega-3 fatty acids, and flavonoids) present in functional foods, in conjunction with diverse exercise interventions, affect DNA repair processes and diminish genotoxic stress. We examine evidence from exercise-only, nutrition-only, and combined lifestyle interventions, with particular attention to whether combined interventions show additive, complementary, or genuinely synergistic effects on oxidative stress, inflammatory responses, epigenetic aging, and DNA repair-related pathways. Particular emphasis is placed on the susceptibility of the brain to DNA damage and the significance of these interventions in safeguarding neuronal integrity and cognitive capabilities. By synthesizing evidence from molecular, animal, and human research, this review underscores the therapeutic promise of functional foods and physical activity as readily available, non-pharmacological approaches to ameliorate genomic integrity and postpone the onset or progression of aging-related and neurodegenerative disorders. In conclusion, we address prevailing limitations, deficiencies in translational research, and prospective avenues for personalized lifestyle medicine aimed at enhancing DNA integrity.},
}

@article {pmid42666495,
year = {2026},
author = {Hölscher, C},
title = {GLP-1 and GIP class drugs have neuroprotective properties in Alzheimer's and Parkinson's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1906426},
pmid = {42666495},
issn = {1662-4548},
abstract = {Alzheimer's and Parkinson's disease are two CNS diseases with a large unmet need for disease-modifying therapies. Recently, two phase 3 clinical trials testing the GLP-1 analogue Semaglutide (Wegovy, Ozempic) in patients with Alzheimer's disease did not show improvements. This failure should not have been a surprise, since it has been known for many years that Semaglutide does not cross the blood-brain barrier (BBB) and enters the brain only in very small amounts. It is designed to stay in the blood stream and has a very long half-life in the blood (168 h). The GLP-1 analogue Liraglutide (Victoza), in contrast, has a much shorter half-life (13 h), and a phase 2 clinical trial showed improvements in cognitive tests after 1 year of treatment. GLP-1 receptor agonists have been tested in clinical trials in Parkinson's patients, and a similar picture emerged. Drugs that can cross the BBB well (exenatide, lixisenatide) show good protection, while a drug that cannot cross the BBB showed no effects (NLY01). Clearly, when treating CNS diseases, it is of importance to get the drug into the brain to ensure target engagement. This review will look at the clinical trials that have been conducted in more detail, describe the mode of action as derived from preclinical trials, and discuss novel strategies for getting GLP-1 receptor agonists into the brain to successfully treat CNS diseases.},
}

@article {pmid42666506,
year = {2026},
author = {Fang, X and Zhang, Z and Hu, X and Zhang, M and Yang, H and He, J and Shi, Y and Li, G and Jia, Y},
title = {Assembling peptides for treating Alzheimer's disease: a supramolecular perspective.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42666506},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current clinical treatments for AD primarily focus on alleviating symptoms but still face limitations such as suboptimal efficacy, side effects, and irreversible neuronal loss. Misfolding of the Aβ peptide plays a key role in AD pathogenesis and progression. By targeting this AD pathology, peptide-based therapeutics, particularly peptide assembly strategies, hold immense potential in AD therapy. Unlike sequence-based conventional reviews, this review reorganizes relevant advances from the perspective of a unified supramolecular framework. We first illustrate the structural, kinetic, and thermodynamic molecular basis of the pathological Aβ assembly and its neurotoxicity. Three mainstream supramolecular intervention strategies are then discussed: peptides redirecting the regulation of aberrant Aβ assembly, neuroprotective peptide scaffolds, and drug-loading peptide hydrogels. Finally, a universal rational design workflow for multifunctional peptide therapeutics is summarized, and perspectives on advanced directions are outlined.},
}

@article {pmid42666544,
year = {2026},
author = {Seraj, F and Maqbool, M and Ali, F and Chigurupati, S and Tariq, SS and Salar, U and Ul-Haq, Z and Mani, V and Felemban, SG and Khan, KM},
title = {Design and synthesis of quinoline-derived thioureas as potential antihyperglycemic, anti-Alzheimer, and antioxidant agents.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42666544},
issn = {2046-2069},
abstract = {A library of quinoline-based thiourea hybrids 1-41 was synthesized via a single-step reaction scheme. All compounds were evaluated for their inhibitory potential against α-amylase, α-glucosidase, AChE, and BChE enzymes as well as for DPPH radical scavenging activity. Among forty-one compounds, 27-31 and 33-37 showed excellent inhibition against α-amylase (IC50 = 18.36-28.21 µM) and α-glucosidase (IC50 = 17.77-29.31 µM) compared to the standard acarbose (IC50 = 16.98 ± 0.12, 14.19 ± 0.06 µM). Moreover, compounds 27, 28, 30, 31, 34, 35, and 37 inhibited AChE (IC50 = 5.60-14.97 µM) and BChE (IC50 = 6.99-15.70 µM) with greater potency than the standard donepezil chloride (IC50 = 1.49 ± 0.13, 2.39 ± 0.06 µM). Kinetic analyses were conducted for the most active compounds to elucidate their modes of enzyme inhibition. Furthermore, molecular docking studies were conducted to explore ligand binding interactions within the enzyme active site. All synthesized derivatives were further evaluated for their DPPH radical scavenging activity, among which compounds 27, 28, 30, 31, 34, and 35 exhibited significant to moderate antioxidant potential (SC50 = 23.92-34.73 µM) compared with the reference standard ascorbic acid (SC50 = 18.28 ± 0.15 µM). Among this library, compound 31, with a difluoro group on the phenyl ring, was identified as the most potent inhibitor against all enzymes. Thus, this study suggests that the reported compounds hold the potential to be further advanced as lead anti-Alzheimer and anti-diabetic agents.},
}

@article {pmid42667001,
year = {2025},
author = {O'Donnell, AJ and Handler, SM and Faieta, J and Jump, R},
title = {Can Telehealth Improve Access to Amyloid-Targeting Therapies for Veterans Living With Alzheimer Disease?.},
journal = {Federal practitioner : for the health care professionals of the VA, DoD, and PHS},
volume = {42},
number = {12},
pages = {458-462},
pmid = {42667001},
issn = {1078-4497},
abstract = {BACKGROUND: Amyloid-targeting therapies, such as lecanemab and donanemab, offer new hope for managing Alzheimer disease (AD). Provision of these medications, however, is challenging for patients, care partners, and clinicians.

OBSERVATIONS: Telehealth has demonstrated success in the assessment and management of individuals living with dementia in the Veterans Health Administration (VHA). It may substantially increase access to evaluation for veterans with early dementia and, when medically appropriate, amyloid-targeting therapies. Telehealth has the potential to overcome barriers related to transportation, access to specialists, and relieve the burden of frequent clinical assessments, as well as associated costs. Although telehealth is not without limitations, VHA is a leader in telehealth and has taken action to overcome patient barriers related to the digital divide.

CONCLUSIONS: The VHA is well-positioned to use a hybrid approach-both telehealth and in-person care-to support the provision of amyloid-targeting therapies for veterans with AD. Lessons learned can be extended to non-VHA care settings to achieve potential benefits for other patients with early AD.},
}

@article {pmid42667351,
year = {2026},
author = {Yuan, Y and Liu, P and Yin, C and Zhu, J and Xu, J and Xiong, H and Xu, R},
title = {Mechanism and progress of deep brain stimulation in the treatment of neurological and psychiatric disorders.},
journal = {MedScience},
volume = {},
number = {},
pages = {},
pmid = {42667351},
issn = {3091-4981},
abstract = {Deep brain stimulation (DBS) is a reversible and adjustable neurostimulation technique, and has been established as a significant therapeutic modality in functional neurosurgery although its mechanisms are not yet fully understood. The primary indications for DBS include movement disorders such as Parkinson's disease (PD) and dystonia, essential tremor (ET), and Huntington's disease (HD). In recent years, its application has expanded to encompass the treatment of various other neurological and psychiatric conditions, including epilepsy, depression, obsessive-compulsive disorder (OCD), Alzheimer's disease (AD), and Tourette syndrome (TS), although the indications for DBS currently approved by the Food and Drug Administration (FDA) are PD, dystonia, ET, OCD, and epilepsy. In this review, we summarize the prevailing hypotheses regarding the mechanisms through which DBS ameliorates neurological and psychiatric disorders. We also describe the advancements in DBS for treating PD, dystonia, epilepsy, and other brain disorders. Furthermore, we outline the limitations associated with DBS treatment to date. Through this comprehensive analysis, we aim to enhance the understanding of DBS applications in neurological and psychiatric diseases and suggest potential avenues for technological advancement.},
}

@article {pmid42667453,
year = {2026},
author = {Liu, C and Zhang, Y},
title = {Ginsenosides: potential therapeutic implications in neurodegenerative diseases by inhibiting ferroptosis.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42667453},
issn = {1573-4978},
mesh = {Humans ; *Ginsenosides/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Ferroptosis/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy ; },
abstract = {A positive correlation exists between the accelerating pace of population aging and the increasing prevalence of neurodegenerative diseases. Conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) profoundly compromise patient quality of life, yet efficacious clinical interventions remain notably limited. The prevention and management of neurodegenerative diseases represent a critical global public health imperative. A comprehensive literature search was performed across PubMed, Web of Science, and Scopus to identify studies on the biological functions, molecular mechanisms, and clinical implications of ginsenosides. The search strategy incorporated MeSH terms and free-text keywords, encompassing "neurodegenerative disease", "ferroptosis", "ginsenosides", "Parkinson's disease", "Alzheimer's disease", "amyotrophic lateral sclerosis", "Huntington's disease" and "multiple sclerosis". From an initial pool of over 400 papers (1998-2026), 107 were selected in this narrative review. Ferroptosis is intricately linked to the pathogenesis of neurodegenerative diseases. Ginsenosides constitute the principal bioactive triterpenoid saponins extracted from plants of the Panax genus, demonstrating broad-spectrum pharmacological efficacy encompassing antitumor, immunomodulatory, anti‑inflammatory, anti‑allergic, anti‑atherosclerotic, antihypertensive, antidiabetic, antistress, and neuroprotective activities. Ginsenosides exert their neuroprotective effects against AD, PD, and ALS predominantly through the modulation of ferroptosis. Herein, this article provides a review of the molecular mechanisms, genetic determinants, signaling cascades, and functional implications of ferroptosis. Ginsenosides represent promising therapeutic agents in neurodegenerative diseases via modulation of iron homeostasis; this paper elucidates mechanistic insights into disease pathogenesis and evaluates their translational therapeutic potential. This narrative review highlights emerging insights that provide novel therapeutic perspectives for neurodegenerative diseases.},
}

Humans
*Ginsenosides/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
*Ferroptosis/drug effects
Animals
Neuroprotective Agents/pharmacology/therapeutic use
Amyotrophic Lateral Sclerosis/drug therapy

@article {pmid42667495,
year = {2026},
author = {Fan, W and Han, S and Wang, C and Gao, J},
title = {Integrative transcriptomics identifies shared aging-associated inhibitory-neuron states and prioritizes RGL2 across postoperative delirium and Alzheimer's disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42667495},
issn = {1559-1166},
support = {20230229//Jincheng Municipal Key Science and Technology R&D Program/ ; SYH-32021-0127//Jiangsu Medical Association Research Project/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; *Aging/genetics/metabolism ; *Nerve Tissue Proteins/genetics/metabolism ; *Transcriptome ; *Delirium/genetics/metabolism ; *Neurons/metabolism ; *Postoperative Cognitive Complications/genetics/metabolism ; Syk Kinase/genetics/metabolism ; Guanylate Kinases/genetics/metabolism ; },
abstract = {Postoperative delirium (POD) and Alzheimer's disease (AD) are increasingly recognized as related neurocognitive conditions, but the aging-associated cell states that may connect them remain poorly defined. Here, we integrated two brain transcriptomic discovery datasets analyzed at single-cell/single-nucleus resolution, including a POD-related cohort (GSE291019) and an AD cohort (GSE129308), together with two independent peripheral-blood bulk transcriptomic datasets (GSE163943 and GSE63060), to identify aging-associated cellular programs and prioritize convergent molecular candidates. Across 184,168 high-quality cells, inhibitory neurons showed the most consistent aging-associated perturbation across the POD- and AD-related datasets. Re-clustering further identified three inhibitory-neuron subtypes, Inh_Neurons2, Inh_Neurons3, and Inh_Neurons5, with relatively high aging-related gene activity and preferential localization to later pseudotime states. Cross-platform integration of aging-associated inhibitory-neuron genes with a shared bulk DEG set identified four convergent candidates: RGL2, AKT1, SYK, and TNFSF13B. Among them, RGL2 emerged as the leading candidate, with the strongest downstream support concentrated in AD-related analyses. In two-sample Mendelian randomization, genetically predicted higher RGL2 expression was associated with increased AD risk, whereas the estimate for the delirium genome-wide association study proxy used for POD-related analyses was not significant. Pathway analyses further linked higher RGL2 expression to complement/coagulation and innate immune-inflammatory programs in AD-related analyses. These findings suggest a model in which POD and AD may partially intersect through aging-vulnerable inhibitory-neuron states and identify RGL2 as a prioritized candidate for downstream mechanistic investigation.},
}

*Alzheimer Disease/genetics/metabolism
Humans
*Aging/genetics/metabolism
*Nerve Tissue Proteins/genetics/metabolism
*Transcriptome
*Delirium/genetics/metabolism
*Neurons/metabolism
*Postoperative Cognitive Complications/genetics/metabolism
Syk Kinase/genetics/metabolism
Guanylate Kinases/genetics/metabolism