@article {pmid42751784,
year = {2026},
author = {Mamangam, S and Dhanabalan, AK and Verma, K and Prasanth, MI and Brimson, S and Brimson, JM},
title = {Neuroprotective Effects of Two N-Benzylamides in Models of Oxidative Stress, Neurite Outgrowth and Neurodegeneration.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e3092494},
doi = {10.1155/omcl/3092494},
pmid = {42751784},
issn = {1942-0994},
support = {N42A670287//National Research Council of Thailand/ ; //Chulalongkorn University/ ; },
mesh = {*Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Humans ; *Neuronal Outgrowth/drug effects ; Receptors, sigma/metabolism ; Sigma-1 Receptor ; Mice ; *Benzamides/pharmacology ; Molecular Docking Simulation ; Reactive Oxygen Species/metabolism ; Caenorhabditis elegans ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {Oxidative stress is a central pathological mechanism in neurodegenerative diseases (NDDs), contributing to mitochondrial dysfunction, impaired proteostasis, and progressive neuronal loss. The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident chaperone that coordinates cellular stress responses and has emerged as a promising therapeutic target for neuroprotection. In this study, we investigated the neuroprotective properties and mechanisms of the structurally related N-benzylamides, N-benzylcinnamide (NBCA) and N-benzylbenzamide (NBBA) using complementary in vitro, in vivo and in silico approaches. Neuroprotective activity was initially evaluated using glutamate-induced oxidative injury in HT22 hippocampal neurones and H2O2-induced oxidative stress in SH-SY5Y neuroblastoma cells. Both compounds significantly attenuated oxidative injury, although NBCA consistently showed greater efficacy and was therefore selected for detailed mechanistic investigation. NBCA reduced intracellular reactive oxygen species (ROS) production and lipid peroxidation while restoring endogenous antioxidant enzyme activities, mitochondrial membrane potential, ATP production, and cholinergic homeostasis. Immunofluorescence analysis showed that NBCA modulated nuclear factor erythroid 2-related factor 2 (NRF2) and S1R immunoreactivity after oxidative stress. NBCA also promoted neurite outgrowth in wild-type (WT) Neuro-2a cells, whereas these effects were absent in S1R knockout cells, supporting the involvement of S1R-associated signalling. Molecular docking predicted favourable interactions between NBCA and the stress-response proteins S1R, BiP and TMEM97, suggesting modulation of interconnected cellular stress-response networks. In Caenorhabditis elegans, NBCA improved resistance to oxidative stress, preserved learning and memory, delayed amyloid-β-induced paralysis, and reduced amyloid deposition in transgenic Alzheimer's disease (AD) models. Collectively, these findings demonstrate that NBCA exerts neuroprotective effects across multiple experimental models by preserving redox homeostasis, mitochondrial function, and neuronal integrity. The convergence of pharmacological, genetic, imaging, computational, and whole-organism evidence supports the involvement of S1R-associated signalling in NBCA's biological activity. Together, these findings demonstrate that modulation of S1R-associated cellular stress-response networks is a promising strategy for preserving neuronal function during oxidative stress and neurodegeneration and identify NBCA as a valuable lead compound for future mechanistic and therapeutic investigation.},
}

*Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
Humans
*Neuronal Outgrowth/drug effects
Receptors, sigma/metabolism
Sigma-1 Receptor
Mice
*Benzamides/pharmacology
Molecular Docking Simulation
Reactive Oxygen Species/metabolism
Caenorhabditis elegans
*Neurodegenerative Diseases/drug therapy/pathology/metabolism
Cell Line, Tumor
Membrane Potential, Mitochondrial/drug effects

@article {pmid42752160,
year = {2026},
author = {Abo Foul, Y and Shamay-Tsoory, S},
title = {Empathy on the edge: A neurocognitive model of empathy in aging and dementia.},
journal = {Psychology and aging},
volume = {},
number = {},
pages = {},
doi = {10.1037/pag0001025},
pmid = {42752160},
issn = {1939-1498},
abstract = {Empathy, the ability to understand others' perspectives (cognitive empathy) and share their emotions (emotional empathy), is critical for social functioning across the lifespan. Although empathy changes with age and is often disrupted in neurodegenerative disease, prior research has largely examined isolated components or focused narrowly on healthy aging or specific disorders. This systematic review addresses this gap by synthesizing behavioral and neuroimaging evidence on empathy across typical and pathological aging, from healthy older adulthood and mild cognitive impairment to Alzheimer's disease and behavioral variant frontotemporal dementia. We reviewed empirical studies published between January 2015 and October 2025 that examined cognitive and/or emotional empathy in healthy older adults or individuals with mild cognitive impairment, Alzheimer's disease, or behavioral variant frontotemporal dementia. We propose an integrative model suggesting that cognitive and emotional empathy follow distinct trajectories across aging. Based on the model, cognitive empathy gradually declines, likely reflecting changes in prefrontal regions and large-scale brain networks, with this process beginning in normal aging and continuing through mild cognitive impairment and dementia. In contrast, emotional empathy is relatively preserved in aging and early disease stages, although it becomes more context-dependent with clearer impairment in behavioral variant frontotemporal dementia. We conclude that understanding these trajectories has important implications for early diagnosis, caregiving, and designing targeted interventions to support empathic functioning in older adults and individuals with neurodegenerative diseases. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42752570,
year = {2026},
author = {Liu, Y and He, Y and Wei, Y and Wang, P and Huang, C and Tao, Q and Zhu, L and Xu, X and Liu, L and Liu, S and Han, L and Zhang, J and Wang, L},
title = {A Molecularly Anchored Spatial Transcriptomic Framework for Precise CA1-Subiculum Parcellation and Region-Resolved Analysis in Alzheimer's Disease.},
journal = {GigaScience},
volume = {},
number = {},
pages = {},
doi = {10.1093/gigascience/giag094},
pmid = {42752570},
issn = {2047-217X},
abstract = {BACKGROUND: The precise molecular delineation of the interface between the Subiculum (Sub) and cornu ammonis 1 (CA1) is a challenge in hippocampal research, as conventional cytoarchitectural boundaries are often ambiguous and limit reproducible regional annotation. Here, we developed a molecularly anchored spatial transcriptomic framework to define CA1-Sub regional identities using high-definition spatial transcriptomics (Stereo-seq) and single-nucleus RNA sequencing (snRNA-seq) references.

FINDINGS: Using a human hippocampal Stereo-seq dataset from 12 donors, we established a data-driven parcellation framework that defines reproducible molecular features distinguishing CA1 and Sub while capturing the transition between these regions. FN1 was identified as a Sub-enriched marker in a subset of EX_Sub and, together with ETV1 and additional regional markers, enabled molecular assignment of CA1 and Sub identities across datasets. The Sub association of FN1 and ETV1 was further supported by human 10X Genomics spatial transcriptomics, mouse in situ hybridization data, and a mouse spatial transcriptomic dataset. Applying this framework to Alzheimer's disease (AD) tissues revealed region-specific transcriptional alterations across CA1 and Sub, including enrichment of mitochondrial energy metabolism-related transcripts in the Sub, suggesting exploratory transcriptional associations of altered metabolic function.

CONCLUSIONS: This study provides a molecularly anchored framework for human CA1-Sub parcellation that complements conventional annotation. By defining regional molecular states while preserving the biological continuum across CA1-Sub interface, this approach enables more consistent regional analysis of human hippocampus tissue across donors, datasets, and disease conditions.},
}

@article {pmid42752707,
year = {2026},
author = {Santos, DH and da Silva, AMP},
title = {Amyloid-beta-targeting monoclonal antibodies in early Alzheimer's disease: a cochrane review summary and appraisal for the neurological community.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42752707},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; *Amyloid beta-Peptides/immunology/metabolism ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Seven amyloid-beta-targeting monoclonal antibodies have been trialled in early Alzheimer's disease. They differ in epitope and in how much plaque they clear; only two have traditional approval. A 2026 Cochrane Review pooled all seven as one class. We ask what that average tells us about any one drug.

METHODS: We summarise the review in mild cognitive impairment or mild dementia due to Alzheimer's disease and report its estimates and certainty ratings unchanged. Our appraisal sits in a separate section and draws on the pivotal trials and regulatory assessments.

RESULTS: Seventeen trials (20,342 participants) were included. At 18 months the pooled standardised mean difference was -0.11 (95 % confidence interval -0.16 to -0.06) for cognition and -0.12 (-0.24 to 0.00) for dementia severity; three functional scales favoured treatment (0.09 to 0.23). Amyloid-related imaging abnormalities with oedema affected 119 versus 12 per 1,000 (risk ratio 10.02, 7.49 to 13.41). Four of the seven antibodies cleared no plaque or cleared it incompletely, so the pooled result cannot test whether clearance produces benefit. In the two approved agents dementia severity differed by 0.45 and 0.67 points, larger than the class average but below thresholds of clinical importance.

CONCLUSIONS: The class average is not an estimate for any single agent. These antibodies clear amyloid and produce small differences on trial scales at 18 months, against a tenfold rise in amyloid-related oedema. Counselling should rest on agent-specific figures and a biomarker-confirmed diagnosis, and should weigh APOE ε4 genotype and antithrombotic use before the first infusion.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal/therapeutic use
*Amyloid beta-Peptides/immunology/metabolism
Cognitive Dysfunction/drug therapy

@article {pmid42752750,
year = {2026},
author = {Jantaratnotai, N and McLarnon, JG},
title = {The Roles of Transcription Factor Ets-1 in Neurological Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42752750},
issn = {1559-1182},
mesh = {Humans ; *Proto-Oncogene Protein c-ets-1/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; },
abstract = {Ets-1 is a member of the Ets family of transcription factors that regulates diverse biological processes including cellular proliferation, development, and immune response. At present, few studies have examined the actions of Ets-1 in brain neurological disorders. One exception is brain tumors where evidence suggests that elevated levels of Ets-1 could induce abnormalities in angiogenic activity in promoting tumor growth. In this review we summarize evidence for the involvement of Ets-1 in brain neurological disorders including brain tumors, stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, neuropathic pain, and depression. Overall findings suggest that Ets-1 is a critical switch in balancing vascular remodeling and neuroinflammation across various neuropathologies; however, whether Ets-1 exerts detrimental or beneficial effects is context- and time-dependent. At present, published work has largely concerned ancillary, rather than primary, roles of Ets-1 in brain with little focus on disorders other than brain tumors. Resolving these divergent and time-dependent roles of Ets-1 will advance its utility as both a diagnostic biomarker and a viable therapeutic target in neurological diseases.},
}

Humans
*Proto-Oncogene Protein c-ets-1/metabolism
Animals
*Nervous System Diseases/metabolism/pathology

@article {pmid42752765,
year = {2026},
author = {Zhang, T and Chen, X and Wang, Y and Wang, Y},
title = {A Lipoylation-PDH-TCA Transcriptional Deficit in the Alzheimer's Disease Cortex - Donor-level Multi-cohort Evidence with Neuronal-composition, Disease-specificity and Matched-null Controls.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42752765},
issn = {1559-1166},
mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; Humans ; *Neurons/metabolism ; Lipoylation ; *Prefrontal Cortex/metabolism/pathology ; *Citric Acid Cycle ; Male ; Cuproptosis ; },
abstract = {Cuproptosis, a copper-dependent form of regulated cell death acting through lipoylated tricarboxylic acid (TCA) cycle proteins, has been proposed as a molecular link between type 2 diabetes and Alzheimer's disease. We asked whether cuproptosis effector genes are dysregulated in a cell-type-specific manner in the human Alzheimer's disease cortex, and whether any such signal survives controls for neuronal composition and disease specificity. Single-nucleus data from 21 prefrontal cortex donors were aggregated to donor-level pseudobulk within each cell type. Four independent bulk cohorts, each contributing one observation per donor, entered a random-effects meta-analysis. Adjustment for estimated neuronal content, competitive and expression-matched null gene-set testing, and comparison against Huntington's disease and vascular dementia were applied as controls. The donor was the unit of replication throughout. No gene-cell-type pair survived correction across the 75 prespecified tests; PDHA1 in inhibitory neurons showed the largest nominal reduction (- 0.418, q = 0.829). In donor-level meta-analysis PDHA1 was lower in Alzheimer's disease in all four cohorts (- 0.457, 95% CI - 0.712 to - 0.201, I[2 ]= 0%) but did not survive correction (q = 0.086). A post hoc lipoylation/pyruvate dehydrogenase/TCA module did reach the adjusted threshold (- 0.245, 95% CI - 0.363 to - 0.127, q = 0.035), whereas the copper modules pooled to zero and moved in opposite directions across cohorts. Comparable reductions occurred in Huntington's disease and vascular dementia, and the disease-control contrasts were not significant. These transcriptional associations do not demonstrate cuproptosis, are not specific to Alzheimer's disease, and are hypothesis-generating only.},
}

*Alzheimer Disease/metabolism/genetics/pathology
Humans
*Neurons/metabolism
Lipoylation
*Prefrontal Cortex/metabolism/pathology
*Citric Acid Cycle
Male
Cuproptosis

@article {pmid42752992,
year = {2026},
author = {Li, X and Liu, X and Song, X and Zhou, Y and Yang, D and Wang, Y and Mao, S and Rang, X and Hong, X and Wang, X and Yue, H and Wang, D and Zhang, X},
title = {Bioinformatics-Driven Discovery of Aβ-Targeted Therapeutics and Diagnostic Biomarkers for Alzheimer's Disease.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e8975137},
pmid = {42752992},
issn = {2314-6141},
support = {LH2020H052//Heilongjiang Provincial Natural Science Foundation/ ; },
mesh = {*Alzheimer Disease/diagnosis/metabolism/genetics/drug therapy ; Humans ; *Amyloid beta-Peptides/metabolism ; *Biomarkers/metabolism ; Molecular Docking Simulation ; *Computational Biology/methods ; Curcumin/pharmacology/chemistry ; Molecular Dynamics Simulation ; Resveratrol/pharmacology ; Apigenin/pharmacology/chemistry ; Gene Regulatory Networks ; Protein Binding ; },
abstract = {The deposition of amyloid-β (Aβ) plaque is widely recognized as one of the core pathological events of Alzheimer's disease (AD). This study focused on uncovering potential diagnostic biomarkers and small-molecule candidates potentially modulating Aβ-associated pathways in AD. Weighted gene coexpression network analysis (WGCNA) and machine learning identified the hub gene. Single-nucleus RNA sequencing (snRNA-seq) identified high-expression cell clusters. We identified potential Aβ-binding small-molecule candidates and calculated their binding affinities using molecular docking techniques. Based on molecular docking, we further evaluated the binding stability and conformational dynamics of the protein-ligand complex through molecular dynamics (MD) simulations. NFKBIA was identified as a hub diagnostic gene. Three small molecules, resveratrol, curcumin, and apigenin, demonstrated strong binding affinities for NFKBIA. These findings clarify the priority candidate gene and feasible strategic directions, which are expected to be translated into practical pathways for precision diagnosis and treatment of AD.},
}

*Alzheimer Disease/diagnosis/metabolism/genetics/drug therapy
Humans
*Amyloid beta-Peptides/metabolism
*Biomarkers/metabolism
Molecular Docking Simulation
*Computational Biology/methods
Curcumin/pharmacology/chemistry
Molecular Dynamics Simulation
Resveratrol/pharmacology
Apigenin/pharmacology/chemistry
Gene Regulatory Networks
Protein Binding

@article {pmid42753025,
year = {2026},
author = {Aydın, AC},
title = {Exosomes in Alzheimer's Disease: From Pathological Mechanisms to Biomarker Potential and Therapeutic Applications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42753025},
issn = {1559-1182},
mesh = {Humans ; *Exosomes/metabolism ; *Alzheimer Disease/therapy/pathology/metabolism ; *Biomarkers/metabolism ; Animals ; Microglia/metabolism/pathology ; },
abstract = {Exosomes are small extracellular vesicles that mediate communication between cells by carrying proteins, lipids, nucleic acids, and other biologically active molecules. In Alzheimer's disease (AD), their role appears to be complex and context-dependent. Evidence suggests that exosomes may contribute to disease progression by supporting the intercellular spread of amyloid-β and tau pathology. At the same time, they are increasingly being investigated as blood-based biomarkers and as potential therapeutic delivery systems. This review summarizes current evidence on the involvement of exosomes in AD biology. Particular attention is given to their role in amyloid-β and tau propagation, microglia-driven neuroinflammation, and the Pellino-1 (Peli1)-related communication between microglia and astrocytes. The review also discusses the diagnostic value of neuron- and astrocyte-derived exosomes as minimally invasive biomarkers. In addition, the therapeutic potential of mesenchymal stem cell-derived exosomes is evaluated, especially in relation to amyloid clearance, neuroinflammation, synaptic repair, and blood-brain barrier crossing. Although preclinical and early clinical findings are encouraging, several barriers still limit clinical translation. These include the lack of standardized isolation methods, cargo heterogeneity, large-scale production difficulties, and insufficient long-term safety and efficacy data. Overall, exosome-based strategies represent a promising but still developing field in AD research, with potential relevance for early diagnosis, disease monitoring, and future therapeutic applications.},
}

Humans
*Exosomes/metabolism
*Alzheimer Disease/therapy/pathology/metabolism
*Biomarkers/metabolism
Animals
Microglia/metabolism/pathology

@article {pmid42753051,
year = {2026},
author = {Pellikka, E and Vauhkonen, PK and Oura, P},
title = {Neuropathological diagnoses and age-related differences in Finnish medico-legal autopsies of individuals aged 65 years and older.},
journal = {Forensic science, medicine, and pathology},
volume = {},
number = {},
pages = {},
pmid = {42753051},
issn = {1556-2891},
abstract = {As populations worldwide continue to grow older, an increase in cases involving aged individuals is also to be expected in medico-legal autopsies. The aim of this study was to report the neuropathological diagnoses of individuals aged ≥ 65 years, and to compare the findings across three age groups: youngest-olds (65-74 years of age), middle-olds (75-84) and oldest-olds (≥ 85). The sample comprised all Finnish medico-legal autopsies of individuals aged ≥ 65 years whose autopsy included a full neuropathological examination performed by a neuropathologist over the period 2016-2022 (n = 629). Neuropathological diagnoses were obtained from the neuropathologists' reports, and background characteristics were collected from medico-legal cause-of-death investigation documents. Of all cases, 97.1% received at least one neuropathological diagnosis. The prevalences of many neurodegenerative diseases increased with age; Alzheimer's disease neuropathological change (30.5%) and cerebral amyloid angiopathy (14.0%) were the most common ones. However, some rarer neurodegenerative diseases were more frequent among youngest-olds. While the prevalence of acute infarcts remained relatively consistent across the age groups (12.4-14.5%), old infarcts and subarachnoid haemorrhages were most common among oldest-olds (22.1% and 16.6%, respectively). The age-related increase in subarachnoid haemorrhage diagnoses appeared to be primarily driven by the male sex. The prevalences of acute and old traumatic brain injuries were rather low (5.7-6.2% and 5.1%, respectively) and remained relatively stable across the age groups. In conclusion, our data suggest that neuropathological diagnoses are highly prevalent among aged individuals undergoing medico-legal autopsy, and many diagnoses become more frequent towards oldest-olds.},
}

@article {pmid42753133,
year = {2026},
author = {Misra, SR and Das, R},
title = {Beyond Oral Hygiene: Medication Burden, Oral Function, and Dysphagia in Alzheimer's Disease.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {5},
pages = {e70255},
doi = {10.1111/scd.70255},
pmid = {42753133},
issn = {1754-4505},
}

@article {pmid42753291,
year = {2026},
author = {Tamiz, AP and Baran, SW and Hartung, T and Wu, WW},
title = {New approach methodologies in neurotherapeutics development.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01056},
doi = {10.1016/j.neurot.2026.e01056},
pmid = {42753291},
issn = {1878-7479},
abstract = {New Approach Methodologies (NAMs) offer substantial opportunities to transform neurotherapeutics discovery, optimization, and development, reducing the timeline to translate central nervous system (CNS) innovations to patients. Strategically deployed, NAMs enhance the predictive value of preclinical studies for human outcomes while reducing reliance on animal models. Current scientific community interest focuses particularly on human-based and -derived systems, in silico and AI-driven models, and advanced microphysiological platforms, reflecting a shift toward human-centric drug development paradigms. Despite this momentum, significant challenges remain, including NAM reproducibility and validation, the establishment of standardized performance criteria, data sharing, and the evolution of regulatory frameworks needed to enable consistent adoption across the neurotherapeutics continuum. Nevertheless, there is a rich history of developing and adopting methodologies, particularly for improving the prediction of neurotherapeutic safety profiles while reducing animal use, and for advancing understanding of drug delivery across the blood-brain barrier, and the assessment of adverse neurological effects. These advances have begun to influence regulatory decision-making and are increasingly reflected in guidance and review practices. Furthermore, NAMs are showing concrete impact in neurological disorders, including Epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, where human-relevant models and computational approaches support more precise characterization of disease mechanisms and therapeutic responses. In this paper, we examine the current and emerging roles of NAMs in neurotherapeutics development from government, academia, and industry perspectives, highlight key opportunities and limitations, and discuss the scientific, technical, and regulatory steps required to fully realize their potential in accelerating safe and effective CNS therapies.},
}

@article {pmid42753292,
year = {2026},
author = {Nam, MH and Park, HJ and Lee, HY and Chen, ZY and Yun, HD and Kim, Y and Lee, JY and Shin, CH and Ha, JY and Seo, YK},
title = {40 Hz vibrotactile stimulation ameliorates amyloid pathology and cognitive deficits in 5xFAD mice and is associated with alterations in Piezo1, ERK, and GSK-3β/p65 signaling.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01077},
doi = {10.1016/j.neurot.2026.e01077},
pmid = {42753292},
issn = {1878-7479},
abstract = {40 Hz vibrotactile stimulation (VTS) is an emerging non-invasive therapy for Alzheimer's disease (AD), yet its specific mechanisms regarding amyloid-beta (Aβ) metabolism remain unclear. Six-month-old 5xFAD mice received daily 40 Hz VTS for four weeks. We assessed cognitive function, Aβ pathology, and underlying molecular pathways. VTS improved spatial learning and recognition memory, whereas no significant improvement was observed in short-term spatial working memory. VTS reduced hippocampal Aβ plaque burden and cortical soluble Aβ40 and Aβ42 levels, accompanied by decreased expression of APP, BACE1, and PS1 and increased expression of ADAM10 and IDE. It further attenuated neuroinflammation, oxidative stress and produced changes in cholinergic and synaptic plasticity-associated proteins. VTS increased hippocampal Piezo1 expression and ERK phosphorylation, increased inhibitory phosphorylation of GSK-3β at Ser9, decreased p65 phosphorylation, and reduced tau phosphorylation. 40 Hz VTS ameliorates several cognitive and neuropathological features of AD in 5xFAD mice. These improvements are associated with the modulation of Piezo1, ERK, and GSK-3β/p65 signaling pathways, highlighting its potential as a promising non-invasive AD therapeutic strategy.},
}

@article {pmid42753425,
year = {2026},
author = {Orzeł, U and Wójcik, E and Filipek, S and Moreira, IS},
title = {ACE2 dysregulation and lipid metabolism: Mechanistic interplay between COVID-19 and neurodegeneration.},
journal = {Molecular aspects of medicine},
volume = {112},
number = {},
pages = {101519},
doi = {10.1016/j.mam.2026.101519},
pmid = {42753425},
issn = {1872-9452},
abstract = {Angiotensin-converting enzyme 2 (ACE2) is the primary cellular receptor of SARS-CoV-2. It is a key regulator of the renin-angiotensin system (RAS) and modulates blood pressure and inflammatory pathways. ACE2 converts pro-inflammatory angiotensin II into the vasoprotective peptide, angiotensin (1-7). This is strongly influenced by the lipid composition of the plasma membrane. Cholesterol-rich lipid rafts play an important role in determining receptor localisation and viral accessibility. Dyslipidaemia, which is common in obesity, diabetes, and metabolic syndrome, has been associated with an increased susceptibility to severe COVID-19 and may amplify systemic inflammation. Aberrant lipid metabolism also contributes to neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, which drive neuroinflammation, synaptic dysfunction, and blood-brain barrier impairment. Notably, similar disturbances and systemic inflammation are increasingly recognised in patients with Long COVID, suggesting overlapping mechanisms that may exacerbate or accelerate neurodegenerative processes. This review explores the interplay between ACE2 regulation, lipid metabolism, and systemic inflammation in COVID-19, with a particular focus on their implications for neurological health. Uniquely, we highlighted the intersection of ACE2 and lipid-related alterations in patients with Long COVID and their potential contribution to the progression of neurodegenerative diseases. In addition, we reviewed therapeutic strategies targeting ACE2, including recombinant soluble ACE2, ACE2-based nanotherapeutics, and lipid-focused interventions, aimed at mitigating acute infection, systemic inflammation, and persistent neurological sequelae. Understanding these mechanisms is essential to prevent long-term neurological consequences of the COVID-19 pandemic.},
}

@article {pmid42753449,
year = {2026},
author = {Xi, L and Wan, J and Hua, Y and Guo, M and Du, J and Luo, X and Yu, H},
title = {Effects of ketogenic diet on cognitive impairment in older adults: a systematic review and meta-analysis.},
journal = {Archives of gerontology and geriatrics},
volume = {151},
number = {},
pages = {106409},
doi = {10.1016/j.archger.2026.106409},
pmid = {42753449},
issn = {1872-6976},
abstract = {BACKGROUND: Cognitive impairment in older adults is associated with substantial functional decline and care burden. The ketogenic diet (KD) may improve cognition, but evidence in older adults with cognitive impairment remains inconsistent. This study evaluated the effects of KD, including related ketogenic dietary strategies, on cognitive outcomes and metabolic markers.

METHODS: PubMed, Web of Science, Embase, the Cochrane Library, CNKI, Wanfang, and VIP were searched from inception to July 2025 for randomized controlled trials of KD or related ketogenic dietary strategies in older adults with cognitive impairment. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Meta-analysis was performed using Review Manager 5.4.

RESULTS: Twelve randomized controlled trials involving 707 participants were included. Compared with control interventions, KD-related dietary strategies improved overall cognitive function [SMD = 0.34, 95% CI (0.16 to 0.52), p < 0.01]. Domain-specific analyses showed significant improvements in memory [SMD = 0.53, 95% CI (0.10 to 0.96), p = 0.01] and language function [SMD = 0.43, 95% CI (0.16 to 0.70), p = 0.002], whereas no significant effects were observed for attention or executive function. KD-related strategies increased acetoacetate and β-hydroxybutyrate concentrations, indicating effective ketone production. Regarding metabolic safety, KD-related interventions increased total cholesterol and LDL-C, while triglycerides and HDL-C remained unchanged.

CONCLUSIONS: KD and related ketogenic dietary strategies may improve cognitive performance and enhance ketone body production in older adults with mild cognitive impairment or Alzheimer's disease. The potential metabolic implications associated with lipid changes should be considered alongside cognitive benefits.},
}

@article {pmid42753521,
year = {2026},
author = {Chen, F},
title = {Bioinformatics-driven discovery and cross-cohort validation of a two-gene signature (RPH3A and HIGD1B) associated with Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109417},
doi = {10.1016/j.compbiolchem.2026.109417},
pmid = {42753521},
issn = {1476-928X},
abstract = {BACKGROUND: Transcriptomic biomarker discovery for Alzheimer's disease (AD) has yielded numerous candidate signatures, yet many fail independent external validations due to overfitting or cohort-specific confounders. We aimed to identify a minimal reproducible gene signature and evaluate its generalizability under locked-model validation.

METHODS: Three GEO datasets were analyzed: GSE118553 (training), GSE122063 (internal validation), and GSE5281 (external validation). Differentially expressed genes were identified in the training set, followed by LASSO and Random Forest feature selection, and intersecting genes were filtered for concordant fold-change direction and P < 0.05 across cohorts. An elastic net model was evaluated using locked training parameters by ROC, calibration, and decision curve analyses,with exploratory threshold optimization performed to assess model performance.

RESULTS: Four genes overlapped between machine-learning methods, but only RPH3A and HIGD1B passed the consistency filter. The locked model achieved AUCs of 0.818 and 0.974 in the internal and external cohorts, respectively. Internal validation showed calibration drift (intercept -2.697, slope 0.705), resulting in 0.000 specificity at the locked threshold. Cohort-specific threshold optimization increased specificity to 1.000 with 0.607 sensitivity. External validation showed good calibration (intercept 1.065, slope 1.203) and favorable decision-curve performance.

CONCLUSION: RPH3A and HIGD1B constitute a reproducible AD-associated molecular signature with robust discrimination across independent postmortem brain cohorts, regions, and platforms. As all datasets were postmortem brain tissue, these findings reflect disease-associated molecular alterations. Calibration, confusion matrix, and decision curve analyses further support model performance and translational relevance.},
}

@article {pmid42753807,
year = {2026},
author = {Shi, H},
title = {Word-Form and Lemma Dependency Networks of Connected Speech in Probable Alzheimer's Disease: Morphological Impacts on Syntactic Topological Metrics.},
journal = {Seminars in speech and language},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2954-9654},
pmid = {42753807},
issn = {1098-9056},
abstract = {BACKGROUND: Alzheimer's disease causes progressive cognitive and linguistic deterioration. Few studies investigate how morphological inflections shape syntactic network topology by comparing word-form and lemma networks.

METHOD: Spontaneous language samples were collected by the Cookie Theft picture description task from 68 individuals with probable Alzheimer's disease (PA) and 68 healthy controls.

RESULTS: In both groups, lemma networks had fewer nodes/edges, higher average degree, density, and clustering coefficient, and shorter average path length than word-form networks. All networks showed small-world properties; only healthy networks obeyed scale-free rules, whereas patient networks deviated slightly. Controls had more nodes and edges, while patients demonstrated higher density and clustering coefficients. Intergroup average degree differences were limited to lemma networks (higher in controls). Average path length and diameter were similar across groups. Significant topological differences were accompanied by modest effect sizes (r = 0.21-0.29), likely arising from variability in spontaneous speech. Function words and basic verbs formed core nodes in both network types.

CONCLUSION: This study identifies quantitative syntactic network biomarkers for linguistic impairments in early PA. Such topological measures may combine with clinical indicators for risk prediction and inform targeted early cognitive interventions.},
}

@article {pmid42753883,
year = {2026},
author = {Lee, JH and Jeong, JH and Mun, BR and Jang, JK and Choi, YM and Baek, JH and Choi, WS},
title = {The phenyl carbamates JBPOS0101 and JBPOS0607 attenuate rotenone-induced dopaminergic neuronal death in mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150555},
doi = {10.1016/j.brainres.2026.150555},
pmid = {42753883},
issn = {1872-6240},
abstract = {Parkinson's disease (PD) is a progressive neurodegenerative disease that causes motor abnormalities such as tremors, rigidity, and posture imbalance. The loss of dopaminergic neurons and Lewy bodies containing the aggregation of α-synuclein are the main neuropathological features of PD. Rotenone, a widely used pesticide and mitochondrial complex I inhibitor, induces dopaminergic neuronal death and is used to model PD in rodents. We previously reported that JBPOS0101, a phenyl carbamate compound, attenuates amyloid β accumulation and memory impairment in the 5xFAD mouse model of Alzheimer's disease. In this study, we investigated the effect of JBPOS0101 and its derivative, JBPOS0607, in rotenone-administered mice as a PD model. Both drugs significantly attenuated the loss of dopaminergic neurons induced by rotenone in mice. Furthermore, the rotenone-induced accumulation of phosphorylated α-synuclein in dopaminergic neurons was also attenuated by the drugs. Additionally, both drugs alleviated rotenone-induced activation of astrocytes and microglia compared to the group treated with rotenone alone. These results indicate that the phenyl carbamates JBPOS0101 and JBPOS0607 attenuate rotenone-induced dopaminergic neurodegeneration in mice. Both compounds preserved nigral dopaminergic neurons and attenuated alpha-synuclein phosphorylation, glial activation, and pro-inflammatory cytokine levels in the striatum, and JBPOS0607 was also effective in restoring the anti-inflammatory cytokine IL-10, striatal dopamine levels, and motor performance, supporting the therapeutic potential of phenyl carbamates in Parkinson's disease.},
}

@article {pmid42753897,
year = {2026},
author = {Green, J and Liu, Z and Timis, S and Nelson, C and Pedin, A and Guo, C and Wang, XY and Zhang, S and Sun, D},
title = {Deletion of NLRP3 gene blocks traumatic brain injury induced abnormal immune response in mice with a genetic background for AD.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116030},
doi = {10.1016/j.expneurol.2026.116030},
pmid = {42753897},
issn = {1090-2430},
abstract = {Traumatic brain injury (TBI) is a significant risk factor for the development of Alzheimer's disease (AD) and related dementia. In both TBI and AD, inflammation plays a pivotal role. It is known that the NLRP3 inflammasome plays an important role in AD pathogenesis while TBI triggers activation of the NLRP3 inflammasome in the brain. To evaluate the importance of the NLRP3 inflammasome in mediating the TBI-induced immune response in animals with a genetic background for AD, we have examined immune profiles in the brain using a novel transgenic mouse line at 3xTg background with the NLRP3 gene deleted. Briefly, a group of 4 months old male and female 3xTg and 3xTg/NLRP3[-/-] mice received a moderate lateral fluid percussive injury or sham. Immune cell phenotypes and cytokine gene expression were assessed at 3- and 7-days post injury (dpi). We found that NLRP3 gene deletion counteracted injury-induced alteration of the immune response in 3xTg mice with a significant sex-related difference. Specifically, TBI induced a significant brain infiltration of neutrophils, macrophages and γδ T-cells in 3xTg mice in both sexes at 3dpi, and NLRP3 gene deletion blocked this injury effect only in males not in females. NLRP3 gene deletion also blocked injury-enhanced IL-1β, TNF-α gene expression in male mice, but not in female mice. In conclusion, our study has confirmed that TBI significantly alters the immune response in 3xTg mice and NLRP3 inflammasome is important in mediating these TBI-induced changes with significant sex-related differences.},
}

@article {pmid42753898,
year = {2026},
author = {Guo, F and Li, T and He, XB},
title = {Dynamic contributions of astrocytes in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116032},
doi = {10.1016/j.expneurol.2026.116032},
pmid = {42753898},
issn = {1090-2430},
abstract = {In Alzheimer's disease, pathological stimuli reshape astrocyte functions, which in turn act on neurons, making astrocytes critical modulators of disease progression. A comprehensive understanding of how astrocytes dynamically shift from physiology to pathology across multiple functional domains remains to be established. This review synthesizes recent findings across four key domains: proteostasis, gliotransmission/synapse regulation, blood-brain barrier integrity and metabolism, and microglial crosstalk. For each domain, we compare homeostatic and pathological functions, analyze how supportive roles turn detrimental, and discuss effects on neuronal fate. We also examine signaling pathways that govern astrocyte reactivity and the potential of astrocyte-derived biomarkers. By tracing these dynamic transitions, we aim to refine Alzheimer's disease mechanisms and identify state-targeted therapeutic opportunities.},
}

@article {pmid42753958,
year = {2026},
author = {Peck, BD and O'Hare, NR and Ferris, CF and Pinals, RL and Ebong, EE},
title = {Fragment morphometry analysis and same-color-channel separation enable reproducible quantification across BBB models.},
journal = {Methods (San Diego, Calif.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymeth.2026.09.003},
pmid = {42753958},
issn = {1095-9130},
abstract = {Quantifying blood-brain barrier (BBB) integrity from fluorescence microscopy remains limited by subjective scoring and categorical classification methods that lack reproducibility. For reproducible BBB phenotyping, we present two semi-automated image-analysis pipelines that replace manual scoring with quantitative, continuous-variable measurements. Our in vitro pipeline, implemented in Python, quantifies the connectivity of tight junction structures by measuring discrete ZO-1 fragment objects within manually traced junction regions. It outputs continuous metrics including average fragment area, total junctional area, and a junctional fragmentation ratio that captures degree of ZO‑1 continuity. In human brain microvascular endothelial cells subjected to glycocalyx component knockdown, the pipeline detected significantly reduced fragment area (37% decrease for both CD44 and syndecan-1 (SDC1) knockdown, p = 0.0148 and 0.0084) and junctional fragmentation ratio (p = 0.0061 and 0.0137). Our in vivo pipeline integrates ilastik-based pixel classification with FIJI macro automation to quantify vascular marker colocalization and to separate vessel signal from microglial contamination within a single fluorescence channel, eliminating the need for dedicated counterstains. Applied across four mouse cohorts [young, aged, Alzheimer's, traumatic brain injury (TBI)] and three brain regions [prefrontal cortex (PFC), hippocampus, midbrain], the pipeline detected concurrent ZO-1 loss and ICAM-1 elevation in the PFC and hippocampus of aged and Alzheimer's cohorts, which were statistically indistinguishable, with eNOS nearly doubling in the Alzheimer's PFC (p = 0.0013). TBI mice showed persistent ZO-1 loss with transient ICAM-1 and eNOS changes. Both deterministic pipelines are available on GitHub and designed for adoption beyond the specific markers and systems analyzed here.},
}

@article {pmid42754468,
year = {2026},
author = {Thomas, ML},
title = {A caution in interpreting reliable cognitive decline in older adults at risk for Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100272},
doi = {10.1016/j.inpsyc.2026.100272},
pmid = {42754468},
issn = {1741-203X},
abstract = {Repeated cognitive screening of functionally independent older adults may help identify decline before performance crosses conventional thresholds for cognitive impairment, but interpreting longitudinal change requires distinguishing true change from measurement error. The Reliable Change Index (RCI) is commonly used for this purpose. Conventional RCI methods based on classical test theory (CTT), however, typically assume that measurement error is constant across examinees, an assumption that may be particularly problematic for screening instruments such as the Mini-Mental State Examination (MMSE), which often show pronounced ceiling effects. We compared conventional CTT- and difference-score-based item response theory (IRT) RCIs in 1136 cognitively unimpaired older adults with elevated brain amyloid from the A4 clinical trial. The two approaches were strongly correlated overall (r = .83). However, among the 92 participants identified as showing reliable decline by at least one method, 44 (47.8%) received discordant classifications. Thus, substantial overall correspondence between CTT- and IRT-based RCIs can co-occur with meaningful disagreement about which individuals have experienced reliable cognitive decline. These findings highlight the importance of accounting for variation in measurement precision when interpreting longitudinal change on cognitive screening measures in older adults. They also provide an important cautionary note for clinicians who rely on repeated cognitive screening, as detection of reliable decline may be particularly challenging among individuals with relatively preserved cognition who may be in the earliest stages of cognitive deterioration.},
}

@article {pmid42754545,
year = {2026},
author = {Nanna, MG and Cohen, AB and Erickson, AC and Sun, B and Rossi, R and Akman, Z and Krishnaswami, A and Damluji, AA and Leggett, CG and Staiger, DO and Agha, L},
title = {Days Alive at Home After Emergency Department STEMI Visits Among Medicare Beneficiaries With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70705},
pmid = {42754545},
issn = {1532-5415},
support = {P30-AG021334//Johns Hopkins University Claude D. Pepper Older Americans Independence Center/ ; NIA P30-AG021334//Johns Hopkins University Claude D. Pepper Older Americans Independence Center/ ; K23-HL153771-01/HL/NHLBI NIH HHS/United States ; K76AG088428/AG/NIA NIH HHS/United States ; P01AG019783/AG/NIA NIH HHS/United States ; //American College of Cardiology Foundation/ ; /PCORI/Patient-Centered Outcomes Research Institute/United States ; P30AG021342//Yale Claude D. Pepper Older Americans Independence Center/ ; },
abstract = {BACKGROUND: As the population of older adults with Alzheimer's disease and related dementias (ADRD) increases, a growing number are presenting with acute cardiovascular events, including ST-elevation myocardial infarction (STEMI). Patient-centered outcomes following treatment for STEMI in this population are not well understood.

METHODS: This retrospective cohort study used Medicare fee-for-service claims from a 100% national sample to identify beneficiaries aged 65 years or older who presented to the emergency department (ED) with STEMI between 2017 and 2022 and underwent cardiac catheterization. Patients were stratified by ADRD status and nursing home admission source. The primary outcome was adjusted days alive at home in the year following the index ED visit. Secondary outcomes included 1-year survival, percent of alive days spent at home, and long-term nursing home care use (≥ 100 days). Multivariable linear regression models controlled for age, sex, and comorbidities.

RESULTS: Of 117,318 patients, 7348 (6.3%) had ADRD and 2617 (2.2%) were admitted from a nursing home. Among community-dwelling patients, those with ADRD had moderately lower adjusted days at home than those without ADRD (225.1 vs. 299.4; adjusted difference -37.8 days; 95% CI, -41.1 to -34.5), but more than half spent over 300 days at home. Among patients admitted from a nursing home, ADRD was associated with markedly worse outcomes (adjusted difference -71.9 days; 95% CI, -84.0 to -59.8), and 1-year survival was 42.4%.

CONCLUSION: Many community-dwelling older adults with ADRD experienced meaningful survival and time at home following cardiac catheterization for STEMI. Dementia status alone should not deter appropriate STEMI care. Treatment decisions should be individualized based on cognitive status, admission source, and patient goals.},
}

@article {pmid42754555,
year = {2026},
author = {Alcaide-Prados, MDC and Gómez-Moreno, G and Leizaola-Cardesa, IO and Moreu, G and Roa-López, A and Aguilar-Salvatierra, A},
title = {Periodontal disease and Alzheimer's disease: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488806},
doi = {10.1177/13872877261488806},
pmid = {42754555},
issn = {1875-8908},
abstract = {BackgroundPeriodontitis is a host-mediated inflammatory disease of microbial origin that results in the loss of periodontal attachment. Its effects are not limited to the oral cavity, as association with systemic diseases, including Alzheimer's disease (AD), has been widely reported.ObjectiveTo evaluate the evidence regarding the potential relationship between periodontitis and AD through a systematic review.MethodsA bibliographic search was conducted in PubMed, Scopus, and WOS. Studies published within the last five years evaluating the biological association between both diseases were selected. The methodological quality and risk of bias of the included studies were assessed using the NOS and ROBINS-I tool, according to the study design.ResultsEleven studies were included. Eight studies analyzed biological samples obtained from brain tissue, blood/serum, saliva, gingival crevicular fluid, and cerebrospinal fluid. Patients with AD exhibited higher levels of periodontopathogenic bacteria, such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia, and an association between bacterial load and systemic inflammatory markers. Although most studies reported an association between periodontitis and AD, the findings were not consistent across studies, as some failed to identify statistically significant differences. Periodontal treatment was associated with a reduction in the AD Score, a neuroimaging surrogate marker of preclinical AD, whereas no effect was observed on brain age gap.ConclusionsEvidence suggests a possible association between periodontitis and AD through inflammatory and neurodegenerative mechanisms. Methodological limitations and study heterogeneity preclude establishing causality, underscoring the need for longitudinal studies and alternative methodological approaches.},
}

@article {pmid42754556,
year = {2026},
author = {Wiseman, FK},
title = {New mouse models for Down syndrome Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488873},
doi = {10.1177/13872877261488873},
pmid = {42754556},
issn = {1875-8908},
abstract = {In this issue Ishihara and colleagues report the development and characterization of new mouse models for Down syndrome Alzheimer's disease, the most commonly occurring genetic cause of dementia worldwide. These new models add to the growing portfolio of in vivo models of Down syndrome. In particular, the new Ts1Kei-APPswe/PS1[dE9] model may be highly useful for the study and identification of novel treatment targets for late onset myoclonic epilepsy of Down syndrome. This seizure disorder is a common comorbidity of Down syndrome Alzheimer's disease affecting around half of all people with the condition and is associated with particularly adverse clinical outcomes.},
}

@article {pmid42754558,
year = {2026},
author = {Zou, C and Chung, AS and Tadigiri, M and Namjoshi, A and Shah, T and Kulshreshtha, A},
title = {Mobile application-based interventions for subjective memory decline and mild cognitive impairment: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488814},
doi = {10.1177/13872877261488814},
pmid = {42754558},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) and mild cognitive impairment (MCI) are early clinical markers along the continuum from normal aging to dementia. Both conditions are associated with an elevated risk of progression to Alzheimer's disease and related dementias. With SCD affecting up to 25% and MCI up to 25.2% of older adults, there is growing interest in non-pharmacological, multidomain interventions to address modifiable risk factors, reduce progression, and enhance quality of life. Mobile application-based interventions offer a promising avenue for older populations due to their convenience, reduced need for travel, and personalized engagement.ObjectiveThis systematic review aimed to evaluate the effectiveness of mobile application-based interventions on cognitive performance in individuals with SCD and/or MCI.MethodsA systematic review of randomized controlled trials was conducted to identify mobile application-based interventions targeting SCD and MCI from 2010 to 2025. We conducted a comprehensive search in PubMed, Web of Science, and Scopus databases following PRISMA guidelines.ResultsA total of 3140 abstracts were screened, of which 19 (0.6%) met the inclusion criteria. Seven studies focused on SCD, while the majority targeted patients with MCI. All but one study reported improvements in at least one cognitive outcome following the intervention.ConclusionsMobile application-based interventions show promising benefits for individuals with SCD and MCI, with most studies reporting improvements in cognitive outcomes, particularly in memory. However, further research with larger samples and more extended follow-up periods is needed to confirm these findings and optimize intervention strategies.},
}

@article {pmid42754564,
year = {2026},
author = {Zhang, H and Liang, B and Chang, Y and Zhang, Z and Wang, Z and Zhu, W and Song, B and Zhang, H},
title = {Exosomal miR-223-3p, associated with NLRP3-related neuroinflammation, as a potential biomarker for mild cognitive impairment in patients with type 2 diabetes mellitus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487620},
doi = {10.1177/13872877261487620},
pmid = {42754564},
issn = {1875-8908},
abstract = {BackgroundNeuroinflammation has been implicated in diabetic cognitive dysfunction, with the NLRP3 playing an important role.ObjectiveThis study aimed to elucidate the regulatory role of miR-223-3p in NLRP3 associated neuroinflammation and its potential as a biomarker for mild cognitive impairment (MCI) in type 2 diabetes mellitus (T2DM).MethodsDiabetic mouse models were generated by 24 weeks of high-fat diet feeding, with cognitive impairment verified by behavioral assessments. Hippocampal tissues were analyzed by microRNA sequencing and validated for miR-223-3p expression. NLRP3-mediated neuroinflammation was examined in vivo, while in vitro assays using BV2 cells assessed mechanistic pathways. BV2 cells with miR-223-3p knockdown and overexpression to evaluate its effects on NLRP3. Clinically, plasma exosomal miR-223-3p was quantified in T2DM patients with and without MCI and correlated with neuropsychological test scores.ResultsDiabetic mice exhibited cognitive decline, reduced hippocampal miR-223-3p, microglial activation, and elevated NLRP3 and pro-inflammatory cytokines. miR-223-3p knockdown and overexpression induced and attenuated neuroinflammation, respectively. Luciferase reporter gene assays confirmed the direct regulatory of miR-223-3p on NLRP3. Clinically, exosomal miR-223-3p levels were significantly lower in T2DM patients with MCI (n = 98) compared with cognitive normal patients (n = 147), correlating with global cognition, and immediate memory performance. ROC analysis demonstrated that, when using the threshold of 0.7565, miR-223-3p achieved a diagnostic specificity of 71.4% and a sensitivity of 68.7% for identifying MCI.ConclusionsmiR-223-3p exerts neuroprotective effects by suppressing NLRP3-mediated neuroinflammation. Its downregulation contributes to cognitive impairment in diabetes, and circulating exosomal miR-223-3p represents a potential biomarker for identifying MCI in T2DM.},
}

@article {pmid42754623,
year = {2026},
author = {Wang, J and Pan, P and Zhang, J and Wang, Y},
title = {Several methodological issues in the systematic review "PD-1/PD-L1 blockade in Alzheimer's disease".},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42754623},
issn = {1476-5578},
}

@article {pmid42754830,
year = {2026},
author = {Castellani, RJ},
title = {Traumatic brain injury and Alzheimer's disease: The null hypothesis wins.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489299},
doi = {10.1177/13872877261489299},
pmid = {42754830},
issn = {1875-8908},
abstract = {The theory that traumatic brain injury initiates Alzheimer's disease owes much of its existence to classical studies on boxers. It now appears that both the complexity of postmortem neuropathology and the clinical syndrome were not fully appreciated. Large scale studies linking epidemiology and biology continue to show that chronic effects of traumatic brain injury and Alzheimer's disease pathophysiology are biologically distinct. Researchers are encouraged to look beyond conventional protein precipitates for explanations of clinical deterioration following traumatic brain injury.},
}

@article {pmid42754972,
year = {2026},
author = {Pillai, JA and Zhu, A and Ma, C and Wang, M and Yang, Y and Bekris, LM and Khrestian, M and DiFilippo, FP and Nasrallah, M and Burberry, A and Leverenz, JB and Hou, Y and Cheng, F and Rao, SM},
title = {Cerebrospinal Fluid Over Plasma Links Analytes to Cognitive Decline in Older Adults at Risk for Alzheimer's Disease.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70532},
pmid = {42754972},
issn = {2328-9503},
support = {K23AG055685//National Institute on Aging (NIA), National Institutes of Health/ ; P30AG072959//National Institute on Aging (NIA), National Institutes of Health/ ; R01AG022304//National Institute on Aging (NIA), National Institutes of Health/ ; R01AG078763//National Institute on Aging (NIA), National Institutes of Health/ ; },
abstract = {OBJECTIVE: To identify inflammatory analytes in cerebrospinal fluid (CSF) and plasma associated with cognitive decline in cognitively normal (CN) older adults at risk for Alzheimer's disease (AD).

METHODS: In a longitudinal study of 118 CN older adults (65-80 years, 54% APOE ε4, 26% preclinical AD), 1331 CSF and 1501 plasma analytes were quantified at baseline and 2-year follow-up using SomaLogic, with key inflammatory findings validated on the Luminex platform. Linear models (Limma), adjusted for age, sex, APOEε4, and amyloid-positive status, identified pathology-associated analytes. Co-expression network and multivariable modeling defined hub analytes and enriched pathways. To assess robustness, a targeted panel of 94 inflammation-related analytes was analyzed using best subsets regression to derive parsimonious models based on adjusted R[2] improvement (≥ 0.01) and ≥ 5 observations per predictor. Subgroup analyses by amyloid and APOE ε4 status were performed, and a two-stage elastic-net approach additionally validated analyte selection.

RESULTS: CSF proteomics revealed stronger APOEε4 and amyloid-associated analyte signatures than plasma. Forty-four CSF analytes were co-regulated by APOEε4 and amyloid-positive status, forming central network hubs (e.g., EFNB2, NPTN, UNC5D) enriched in axon guidance, synaptic signaling, and extracellular matrix pathways. In contrast, inflammatory analytes including eotaxin-1 and IL-17 pathway-related molecules were associated with longitudinal cognitive decline, with stronger effects observed in females. Eotaxin-1 demonstrated the most consistent predictive performance across analytic methods, subsets, and assay platforms, whereas network hub analytes were not predictive of cognitive outcomes.

INTERPRETATION: CSF reflects strong APOEε4/amyloid related proteomic network alterations linked to cognitive decline, while plasma provides weaker but complementary signals. CSF inflammatory signaling, particularly eotaxin-1, may serve as a correlate of longitudinal cognitive decline in cognitively normal older adults at risk for AD.},
}

@article {pmid42755059,
year = {2026},
author = {Lee, SK and Han, M and Park, S and Song, J and Park, SJ and Kim, H and Kim, J and Lee, H and Shin, HY and Kim, KH and Park, SM},
title = {Impact of Changes in Physical Activity on Dementia Risk Among Cancer Survivors: A Nationwide Cohort Study Comparing Chemotherapy and Non-Chemotherapy Groups.},
journal = {Cancer research and treatment},
volume = {},
number = {},
pages = {},
doi = {10.4143/crt.2026.0451},
pmid = {42755059},
issn = {2005-9256},
abstract = {PURPOSE: Chemotherapy-associated cognitive decline is well recognized; however, the role of changes in physical activity in reducing dementia risk among cancer survivors remains unclear. This study evaluated the association between physical activity changes and dementia risk.

MATERIALS AND METHODS: This nationwide retrospective cohort study used health screening and claims data from the Korean National Health Insurance Service. A total of 260,659 adults diagnosed with cancer between 2009 and 2015 who survived ≥3 years and underwent both pre- and post-diagnosis health examinations were included. Individuals with prior dementia or missing data were excluded. Physical activity was assessed as metabolic equivalent task-minutes per week at two time points and categorized as decreased, maintained, or increased. The primary outcome was incident all-cause dementia (ICD-10 codes F00-F03, G30). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, stratified by chemotherapy exposure.

RESULTS: Decreased physical activity was associated with increased dementia risk compared with maintaining high activity (aHR, 1.46; 95% CI, 1.31-1.62), whereas maintaining or increasing activity was associated with reduced risk (aHR, 0.82; 95% CI, 0.75-0.91). The protective association was stronger among chemotherapy-treated patients (aHR, 0.80; 95% CI, 0.72-0.90). No significant association was observed among those not receiving chemotherapy.

CONCLUSION: Maintaining or increasing physical activity after cancer diagnosis was associated with lower dementia risk, particularly among chemotherapy-treated patients.},
}

@article {pmid42755290,
year = {2026},
author = {Xu, L and Wei, N and Ran, Y},
title = {The dynamic connectome in Alzheimer's disease: From static snapshots to a symphony in time-A hypothesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488872},
doi = {10.1177/13872877261488872},
pmid = {42755290},
issn = {1875-8908},
abstract = {The static functional connectivity (sFC) model has established Alzheimer's disease (AD) as a large-scale brain network disorder, yet it rests on a questionable assumption of temporal stationarity. This assumption obscures the brain's intrinsic dynamics, which are essential for flexible cognition. Here, we advance the hypothesis that the core deficit in AD is not merely a weakening of average connections, but a fundamental loss of the brain's capacity for temporal coordination, adaptive reconfiguration, and metastable dynamics-a state we term dynamic network dysrhythmia. Synthesizing evidence from dynamic functional connectivity (dFC) studies across the AD continuum, from subjective cognitive decline to mild cognitive impairment and AD dementia, we argue that the AD brain exhibits a progressive collapse in temporal flexibility: reduced state transition frequency, diminished connectivity variability, and entrapment in inefficient network configurations. These dynamic abnormalities correlate with molecular pathology, structural disconnection, and domain-specific cognitive deficits, positioning dFC metrics as sensitive, systems-level digital biomarkers. We further outline methodological challenges and translational opportunities for dFC in early detection, prognostic stratification, and treatment monitoring. This hypothesis reframes AD from a static disconnection syndrome to a dynamic dysrhythmia, with profound implications for both mechanistic understanding and clinical practice.},
}

@article {pmid42755349,
year = {2026},
author = {Wittlinger, M and Jevtic, S and Teimann, S and Scherbaum, N and Wiltfang, J and Benninghoff, J},
title = {The potential of nature exposure to reduce agitation: lessons from a naturalistic observational study in a stage-adaptive, dementia-friendly therapy garden.},
journal = {BJPsych open},
volume = {12},
number = {5},
pages = {e242},
doi = {10.1192/bjo.2026.12093},
pmid = {42755349},
issn = {2056-4724},
abstract = {BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD), particularly agitation, are common among people living with dementia, negatively affecting their psychological well-being and quality of life. Non-pharmacological interventions such as therapeutic gardens may offer a holistic approach to managing these symptoms.

AIMS: This study aimed to investigate whether participation in a multimodal, dementia-specific therapeutic garden intervention could reduce BPSD, with a particular focus on agitation, and improve psychological well-being among people with dementia.

METHODS: A naturalistic observational study was conducted with 24 residents of a dementia-friendly garden. Participants engaged in tailored, nature-based therapy over 6 months. The intervention was adapted to individual cognitive and physical abilities and included motor, sensory and social activities within the participants' familiar living environment. Standardised assessments of BPSD and psychological well-being were administered, including evaluations reported by relatives.

RESULTS: The intervention was associated with a significant reduction in agitation, as measured by the non-cognitive subscales of the Alzheimer's Disease Assessment Scale (p < 0.05). Furthermore, reduced agitation was linked to improved psychological well-being among participants.

CONCLUSIONS: The findings suggest that multimodal therapeutic gardens can serve as an effective non-pharmacological intervention in reducing agitation and supporting psychological well-being in people with dementia. This study adds to the growing evidence that therapeutic gardens could contribute to the functional and emotional health of individuals living with dementia.},
}

@article {pmid42755454,
year = {2026},
author = {Wang, Y and Wu, W and Yan, L and Zhang, B and Li, Q and Zhou, Y},
title = {Synaptic mitochondrial dysfunction and Alzheimer's disease: from molecular mechanisms to therapeutic strategies.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1849218},
pmid = {42755454},
issn = {1663-9812},
abstract = {The ability of AD treatments targeting classic pathological proteins to achieve meaningful clinical outcomes has been severely limited, shifting attention to the earlier upstream pathways that drive disease progression. Increasing evidence indicates that synaptic mitochondrial dysfunction is an early pathological event that directly contributes to synaptic loss and cognitive decline. This review focuses on how four interrelated pathologies-disrupted energy metabolism, calcium overload, imbalanced mitochondrial fission/fusion, and defective autophagy-converge to impair synaptic function and plasticity. Emerging therapeutic strategies aimed at protecting and restoring synaptic mitochondrial health, including mitochondria-targeted antioxidants, metabolic modulators, calcium signaling inhibitors, dynamics regulators, and autophagy inducers, are also examined. A central focus of the review is clinical translation: we summarize the preclinical evidence and critically evaluate major obstacles such as the lack of synapse-specific biomarkers, challenges in blood-brain barrier penetration and targeted delivery, and substantial patient heterogeneity. Rather than proposing a fully defined translational framework, we highlight the essential requirements for building one, centered on synaptic mitochondrial bioenergetics and quality control. Specifically, early and accurate biomarkers must be developed, patients should be stratified promptly, and rational combination therapies with complementary mechanisms need to be implemented. This organelle-centered perspective will clarify AD pathogenesis and help guide the development of next-generation neuroprotective therapies.},
}

@article {pmid42755539,
year = {2026},
author = {Bouchard, T and Russell, B and Guo, LL and Nguyen, T and Cheng, Y and Sanders, YY and Guo, ML},
title = {The effects of abused drugs on ferroptosis pathways: potential therapeutic targets for substance use disorders.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1899553},
pmid = {42755539},
issn = {1662-5102},
abstract = {Substance use disorders (SUDs) remain major public health concerns worldwide, particularly in developed countries. SUDs are characterized by persistent neuroinflammation and synaptic dysfunction in the brain. Despite decades of extensive investigation, the detailed mechanisms underlying SUDs remain elusive. Ferroptosis is a highly regulated cell death process deeply affected by iron metabolism, lipid peroxidation, reactive oxygen species (ROS) production, and antioxidant systems. It has been implicated in multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Recently, emerging evidence has highlighted the role of ferroptosis in drug-induced pathological changes. Various types of abused substances including alcohol, cocaine, methamphetamine (METH) nicotine, cannabis, and opioids have been shown to disrupt ferroptosis-relevant pathways, leading to microglial activation and neuronal injury. Inhibition of ferroptosis could mitigate these pathological changes in preclinical models. Here, we summarize current evidence demonstrating the effects of abused drugs on ferroptosis pathways. Collectively, these findings underscore the potential role of ferroptosis in the pathophysiology of SUDs. Targeting ferroptosis may represent a promising therapeutic strategy for alleviating drug-induced neurological damage and improving recovery outcomes such as cognitive and memory deficiency in individuals with addiction.},
}

@article {pmid42755642,
year = {2026},
author = {Xi, W and Rodriguiz, RM and Wetsel, WC and Shinohara, ML},
title = {Microglial dectin-1/Clec7a in an alzheimer's disease model: a double-edged sword across the lifespan.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1864888},
pmid = {42755642},
issn = {1664-3224},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/psychology ; Dectin-1 ; *Microglia/metabolism/pathology ; Mice ; Disease Models, Animal ; *Lectins, C-Type/metabolism/genetics ; Plaque, Amyloid/pathology/metabolism ; Brain/metabolism/pathology ; Mice, Knockout ; Mice, Transgenic ; Humans ; Male ; },
abstract = {INTRODUCTION: Dectin-1, encoded by Clec7a, is highly expressed in disease-associated microglia in Alzheimer's disease (AD), yet its in vivo function remains largely unknown.

METHODS: We generated Clec7a-floxed mice and conditionally deleted dectin-1 in microglia to determine its effects on pathology and behavior using the 5xFAD mice model. No dectin-1 ligand injection was used. Amyloid pathology, immune phenotypes in the brain, and behavior were examined across disease stages.

RESULTS: In 6-month (mo) old mice, microglial dectin-1 reduced dense Aβ plaques in the subiculum without detectable behavioral effects. At 9-mo, microglial dectin-1 impaired memory retention and spatial learning, accompanied by an increased diffuse/dense Aβ plaque ratio in the hilus of the dentate gyrus and limited brain infiltration of Ly6G[lo] neutrophils. At 16-mo, microglial dectin-1 increased freezing behavior suggestive of heightened emotional reactivity.

DISCUSSION: Microglial dectin-1 exerts age-dependent effects: beneficial for amyloid pathology in mid-life but detrimental for cognition and anxiety-related behavior in later life. These context-specific outcomes highlight the need to consider age, the cell types expressing dectin-1, and dectin-1-activating ligands. Future studies should define the classes of ligands and signaling landscape of microglial dectin-1 across the disease course with the goal of identifying windows where intervention could tilt its function toward sustained neuroprotection.},
}

Animals
*Alzheimer Disease/metabolism/pathology/psychology
Dectin-1
*Microglia/metabolism/pathology
Mice
Disease Models, Animal
*Lectins, C-Type/metabolism/genetics
Plaque, Amyloid/pathology/metabolism
Brain/metabolism/pathology
Mice, Knockout
Mice, Transgenic
Humans
Male

@article {pmid42755739,
year = {2026},
author = {de Ávila, C and Chakraborti, A and Gundlach, AL and Maeng, LY},
title = {Sex hormones in the nucleus incertus: a novel perspective on sex/gender differences in memory and mood dysfunction in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1852733},
pmid = {42755739},
issn = {1663-4365},
abstract = {About 60% of the individuals living with Alzheimer's disease (AD) in the United States are women. Increasing evidence points to a role for sex hormones, especially estrogen, in making women more vulnerable to AD than men. Several brainstem signaling pathways, as well as multiple neuropeptide modulators and their receptors, are implicated in AD pathology and therapeutic possibilities. However, there is limited research evaluating how the modulatory effects of sex hormones on mood and cognition interact with these brainstem systems. This review seeks to examine possible connections between the nucleus incertus (NI) relaxin-3/relaxin-family peptide receptor 3 (RLN3/RXFP3) system and sex hormone influences in AD to encourage further investigation into how sex hormones may modulate this pathway and contribute to sex differences in disease risk and progression. Understanding how hormone-based interventions, such as hormone replacement therapy (HRT) and hormonal contraceptives (HC), affect NI RLN3/RXFP3 signaling may provide novel insights into how these treatments can slow AD-associated cognitive decline. It is hoped that this data and concept synthesis will drive detailed investigations of these circuits and support the development of sex/gender-informed therapeutic strategies that better reflect the heterogeneity of AD dementia.},
}

@article {pmid42755753,
year = {2026},
author = {Angarita-Rodríguez, A and Largo-González, JH and Pérez-Mejía, J and Balcazar, D and Vargas-López, V and Papin, JA and Pinzón, A and González, J},
title = {Integrative genome-scale metabolic model of GABAergic neurons reveals metabolic signatures across the mild cognitive impairment - Alzheimer disease continuum.},
journal = {Frontiers in systems biology},
volume = {6},
number = {},
pages = {1897648},
pmid = {42755753},
issn = {2674-0702},
abstract = {INTRODUCTION: Mild cognitive impairment (MCI) represents a prodromal stage of Alzheimer's disease (AD), but the metabolic mechanisms underlying early neuronal dysfunction remain incompletely understood. GABAergic neurons, which maintain excitatory-inhibitory balance and network stability, exhibit early vulnerability during neurodegeneration, although the metabolic alterations associated with their dysfunction remain poorly characterized.

METHODS: We developed a context-specific genome-scale metabolic model (GEM) of human GABAergic neurons across the MCI-AD continuum using deconvolved hippocampal transcriptomic data. By integrating transcriptomic deconvolution with constraint-based modeling, including flux balance analysis (FBA) and flux variability analysis (FVA), we inferred disease-stage-associated metabolic alterations under Control, early MCI (E-MCI), advanced MCI (A-MCI), and AD conditions.

RESULTS: Our analyses suggest progressive remodeling of energy metabolism, the glutamate-glutamine-GABA cycle, redox homeostasis, lipid metabolism, and neuron-astrocyte metabolic interactions. FVA identified reaction-specific changes in feasible flux ranges, indicating remodeling of the feasible metabolic solution space rather than a uniform contraction across pathways. These predicted metabolic alterations were accompanied by transcriptional changes in GABAergic markers and showed qualitative agreement with independent metabolomic observations, supporting their biological plausibility.

DISCUSSION: Overall, this work provides a systems-level computational framework linking transcriptomic alterations with predicted metabolic remodeling in GABAergic neurons and generates experimentally testable hypotheses regarding metabolic dysfunction during progression from MCI to AD.},
}

@article {pmid42755830,
year = {2026},
author = {Li, Y and Liao, Y and Zhang, S and Xu, C and Lan, R and Zhao, P and Liu, R and Song, Y and Zhang, X},
title = {Activation of silent synapses driven by emerging technologies: mechanisms, disease associations, and prospects for clinical translation.},
journal = {Frontiers in synaptic neuroscience},
volume = {18},
number = {},
pages = {1923815},
pmid = {42755830},
issn = {1663-3563},
abstract = {Silent synapses represent a unique class of synaptic connections that are non-functional at rest but possess the potential to become functional, serving as a critical reservoir for neural plasticity. Their activation mechanisms not only challenge traditional models of synaptic maturation but also provide novel insights into brain function regulation and disease pathology. This article provides a systematic review of the regulatory mechanisms underlying silent synapse activation, encompassing pre-synaptic calcium signaling-mediated vesicle cycling and active zone (AZ) optimization, post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) membrane insertion and post-synaptic density protein 95 (PSD-95) anchoring, Mg[2+] blockade release by N-methyl-D-aspartate receptor (NMDAR), as well as synergistic integration of upstream signaling pathways. Additionally, it explores the roles of astrocytes, epigenetic modifications, ubiquitin-proteasome systems, and autophagy-lysosomal systems in multi-level regulatory processes. Notably, abnormal regulation of silent synapses exhibits two contrasting pathological patterns in diseases: "desilencing impairment" (e.g., Alzheimer's disease, depression) and "abnormally excessive desilencing" (e.g., drug addiction, chronic pain), which establishes a theoretical framework for targeted interventions. The study further evaluates the applicability and limitations of emerging technologies-including high-resolution imaging, single-cell omics, optogenetics, and AI-driven brain-inspired computing-in silent synapse research, while systematically summarizing clinical advancements, current challenges, and future directions, aiming to inform both fundamental neuroscience studies and therapeutic interventions.},
}

@article {pmid42756074,
year = {2026},
author = {Jekpoo, S and Booncharoen, K and Prompila, S and Wongpakaran, T and Wang, H and Wongpakaran, N},
title = {Clinical characteristics and neuropsychiatric profiles of young-onset dementia: a retrospective cross-sectional study at a tertiary care center in Northern Thailand.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1912953},
pmid = {42756074},
issn = {1664-0640},
abstract = {BACKGROUND: Data on young-onset dementia (YOD) in Thailand remain limited. We aimed to describe clinical presentation, general cognitive performance, neuropsychiatric symptoms, neuroimaging features, and selected laboratory findings across YOD subtypes in a tertiary-care cohort in Northern Thailand.

METHODS: We conducted a retrospective cross-sectional study of 295 individuals with YOD (symptom onset < 65 years) treated at Chiang Mai University Hospital (2010-2025). Data extracted included demographics, presenting complaints, general cognitive scores (MoCA/TMSE/MSET-10), neuropsychiatric symptoms (NPI-Q, TGDS), functional status, neuroimaging findings, and laboratory results (HIV, syphilis serology, glycemic indices, and lipid profiles).

RESULTS: Alzheimer's disease (AD) and vascular dementia (VaD) were the most common subtypes. Memory impairment was the most frequent presenting complaint overall (78.3%) and was more common in AD than VaD (93.4% vs 77.8%), whereas behavioral change was more common in VaD than AD (31.1% vs 13.2%). General cognitive scores did not significantly differ between AD and VaD. Neuropsychiatric symptoms were frequent, with aberrant motor behavior (42.2%) and irritability/lability (35.1%) being the most prevalent domains. Regarding neuroimaging features, a substantial burden of subcortical and basal ganglia lesions co-occurred predominantly within the VaD group. Behavioral variant frontotemporal dementia (bvFTD) accounted for 3.7% of cases; most met the International Behavioral Variant FTD Criteria Consortium (FTDC) criteria for probable bvFTD. All tested participants had non-reactive HIV results, and reactive syphilis screening results were uncommon and were not supported by confirmatory treponemal testing.

CONCLUSION: Presenting complaints differed between young-onset AD and VaD despite similar general cognitive performance, underscoring the importance of informant history and multimodal assessment for accurate subtyping. Frequent motor-related neuropsychiatric symptoms highlight the clinical relevance of subcortical/basal ganglia lesion burden in this cohort.},
}

@article {pmid42756205,
year = {2026},
author = {Liu, D and Zhuo, Y and Chen, S and Wang, Y and Chen, X and Yao, Y},
title = {The role of apolipoprotein E4 on calcium homeostasis in primary hippocampal neurons: an in vitro study.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1845934},
pmid = {42756205},
issn = {1662-4548},
abstract = {BACKGROUND: We previously demonstrated that apolipoprotein E (apoE4) accelerates neurodegeneration in a transgenic mouse model, but the mechanism is still unclear. A previous study reported that death-associated protein kinase 1 (DAPK1) interacts with the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor, this DAPK1-NR2B interaction increases calcium intake in cells, leading to cell damage. As apoE4 is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD) and calcium dyshomeostasis is a key driver of sAD-related neurotoxicity, the unclear mechanism linking apoE4 to calcium imbalance remains a critical gap in developing targeted therapies for sAD. Addressing this gap is urgent to advance our understanding of sAD pathogenesis and identify new therapeutic targets. Our study aimed to determine whether the neurotoxic effects of apoE4 are mediated by the interaction between DAPK-1 and the NMDA receptor NR2B subunit.

METHODS: Primary mouse hippocampal neurons were cultured with apoEs in the presence or absence of an NMDA receptor antagonist that preferentially targets NR2B-containing receptors. Intracellular calcium concentration, cell viability and the proteins related to calcium homeostasis were detected.

RESULTS: Cells treated with apoE4 showed increased levels of intracellular calcium and cell death. The expression of DAPK-1 and NR2B was up-regulated, and interacted with each other under the condition of ApoE4 culture.

CONCLUSION: Our study showed that apoE4 causes neurotoxicity by increasing intracellular calcium concentration. The possible mechanism of which was that apoE4 increased the expression of DAPK-1/NMDAR2B, and further promoted the interaction between the two. These results may provide new targets and ideas for the treatment of AD.},
}

@article {pmid42756207,
year = {2026},
author = {Panabakam, N and Elangovan, K and Seerangan, K and Manogaran, N and Malleeswaran, K and Yogarayan, S},
title = {Alzheimer's disease detection from structural brain MRI using FFA U-Net segmentation and transfer learning.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1871982},
pmid = {42756207},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to a gradual decline in cognitive and memory function. Multimodal neuroimaging, particularly magnetic resonance imaging (MRI), has become a central diagnostic tool for tracking disease progression, supporting diagnosis, treatment planning, and follow-up monitoring. Manual delineation of brain structures by clinicians remains time-consuming and labor-intensive, and computer-assisted segmentation is complicated by spatial and structural variability as well as intensity inhomogeneity across images. This study proposes an integrated framework for automated brain image segmentation and AD classification to address these challenges.

METHODS: The framework combines a modified U-Net architecture, termed FFA U-Net, with a fine-tuned VGG16 classifier. FFA U-Net incorporates a residual inception module and a feature fusion attention mechanism into the standard U-Net backbone to perform end-to-end brain tissue segmentation. Segmented outputs are subsequently passed to the fine-tuned VGG16 model for classification of AD status. The framework was evaluated on two datasets, ADNI (843 images) and OASIS (416 images), using subject-wise, non-overlapping training, validation, and test splits to prevent data leakage.

RESULTS: The proposed framework achieved a segmentation Dice Similarity Coefficient (DSC) of 0.929 and a classification accuracy of 98.90%, based on a single data split. These results were consistent across both the ADNI and OASIS datasets, indicating competitive segmentation and classification performance.

DISCUSSION: The findings suggest that combining attention-augmented segmentation with transfer learning-based classification can effectively support automated AD detection from structural MRI, potentially reducing the manual burden on clinicians. As results are based on a single split, further validation using cross-validation or independent cohorts is warranted to confirm robustness and generalizability. The framework should currently be regarded as an experimental research tool that requires additional clinical validation before deployment in practice.},
}

@article {pmid42756234,
year = {2026},
author = {Liu, M and Gresham, LK and Puccetti, NA and Betthauser, TJ and Johnson, SC and Schaefer, SM},
title = {Amygdalar Pattern Similarity to Negative and Neutral Images, Ratings of the Images, and PET-Measured Amyloid and Tau Levels in Older Adults Without Dementia.},
journal = {Affective science},
volume = {7},
number = {3},
pages = {483-497},
pmid = {42756234},
issn = {2662-205X},
abstract = {UNLABELLED: This study examines associations between brain levels of amyloid-β and tau with representational pattern similarity in amygdalar reactivity to negative and neutral images in older adults without dementia. 81 participants viewed affective images during functional magnetic resonance imaging (fMRI). Participants rated the images on valence and arousal outside the scanner. Amyloid-β and tau were measured with [11]C-Pittsburgh compound B and [18]F-MK-6240 positron emission tomography (PET) imaging. Representational pattern similarity analyses compared amygdalar responses to negative and neutral stimuli, while preserving the voxel-wise pattern of fMRI activation. Greater differentiation in the pattern of responding across the amygdala was indicated by lower similarity between negative and neutral stimuli. Greater tau levels in the entorhinal cortex and amygdalae were associated with less pattern similarity in left amygdalar reactivity to negative and neutral images in participants whose tau level was below standard positivity thresholds. Less pattern similarity in right amygdalar reactivity to negative and neutral images was also associated with the participants' valence and arousal ratings of the stimuli. No associations were found with global amyloid levels and only the association between entorhinal tau and amygdalar similarity remained significant after Bonferroni correction. Greater amygdalar pattern separation in response to negative and neutral stimuli with higher levels of entorhinal tau suggest greater amygdalar sensitivity to negative compared to neutral information as tau accumulates in the brain, suggesting a potential underlying mechanism for the disrupted emotional processes often observed in preclinical Alzheimer's Disease and other Related Dementias.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s42761-026-00394-5.},
}

@article {pmid42756260,
year = {2026},
author = {Subramani, S and Priya, SB},
title = {Hybrid quaternion-based denoising and deep feature fusion for early Alzheimer's prognosis.},
journal = {Health information science and systems},
volume = {14},
number = {1},
pages = {84},
pmid = {42756260},
issn = {2047-2501},
abstract = {Alzheimer's Disease (AD) is one of the most common neurodegenerative diseases that causes irreversible cognitive impairment and agnosia. Early detection is extremely valuable in diagnostics, but diagnostic procedures continue to rely on subjective approaches as well as traditional neuroimaging biomarkers, which frequently exhibit low tolerance to noise interference and imprecise structure localization. Traditional approaches also have difficulty combining multi-modal scans (MRI and PET) and detecting early-stage Alzheimer's disease characteristics (e.g., hippocampal atrophy). Some critical limitations of the current state-of-the-art include: (1) extreme sensitivity to noise; (2) poor spatio-temporal feature fusion; and (3) a lack of biomarker prioritization during disease progression. This problem is difficult to solve because the stages of Alzheimer's disease (AD) are not well differentiated. To address the aforementioned challenges, we propose a new study using the Hybrid Quaternion-Based Denoising and Deep Feature Fusion (HQD-FF) framework. The architecture will include a Quaternion Non-Local Means (QNLM) denoising procedure to suppress Rician/Rayleigh noise while keeping the structure intact. Following that, a hybrid CNN-RNN architecture will be used to extract spatial and temporal features using an attention-based fusion technique, allowing the identification of important biomarkers such as cortical thinning. The evaluation was carried out using the public multi-modal neuroimaging ADNI and OASIS datasets, as well as a private set of MRI and PET images. The experimental results show that HQD-FF achieves a PSNR of 23.47 dB and SSIM of 0.745, which is 12-15% better than traditional denoising techniques. HQD-FF also achieves 93.4% classification accuracy, outperforming current baselines by 6.2% in terms of AD diagnosis and stage differentiation (EMCI, LMCI, and AD). The proposed framework was also tested for robustness and statistical significance using ROC analysis, Area Under the Curve analysis, Confusion matrix analysis, and the Wilcoxon signed-rank statistical test. HQD-FF provides a robust, interpretable, and scalable framework for Alzheimer's diagnosis, with the potential to support early intervention and personalized medicine. The generalizable framework may pave the way for multimodal disease classification in broader neurodegenerative research.},
}

@article {pmid42756367,
year = {2026},
author = {de Boer, L and Aro, OA and Seelaar, H and Jiskoot, LC and Poos, JM},
title = {Digital health technologies in frontotemporal dementia: A scoping review.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261483445},
pmid = {42756367},
issn = {2055-2076},
abstract = {OBJECTIVE: Digital health technologies are increasingly used to assess cognition and behavior in neurodegenerative diseases. While such tools have shown promise in Alzheimer's disease, including the preclinical stages, their use in frontotemporal dementia (FTD) remains underexplored. This scoping review provides an overview of the current literature on digital health technologies in FTD.

METHODS: We conducted a literature search according to the PRISMA-ScR guidelines and included 62 studies investigating digital health technologies in individuals with FTD.

RESULTS: The identified technologies included eye tracking paradigms, smartphone- and tablet-based cognitive assessments, and passive monitoring approaches such as wearable sensors and mobile applications. Most studies reported that these technologies could distinguish individuals with FTD from healthy controls or other dementia syndromes. However, many studies were experimental or feasibility-focused, and systematic evaluation of psychometric properties remains limited.

CONCLUSION: In order to move the field forward, we argue that an in-depth investigation of the relationships between digital health technologies, classical pen-and-paper assessments of cognitive and behavioral functioning, and other biomarkers is necessary to establish clinical validity. Other important aspects to address in future research include the use of diverse cohorts and studying longitudinal effects. In our view, these next steps are crucial to advance digital health technologies toward implementation in clinical practice and clinical trials for FTD.},
}

@article {pmid42756424,
year = {2026},
author = {Bai, Q and Yan, Y and Zeng, C and Li, X and Zeng, G and Saidova, A and Li, H and Qing, H},
title = {Engram cell vulnerability in neurodegeneration: from mechanistic insights to therapeutic horizons.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1873893},
pmid = {42756424},
issn = {1663-4365},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) share progressive memory impairment, yet their upstream pathologies differ. This review synthesizes evidence across these disorders to frame memory decline through engram ensembles and proposes an excitability-vulnerability tradeoff, in which the physiological requirements for engram function, including elevated excitability, synaptic plasticity, and coordinated network activity, also increase sensitivity to synaptic stress, network disruption, and inflammatory perturbations. We summarize disease-related pathological cascades. To date, AD has the most robust body of direct experimental evidence linking pathology to impaired engram function. Solid experimental findings demonstrate that amyloid-β (Aβ)/tau causes hippocampal engram inaccessibility in AD. For PD and HD, inferences drawn from synaptic and circuit dysfunction suggest that α-synuclein (α-syn) pathology and dopaminergic loss may disrupt striatal ensembles, and mutant huntingtin (mHTT) presumably impairs striatocortical coordination. We further integrate a shared amplification route in which microglial activation and complement-linked synaptic remodeling weaken memory-relevant connectivity and reduce cue-driven ensemble reinstatement. This mechanism is well validated in AD, while supporting evidence for PD and HD remains largely indirect. Finally, we outline a translational roadmap that integrates circuit-targeted delivery, engram-relevant clinical endpoints, and scalable neuromodulation, supported by human neuronal-glial molecular profiling to guide mechanism-informed combination strategies. Importantly, these multi-tiered therapeutic approaches act on the full spectrum of neural cells rather than only memory engram ensembles, and cognitive rescue arises from a multifactorial regulatory process involving both global neuroprotection and ensemble stabilization. We also systematically discuss key limitations of current engram research, including methodological heterogeneity in engram labelling tools, interspecies translational barriers, and substantial clinical obstacles for optogenetic and circuit-based therapeutic applications.},
}

@article {pmid42756469,
year = {2026},
author = {Terrando, N and Maze, M and Yang, T},
title = {What is new in delirium: A vascular etiology outlook.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70324},
pmid = {42756469},
issn = {2352-8737},
abstract = {Emerging studies have highlighted the vascular contributions to cognitive impairment and dementia (VCID), especially in the context of neurodegenerative disorders that cause cognitive decline (i.e., Alzheimer's disease and related dementias [ADRD]). More recent research on perioperative neurocognitive disorders, including postoperative delirium, is describing a potential role of neurovascular dysfunction in the pathogenesis of these common complications for many older adults. These findings support an expanded conceptual framework in which delirium is not simply a transient disorder of neuronal function but may represent an acute neurovascular phenotype that links systemic inflammation, blood-brain barrier injury, and VCID. Delirium is characterized by acute and fluctuating disturbances in attention, awareness, and cognition. It is a common, costly, neurologic complication in patients, especially critically ill patients, patients with chronic metabolic disorders, or older adults. In older adults, delirium is among the most consequential complications of hospitalization. A 2025 national cohort of > 5.5 million older adults undergoing major non-cardiac surgery found that postoperative delirium was associated with markedly higher odds of death or major complications, and 30-day mortality. These contemporary data reinforce a shift in framing: delirium should be treated as acute brain failure and as a quality target for perioperative and critical care systems, not merely as a temporary behavioral syndrome. In addition to the acute negative impacts, delirium significantly escalates the risk of persistent cognitive decline, presaging the potential onset of neurodegenerative disorders. Despite substantial research into delirium epidemiology, prevention, and control, its management is complicated by the elusive nature of its pathophysiological mechanisms. Here, we propose a vascular etiology outlook for delirium, with emphasis on the neurovascular unit as a key interface in determining the onset of this complication and potentially jump-starting permanent brain dysfunction and ADRD.},
}

@article {pmid42756499,
year = {2026},
author = {Feng, S and Zhuang, H and Xu, C and Guo, X and Cao, L and Liu, Y and Guan, Y and Li, Y and , },
title = {Individualized cholinergic pathway degeneration in Alzheimer's disease characterized by normative modeling.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70485},
pmid = {42756499},
issn = {2352-8729},
abstract = {INTRODUCTION: Cholinergic pathway degeneration is implicated in Alzheimer's disease (AD), but its individualized characterization in AD and mild cognitive impairment (MCI) remains limited.

METHODS: We constructed lifespan normative models of medial and lateral cholinergic pathways using >6000 diffusion MRI scans from healthy individuals. These models were applied to 1742 scans from 725 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Individualized diffusion abnormalities were integrated into a composite cholinergic pathway degeneration index (CPDI). Group differences and longitudinal associations with cognitive decline and progression were evaluated.

RESULTS: CPDI was higher in MCI and AD participants than in controls, and increased longitudinally in patients with AD and in patients with MCI who progressed to AD. Higher baseline CPDI was associated with an increased risk of progression from MCI to AD and faster decline in global cognition, memory, language, and executive function.

DISCUSSION: CPDI provides an individualized biomarker of cholinergic pathway degeneration with prognostic relevance in AD.},
}

@article {pmid42756662,
year = {2026},
author = {Mirshekar, MA and Nadi, F and Fanaei, H and Chahkandi, M},
title = {Modulation of spatial learning and memory by cannabinoid-estrogen interaction in an AD-like cognitive impairment: The role of cannabinoid receptors and BDNF protein.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {780-789},
pmid = {42756662},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is an increasingly prevalent neurodegenerative disorder worldwide, with women showing a higher risk of developing the disease. The decline in steroid hormones after menopause may contribute to the increased susceptibility of women to neurodegenerative conditions. In parallel, cannabis-derived compounds have been reported to alleviate certain symptoms associated with neurological disorders. The present study was designed to investigate the effects of marijuana extract on cognitive impairment and hippocampal molecular markers in an ovariectomized AD-like rat model, and to evaluate whether co-administration with estradiol modifies these effects. The marijuana extract used in this study was characterized by HPLC and was found to contain 8.5% Δ9-THC. AD-like cognitive impairment pathology was induced by intra-hippocampal administration of Aβ25-35 in OVX rats. Animals were treated with marijuana extract (60 mg/kg/day, corresponding to approximately 5.1 mg/kg/day Δ9-THC) either alone or in combination with 17β-estradiol (1 mg/kg every 4 days) for 28 days. Cognitive performance was evaluated using the Morris water maze (MWM). In addition, hippocampal CB1/CB2 receptor expression and BDNF protein levels were measured to examine potential molecular associations. Our findings showed that chronic administration of the marijuana extract improved Aβ25-35-induced deficits in spatial learning and memory. Alterations in CB1 receptor expression and BDNF levels accompanied these behavioral effects. Notably, co-treatment with estradiol did not produce a synergistic effect, suggesting a complex interaction between cannabinoid-related and estrogen-related signaling pathways. These preclinical findings suggest that a THC-standardized marijuana extract may exert neuroprotective-like effects in an AD-like cognitive impairment model. However, because the extract was not fully phytochemically characterized and the mechanistic analyses were correlational, the results should be interpreted cautiously. Further studies are needed to clarify the underlying mechanisms and translational relevance of these findings.},
}

@article {pmid42756762,
year = {2026},
author = {Thompson, L and Eaton, C and Prieto, S and Lawrence, M and Czech, S and Rosenbaum, J and Anthony, D and Chandran, R and Kelly, L and Ngo, I and Goldberg, A and Gillooly, C and Richardson, C and Elwy, AR and Jones, RN and Rentz, DM},
title = {A pilot study of at-home online cognitive screening prior to primary care wellness visits for older adults.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1823218},
pmid = {42756762},
issn = {2673-253X},
abstract = {BACKGROUND: Improved methods of cognitive testing are urgently needed for primary care settings faced with a growing older adult population and higher rates of dementia. We tested the feasibility and acceptability of a novel online cognitive test that can be completed at home prior to an annual exam.

METHODS: 32 older adults completed testing at home on personal devices 1-4 weeks prior to an annual exam with their primary care provider. Additional cognitive screening was completed in-clinic to provide preliminary validation evidence. Completion rates were examined to assess feasibility, and patient acceptability was assessed via survey.

RESULTS: Completion rate was 78.5% for at-home testing online. Participants reported that they generally preferred at-home over in-clinic testing. At-home test performance was moderately correlated with the standard Montreal Cognitive Assessment completed in clinic.

CONCLUSION: Findings provide initial support for the acceptability of self-administered online cognitive screening for older adults in primary care. Completion rates were slightly below a preset benchmark, suggesting that additional support may be needed to facilitate at-home testing in routine care. Further validation research is needed in larger samples including examination of digital measure convergence with clinical diagnoses and additional cognitive testing.},
}

@article {pmid42756830,
year = {2026},
author = {Li, X and Miao, Z and Bi, J and Zhang, J and Wang, N},
title = {Sucralose Induces Neurobehavioral Alterations and Exacerbates Alzheimer's Disease-Like Phenotypes in Zebrafish Models.},
journal = {ACS omega},
volume = {11},
number = {36},
pages = {54169-54186},
pmid = {42756830},
issn = {2470-1343},
abstract = {Artificial sweeteners are widely consumed, yet their potential neurotoxic effects remain poorly understood. Using sucralose (SUC) as a model compound, this study develops an approach to rapidly screen the neurotoxicity of artificial sweeteners and explore their potential associations with neurodegenerative-like processes, especially Alzheimer's disease (AD)-like phenotypes. SUC is minimally absorbed and metabolized by mammals, leading to its widespread presence in the environment. Here, we integrate high-throughput behavioral phenotyping in larval zebrafish with targeted analyses in adult and AD transgenic models, employing a "behavioral phenoblast" strategy adapted from prior large-scale sleep-wake drug screens. SUC effects were evaluated across a broad concentration range (5 μg/L to 100 mg/L), covering low-dose to high-dose exposure conditions. Hierarchical and K-means clustering revealed that SUC's behavioral signatures closely resembled those of compounds associated with neurodegenerative risks. To validate these findings, adult zebrafish were exposed to SUC within the Acceptable Daily Intake (ADI) range (1-100 mg/L) for 3 months, resulting in dose-dependent increases in anxiety-like behaviors and impairments in learning and memory. Notably, treatment of transgenic zebrafish expressing human misfolded Aβ protein with SUC exacerbated Aβ-related pathological phenotypes in a dose-dependent manner. These findings highlight the need for further investigation into the long-term neurological impacts of artificial sweeteners and provide a methodological framework for evaluating the potential health risks of artificial sweeteners.},
}

@article {pmid42757183,
year = {2026},
author = {Vairavan, S and Griffin, N and Wilson, D and Triana-Baltzer, G and Brugada-Ramentol, V and Vera-Campuzano, E and Alcolea, D and Fallone, S and Mackintosh, L and Mette, L and Doecke, JD and Robertson, J and Ward, L and Benavides, GS and Minguillon, C and Mas, CP and Tort-Merino, A and Balasa, M and Rivera, OG and Calvet, MS and Taylor, L and Rodríguez-Baz, Í and Arranz, J and Fortea, J and Tarnanas, I and Jones, M and Wittenberg, G and Streel, E and Iulita, MF},
title = {A scalable workflow using digital cognitive assessment and pTau217 for MCI detection.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70486},
pmid = {42757183},
issn = {2352-8729},
abstract = {INTRODUCTION: Blood biomarkers like phosphorylated tau (p-tau)217 offer high diagnostic accuracy for Alzheimer's disease (AD) but face implementation challenges in low-prevalence settings. We evaluated the Altoida NeuroMarker Platform as a digital cognitive triage tool before plasma p-tau217 testing.

METHODS: XGBoost models were trained to predict mild cognitive impairment (MCI) and p-tau217 status in 688 individuals across Australia, Spain, and the United States using the Altoida NeuroMarker. p-tau217 status was dichotomized using a threshold of 0.04 pg/mL (LucentAD). We modeled a two-step workflow (Altoida, plasma p-tau217) to enrich downstream biomarker testing, assuming 30% prevalence of AD pathology.

RESULTS: The Altoida NeuroMarker accurately identified MCI (receiver operating characteristic area under the curve [ROC AUC] = 0.89 ± 0.01) and p-tau217 elevation (ROC AUC = 0.77 ± 0.08). Predicted MCI was significantly associated with elevated pTau217 (p = 0.004). When used upstream, the Altoida NeuroMarker ruled out 64.4% of participants (negative predictive value 90.2%), shifting the pre-test probability of AD pathology to 66.6%, and improving the modeled positive predictive value of plasma p-tau217 from 81.7% to 95.3%.

DISCUSSION: This workflow outlines a scalable path to enrich blood-based biomarker testing after digital cognitive screening.},
}

@article {pmid42757362,
year = {2026},
author = {Benito-León, J and Serrano, JI and Del Castillo, MD and Escolà-Gascón, Á and Benito-Rodríguez, CM and Ramo-Tello, C and Ghosh, R and Bermejo-Pareja, F},
title = {Population-based cohort study of modifiable risk factors for dementia and Alzheimer disease mortality in Spain.},
journal = {Communications health},
volume = {1},
number = {1},
pages = {26},
pmid = {42757362},
issn = {3091-4841},
abstract = {BACKGROUND: Although many modifiable factors are linked to dementia risk, their association with dementia and Alzheimer disease (AD) mortality remains unclear. We aimed to identify late-life modifiable factors associated with these outcomes and assess sex differences.

METHODS: In the population-based Neurological Disorders in Central Spain (NEDICES) cohort, we followed 3085 older adults enrolled in 1994-1995 through 2017. We examined 13 modifiable factors measured at study entry. Dementia and AD deaths were defined by the underlying cause recorded on death certificates. Fine-Gray competing risk models accounted for death from other causes and generated subdistribution hazard ratio (SHR) estimates and adjusted population attributable fractions (PAFs).

RESULTS: During follow-up, there were 182 dementia-coded deaths (including 105 AD-coded deaths) and 2423 deaths from other causes. Here we show that depressive symptoms are associated with higher dementia-coded mortality in women (SHR 1.52, 95% confidence interval [CI] 1.00-2.30; PAF 13.6%, 95% CI 0.0-28.4) and higher AD-coded mortality overall (SHR 1.76, 95% CI 1.11-2.79; PAF 15.4%, 95% CI 2.6-29.9), with a stronger association in women (SHR 2.23, 95% CI 1.28-3.88; PAF 27.2%, 95% CI 7.8-46.7). Several exposures show inverse associations (e.g., smoking, obesity, and arterial hypertension in men), consistent with competing mortality and late-life reverse causation. Combined positive PAFs are 10.8% for dementia-coded mortality and 18.2% for AD-coded mortality overall, reaching 41.1% in women for AD-coded mortality.

CONCLUSIONS: Late-life depressive symptoms, particularly among women, emerged as the most prominent modifiable correlate of dementia- and AD-coded mortality, supporting improved recognition and management of depressive symptoms in older adults.},
}

@article {pmid42757589,
year = {2026},
author = {Austin, G and Ferguson, JJA and Eslick, S and Garg, ML and Martins, R},
title = {Plant-based diets, cognitive function, and Alzheimer's disease.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo01946c},
pmid = {42757589},
issn = {2042-650X},
abstract = {Background: Alzheimer's disease (AD) represents 60-70% of global dementia cases, with up to 45% attributed to modifiable risk factors. Plant-based diets (PBDs) are increasingly recognised for their potential benefits on the gut microbiome, cardiometabolic risk factors and prevention of neurodegenerative disorders. This narrative review synthesises PBDs association with cognitive decline and AD risk. Methods: This review aims to summarise evidence from observational and interventional studies examining vegan, vegetarian, pesco-vegetarian, semi-vegetarian dietary patterns, and PBD indices in relation to cognitive function, incident dementia, AD biomarkers, and neuroimaging outcomes. Results: Long-term observational studies suggest greater adherence to vegan, vegetarian and healthy PBD indexs are associated with lower risk of cognitive decline and dementia, while higher intake of red and processed meat is linked to increased risk. Pesco-vegetarian dietary patterns and higher fish intake appear to confer benefits in memory tests and reduced risk of all-cause dementia, although research is limited. Mechanistically, PBDs are rich in unsaturated fats, fibre, polyphenols and low in saturated fats, which contribute to improving lipid profiles, glycaemic control, endothelial function, and favourable gut-derived metabolites, thereby reducing cardiometabolic burden that is known to accelerate early-stage AD pathophysiology. However, nutritional considerations, including potential deficiencies in vitamin B12 and long-chain omega-3 fatty acids, require consideration when following a PBD. Conclusions: Current evidence suggests PBDs may support cognitive health and reduce the risk of dementia including AD through vascular and metabolic pathways, though long-term interventional studies incorporating biomarkers and neuroimaging are needed to clarify effects and optimise dietary recommendations for AD prevention.},
}

@article {pmid42757822,
year = {2026},
author = {Gaber, DA},
title = {Engineering centrifugally spun nanofibrous matrices as high-performance transdermal patches for accelerated Alzheimer's treatment.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/09205063.2026.2734516},
pmid = {42757822},
issn = {1568-5624},
abstract = {This study aimed to develop and optimize a centrifugally spun polycaprolactone/poly(vinyl alcohol) (PCL/PVA) nanofibrous transdermal patch containing polyethylene glycol 400 (PEG 400) and oleic acid to improve rivastigmine delivery for the long-term management of Alzheimer's disease. Rivastigmine-loaded nanofibrous patches were fabricated by centrifugal spinning and characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). Mechanical properties, drug release, ex vivo skin permeation and deposition, dermal irritation, pharmacokinetics in New Zealand White rabbits, and stability were systematically evaluated. The optimized formulation (F5) produced uniform, bead-free nanofibers (1.7 ± 0.3 μm) with rivastigmine molecularly dispersed in an amorphous state within the polymeric matrix. The patch exhibited favorable mechanical properties, sustained drug release, enhanced ex vivo skin permeation (0.50 ± 0.04 mg/cm[2] at 24 h), and increased drug deposition within the viable epidermis and dermis, indicating cutaneous reservoir formation. Dermal irritation was negligible (Primary Irritation Index = 0.08). Pharmacokinetic studies demonstrated prolonged systemic absorption (Tmax = 6.0 ± 1.0 h) and approximately five-fold greater systemic exposure (AUC0-∞ = 345 ± 28 ng·h/mL) than the oral formulation (67 ± 9 ng·h/mL, p < 0.05).The optimized centrifugally spun nanofibrous patch provided sustained rivastigmine delivery, excellent dermal biocompatibility, enhanced skin deposition, and improved systemic bioavailability, supporting its potential as a scalable transdermal platform for long-term Alzheimer's disease therapy.},
}

@article {pmid42758029,
year = {2026},
author = {Choi, JJ and Engelman, CD and Lu, T},
title = {Multi-omics integration of transcriptomics and metabolomics with machine learning uncovers novel risk factors for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487621},
doi = {10.1177/13872877261487621},
pmid = {42758029},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, memory impairment, and functional deterioration. Its complex pathogenesis involves amyloid plaques, tau tangles, neuroinflammation, synaptic dysfunction, and interacting genetic, environmental, and lifestyle factors. Transcriptomic and metabolomic studies have revealed molecular disruptions relevant to AD, supporting integrative approaches for biomarker discovery.ObjectiveTo integrate genetically imputed whole-blood transcriptomics and measured plasma metabolomics to predict cognitive performance, assessed using the PACC3 score, and identify influential genes and metabolites associated with cognition.MethodsA machine learning model integrated transcriptomic and metabolomic data from 1046 participants in the Wisconsin Registry for Alzheimer's Prevention (WRAP). Performance was evaluated in a WRAP holdout test set and independently validated in 85 participants from the Wisconsin Alzheimer's Disease Research Center (ADRC). Feature importance was used to identify molecular contributors to prediction.ResultsThe model achieved a normalized root mean squared error of 0.707 and an R[2] of 0.338 in the WRAP holdout dataset (p = 5.93 × 10[-30]), and corresponding values of 0.915 and 0.061 in ADRC (p = 4.71 × 10[-2]). Higher imputed expression of RIPK1, IL6ST, and BIN1 was associated with poorer cognitive performance, whereas UGP2, NDUFB5, and TMOD2 were associated with better performance. Predictive metabolites included benzoate, 3-phenylpropionate, imidazolelactate, hexanoylcarnitine, and propionate-related metabolites.ConclusionsMulti-omics integration identified candidate biomarkers reflecting inflammatory signaling, mitochondrial dysfunction, and lipid metabolism. Together, these findings demonstrate complementary biological information captured across both omics layers. These convergent signals support improved molecular characterization of AD and biomarker prioritization for future mechanistic and translational studies.},
}

@article {pmid42758031,
year = {2026},
author = {Ramezannezhad, E and Dehghani, M and , },
title = {Utility of biomarkers in prediction of future cognition in Alzheimer's disease continuum changes over time.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487572},
doi = {10.1177/13872877261487572},
pmid = {42758031},
issn = {1875-8908},
abstract = {BackgroundWhile multiple biomarkers of Alzheimer's disease (AD) and mild cognitive impairment (MCI) predict cognitive decline over time, their predictive value at each of the disease stages remains unclear.ObjectiveTo examine how the predictive power of biomarkers changes over time.MethodsWe dynamically ranked a comprehensive set of multimodal biomarkers-including APOE genotype, medical history, structural MRI, FDG-PET, amyloid PET, CSF markers, metabolic measures, and neuropsychiatric tests-from baseline to 30 months in ADNI participants. Feature importance for each timepoint was estimated using random forests and features were clustered based on their patten of importance over time. As a post-hoc, the top features over time were input into a long short-term memory (LSTM) model for future ADAS-13 prediction.ResultsIn 981 participants (751 MCI, 230 AD), clustering of top feature importances over time revealed three trajectories in MCI (stable, early-only, and declining) and four in AD (early-only, stable, early-declining, and late-increasing). The top important features over time were cognitive scores, CSF Aβ42, tau, imaging biomarkers (FDG-PET hypometabolic convergence index, temporal/parietal cortical thickness), metabolic measures (serum albumin, glucose), and apolipoproteins and omega-3. Optimized LSTM models achieved peak R[2] = 0.86 (RMSE = 3.90) in MCI and R[2] = 0.78 (RMSE = 5.86) in AD using as few as 10 features.ConclusionsEarly-stage prognosis relies on CSF Aβ42, p-tau181, and tau; short-term decline is best predicted by FDG-PET; structural MRI shifts from hippocampal/entorhinal to parietal/network regions over time; metabolic markers remain consistently informative; and ADAS/MMSE gain value with advancing global decline.},
}

@article {pmid42758043,
year = {2026},
author = {Li, R and Zhang, B and Qiao, Y and Zhu, L},
title = {Association between caregiving status and cognitive function as well as activities of daily living among community-dwelling older adults with Alzheimer's disease: A cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488017},
doi = {10.1177/13872877261488017},
pmid = {42758043},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease is associated with progressive cognitive decline and impaired activities of daily living. Professional institutional care and family home care are common long-term care models, but their associations with patient outcomes and potential mediating pathways remain unclear.ObjectiveTo examine the associations of care model with cognitive function and activities of daily living in patients with mild-to-moderate Alzheimer's disease and to assess the mediating roles of neuropsychiatric symptoms and social support.MethodsThis cross-sectional study included 309 patients: 194 receiving professional institutional care and 115 receiving family home care. Cognition, daily functioning, neuropsychiatric symptoms, and social support were assessed using standardized scales. Multiple linear regression, propensity score matching, bootstrap mediation analysis, and subgroup analyses were performed.ResultsAfter full adjustment, professional institutional care was associated with higher Montreal Cognitive Assessment scores (β=1.87, 95% confidence interval [CI] 0.87-2.87; p < 0.001) and lower Activities of Daily Living scores (β=-3.04, 95% CI -5.16 to -0.92; p = 0.005). Propensity score matching yielded consistent results. Neuropsychiatric symptoms mediated 22.37% of the association with daily functioning, whereas social support did not show a significant mediating effect. Associations were consistent across subgroups.ConclusionsProfessional institutional care was associated with better cognition and greater independence in daily living, partly through fewer neuropsychiatric symptoms. Because of the cross-sectional design, these findings do not establish causality.},
}

@article {pmid42758107,
year = {2026},
author = {Abdanipour, A and Nikfar, A and Feizi, H},
title = {Selegiline induces neuroprotection via PGC-1α/Nrf2 gene upregulation in H2O2 -treated hippocampal-derived neural stem/progenitor cells.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {72},
number = {5},
pages = {47-53},
doi = {10.14715/cmb/2026.72.5.7},
pmid = {42758107},
issn = {1165-158X},
mesh = {*Selegiline/pharmacology ; *Hydrogen Peroxide/pharmacology/toxicity ; Animals ; *NF-E2-Related Factor 2/genetics/metabolism ; *Hippocampus/cytology ; *Neural Stem Cells/drug effects/metabolism/cytology ; *Up-Regulation/drug effects ; Apoptosis/drug effects ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; Oxidative Stress/drug effects ; Rats ; Cells, Cultured ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Neuroprotection/drug effects ; },
abstract = {Oxidative stress mediated by reactive oxygen species (ROS) is a major contributor to the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and amyotrophic lateral sclerosis. Selegiline, a monoamine oxidase B inhibitor, has been reported to exert neuroprotective effects, although its precise cytoprotective mechanisms remain unclear. In this study, we investigated the effects of selegiline on apoptosis, necrosis, and cell survival in hydrogen peroxide (H2O2)-treated hippocampal-derived neural stem/progenitor cells (HD-NSPCs) in vitro. Passage 3 HD-NSPCs were treated with varying concentrations of selegiline (10[-3] to 10[-9] M) prior to exposure to 125 μM H2O2. Cell viability was assessed using the MTT assay, while apoptosis and necrosis were evaluated using TUNEL and acridine orange/ethidium bromide staining, respectively. Real-time RT-PCR was performed to quantify mRNA levels of PGC-1α, Nrf2, and Bcl-2. Treatment with 10[-7] M selegiline significantly enhanced HD-NSC viability, reduced apoptotic and necrotic cell fractions, and upregulated PGC-1α, Nrf2, and Bcl-2 expression compared to untreated cells (P < 0.05). These findings suggest that selegiline mitigates oxidative stress-induced cytotoxicity by activating Nrf2/PGC-1α signaling and promoting anti-apoptotic gene expression, thereby preserving mitochondrial function and enhancing cell survival. Overall, selegiline may represent a promising therapeutic agent for protecting neural progenitor cells and alleviating neuronal damage in neurodegenerative disorders.},
}

*Selegiline/pharmacology
*Hydrogen Peroxide/pharmacology/toxicity
Animals
*NF-E2-Related Factor 2/genetics/metabolism
*Hippocampus/cytology
*Neural Stem Cells/drug effects/metabolism/cytology
*Up-Regulation/drug effects
Apoptosis/drug effects
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism
*Neuroprotective Agents/pharmacology
Cell Survival/drug effects
Oxidative Stress/drug effects
Rats
Cells, Cultured
Proto-Oncogene Proteins c-bcl-2/metabolism/genetics
*Neuroprotection/drug effects

@article {pmid42758112,
year = {2026},
author = {Abdelnaby Khalyfa, and Jose M Marin, and David Sanz-Rubio, and Sneha S Pillai, and Xiaoman Zhang, and David Gozal, and Komal Sodhi, },
title = {Congruency of exosome-mediated blood-brain barrier dysfunction by activation of Na/K-ATPase in obstructive sleep apnea and Alzheimer's disease.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {72},
number = {5},
pages = {25-29},
doi = {10.14715/cmb/2026.72.5.4},
pmid = {42758112},
issn = {1165-158X},
mesh = {Humans ; *Blood-Brain Barrier/pathology/metabolism/physiopathology ; *Sleep Apnea, Obstructive/pathology/enzymology/metabolism ; Male ; *Exosomes/metabolism ; *Alzheimer Disease/pathology/enzymology/metabolism ; *Sodium-Potassium-Exchanging ATPase/metabolism/antagonists & inhibitors ; Endothelial Cells/metabolism/drug effects/pathology ; Signal Transduction/drug effects ; Middle Aged ; Aged ; },
abstract = {Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are highly prevalent chronic disorders that share several pathological features, including oxidative stress, inflammation, vascular dysfunction, and cognitive impairment. Although epidemiological studies have demonstrated a strong association between OSA and an increased risk of AD, the mechanisms linking these disorders remain poorly understood. We hypothesized that circulating plasma exosomes from patients with OSA or AD disrupt blood-brain barrier (BBB) integrity through activation of Na[+]/K[+]-ATPase signaling. Plasma exosomes were isolated from adult male patients with OSA or AD (n = 10/group) and applied to naïve human brain microvascular endothelial cells (hCMEC/D3). BBB integrity was continuously monitored using electric cell-substrate impedance sensing (ECIS) in the presence or absence of the Na[+]/K[+]-ATPase signaling inhibitor pNaKtide (0-2.0 µM). Exosomes derived from both OSA and AD patients significantly impaired endothelial barrier function, indicating that circulating extracellular vesicles carry bioactive cargo capable of disrupting BBB integrity. Pharmacological inhibition of Na[+]/K[+]-ATPase signaling with pNaKtide significantly restored barrier function at concentrations of 1.0 and 2.0 µM, although the degree of protection differed between the OSA- and AD-derived exosomes, suggesting disease-specific mechanisms of endothelial injury. These findings identify Na[+]/K[+]-ATPase signaling as a key mediator of exosome-induced BBB dysfunction and provide mechanistic evidence linking circulating extracellular vesicles to neurovascular injury in both OSA and AD. Collectively, our results suggest that plasma-derived exosomes contribute to BBB disruption and highlight Na[+]/K[+]-ATPase signaling as a promising therapeutic target for preventing or attenuating neurovascular dysfunction associated with OSA and AD.},
}

Humans
*Blood-Brain Barrier/pathology/metabolism/physiopathology
*Sleep Apnea, Obstructive/pathology/enzymology/metabolism
Male
*Exosomes/metabolism
*Alzheimer Disease/pathology/enzymology/metabolism
*Sodium-Potassium-Exchanging ATPase/metabolism/antagonists & inhibitors
Endothelial Cells/metabolism/drug effects/pathology
Signal Transduction/drug effects
Middle Aged
Aged

@article {pmid42465886,
year = {2026},
author = {Zhang, C and Li, H and Tian, F and Sina, ML and Orban, C and Chen, C and Zhou, JH and Yeo, BTT and , and , },
title = {Robust Longitudinal Dementia Prediction under Systemic Missingness via Hierarchical Fusion and Test-Time Adaptation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42465886},
abstract = {Longitudinal dementia progression prediction is essential for clinical decision-making. However, models often degrade on external cohorts due to systemic missingness - where certain biomarkers available during training are completely absent at test time - compounded by distribution shifts and patient-specific variability. Here, we propose Progression-aware Feature Fusion with Test-Time Adaptation (ProFuse-TTA), a two-stage hierarchical Transformer for longitudinal dementia prediction. Stage 1 learns per-biomarker temporal representations from irregular observations without imputation. Stage 2 fuses them via cross-feature attention, with simulated modality dropout during training for robustness to systemic missingness. At inference, a lightweight test-time adaptation module performs per-individual calibration. We trained on ADNI and evaluated on three external cohorts comprising 2,316 participants and 13,205 timepoints, with controlled modality ablation experiments isolating the effect of systemic missingness. We compared against six baselines, four from a recent benchmark study and two new baselines including one built on a tabular foundation model. ProFuse-TTA achieved the best cross-dataset performance in 8 of 9 settings across clinical diagnosis, MMSE, and hippocampal volume prediction, and ranked first in 14 of 15 ablation scenarios. The model maintained superior performance across varying input lengths and prediction horizons up to 6 years. Pretrained ADNI models are available at XXX.},
}

@article {pmid42747213,
year = {2026},
author = {Petrella, JR and Barkhof, F and Benzinger, TLS and Cogswell, PM and Franceschi, AM and Sabbagh, MN and Salloway, SP and Zaharchuk, G and Doraiswamy, PM},
title = {Artificial Intelligence-Based Detection of ARIA on MRI During Alzheimer Disease Therapy: Expert Opinion on Responsible Clinical Integration.},
journal = {AJR. American journal of roentgenology},
volume = {},
number = {},
pages = {},
doi = {10.2214/AJR.26.35514},
pmid = {42747213},
issn = {1546-3141},
abstract = {Amyloid-targeted monoclonal antibody therapies have introduced a new era in the treatment of early Alzheimer disease. However, their use has increased the importance of detecting and monitoring amyloid-related imaging abnormalities (ARIA) on MRI, as such findings may influence treatment continuation, dose modification, and patient safety assessment. As anti-amyloid therapies expand into routine practice, increasing surveillance MRI volumes, interreader variability, and the potential for missed subtle abnormalities have generated interest in artificial intelligence (AI)-based clinical decision support tools. A multidisciplinary panel of neuroradiologists and Alzheimer disease clinicians examined the extent of evidence supporting clinical implementation of AI-assisted ARIA detection tools, these tools' safe integration into practice, and remaining evidence gaps. The panel concluded that AI-assisted ARIA detection is likely to enhance patient safety when used as clinical decision support within a radiologist-in-the-loop framework. Panelists also noted substantial variation among commercially available tools in regulatory status, technical capabilities, and validation evidence. Moreover, they emphasized the need for further studies to assess the impact of improved detection on clinical outcomes. Overall, the panel supported conditional implementation with radiologist oversight, ongoing quality assurance, and prospective monitoring of clinical performance.},
}

@article {pmid42747246,
year = {2026},
author = {Urso, D and Giannelli, T and Tafuri, B and Giannoni-Luza, S and Gnoni, V and Giugno, A and Vilella, D and Zecca, C and De Blasi, R and Nigro, S and Aarsland, D and Logroscino, G},
title = {Alzheimer's Co-Pathology Burden on Basal Forebrain Atrophy and Cognitive Impairment in Dementia with Lewy Bodies: A Cross-Sectional Pilot Study.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78357},
pmid = {42747246},
issn = {1531-8249},
abstract = {OBJECTIVE: Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease (AD), with significant pathological overlap between the two conditions. However, the impact of Alzheimer's co-pathology on basal forebrain (BF) atrophy and its relationship with neurodegeneration and cognitive decline in patients with DLB remains underexplored.

METHODS: Forty patients with DLB and 14 healthy controls (HCs) were included from the Centre for Neurodegenerative Diseases, University of Bari. Participants underwent neuropsychological evaluations, 3T magnetic resonance imaging (MRI) scans, and Alzheimer's biomarkers assessment. Patients with DLB were grouped by AD co-pathology using in vivo biomarkers. BF and hippocampal volumes and mean cortical thickness values were analyzed using analysis of covariance (ANCOVA), adjusted for age, sex, and total intracranial volume. Mediation analyses were conducted to examine the indirect effects of Alzheimer's pathology and BF atrophy on neurodegeneration (hippocampal volume and cortical thickness) and cognitive function (Mini-Mental State Examination [MMSE]).

RESULTS: Patients with DLB exhibited significant BF atrophy compared with HCs (p < 0.001). AD co-pathology was associated with greater BF atrophy (p = 0.046) and reduced mean cortical thickness (p = 0.025). Significant correlations were found between BF volume and the pTAU181/Aβ1-42 ratio (p = 0.009) and between BF volume and MMSE scores (p = 0.016). Mediation analysis revealed that BF atrophy mediated the relationship between the pTau/Aβ42 ratio and neurodegeneration, and that the BF has a direct association with cognitive impairment.

INTERPRETATION: AD co-pathology in DLB exacerbates BF atrophy, correlating with cognitive decline. These results emphasize the need to consider AD co-pathology in evaluating neurodegeneration in DLB, suggesting future studies should explore targeted interventions to address this pathological overlap. ANN NEUROL 2026.},
}

@article {pmid42747250,
year = {2026},
author = {Thilagavathy, R and Pandiselvam, R and Govindarajan, N},
title = {Immunosenescence and immune-organ axis dysfunction: Potential of algal bioactives and nutritional interventions for healthy ageing.},
journal = {International reviews of immunology},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/08830185.2026.2729156},
pmid = {42747250},
issn = {1563-5244},
abstract = {Aging-associated immunosenescence disrupts various immune pathways-signaling, cellular, metabolic, epigenetic, and inflammatory mechanisms-leading to impaired bidirectional interactions between the immune system and organs. This dysfunction exacerbates geriatric conditions, including neurodegenerative disorders, chronic inflammation, and metabolic syndromes. This review introduces the concept of the immune-organ axis, an underexplored framework connecting immune dysregulation to organ-specific dysfunction. Nutritional interventions, including bioactive compounds, essential nutrients, functional foods, and phytochemicals, are highlighted for their ability to modulate these pathways by inducing autophagy, resolving inflammation, and promoting cellular repair. Furthermore, stabilization and delivery systems are proposed as technological solutions to enhance the efficacy of these interventions. This review emphasizes the need for integrative approaches to mitigate immune dysfunction and improve health outcomes in aging populations, while outlining future research directions to advance this field.},
}

@article {pmid42747944,
year = {2026},
author = {Burton, E and Barry, V and Parkin, B and Hersh, D},
title = {One of the Many Things That I've Learned on This Journey…: A Co-operative, Narrative Inquiry With Two Care Partners of Spouses With Young Onset Dementia.},
journal = {Health expectations : an international journal of public participation in health care and health policy},
volume = {29},
number = {5},
pages = {e70827},
pmid = {42747944},
issn = {1369-7625},
support = {WANMAEL2024-25/1//Western Australian Future Health Research and Innovation Fund/ ; },
mesh = {Humans ; *Dementia/psychology/diagnosis ; *Spouses/psychology ; *Caregivers/psychology ; Narration ; Male ; Age of Onset ; Female ; Middle Aged ; },
abstract = {INTRODUCTION: Young-onset dementia (YOD) is a term used when people demonstrate symptoms or are diagnosed with dementia before 65 years of age. YOD can be challenging to diagnose because health practitioners often do not initially consider dementia as the cause of someone's change in health or function in their 40 s, 50 s or even early 60 s. This can be the start of a complex journey for both the person living with YOD and their care partner. The aim of this study was to explore the journey for two care partners whose spouses were diagnosed with YOD.

METHODS: Co-operative, narrative inquiry, which is a collaborative, participatory research approach was used. This enabled in-depth reporting of the experiences of the two care partners, who were also research partners and authors on this project.

RESULTS: The story is told through a timeline lens where both care partners' narratives described their journeys prior to diagnosis, diagnosis, life after diagnosis through to transitioning to a care home. Both care partners experienced long periods of uncertainty as initial changes became evident, followed by frustration with health professionals leading to delays in onward referral and diagnosis. Both found the change of role to be confronting and their care for their spouse with YOD to significantly impact on their finances, work, social lives and wellbeing. Both worked hard to maintain their spouses' dignity and quality of life. They became innovative problem-solvers and strong advocates. Both continue in advocacy roles at the local, state and national levels.

CONCLUSION: Giving space to reflect on the stories of family care partners of people living with YOD is helpful in sensitising health professionals to the needs of their clients over time and highlighting the integral role of families in managing the condition.

Two lived-experience contributors, both care partners of people living (or having lived) with young onset dementia, were involved as research partners throughout the project. They reviewed and edited the ethics application (including project proposal) to ensure the proposed research and participant materials were acceptable and understandable to care partners. They each participated in an individual interview (after providing written consent as required by the local Human Research Ethics Committee), shared their lived experience to help interpret and contextualise the findings, and provided detailed feedback on drafts of the manuscript. They also contributed additional information to strengthen the implications for practice and have been included as named authors on the paper in recognition of their substantial contribution and partnership in the project.},
}

Humans
*Dementia/psychology/diagnosis
*Spouses/psychology
*Caregivers/psychology
Narration
Male
Age of Onset
Female
Middle Aged

@article {pmid42748320,
year = {2026},
author = {Izhytska, N and Sobczyk, KA and Ogrodnik, KW and Mazurkiewicz, M and Malentowicz, D and Szafraniec, NJ and Brożyna, D and Sałapski, B and Pastuszka, M},
title = {Emerging therapeutic targets beyond amyloid and tau in Alzheimer's Disease: Implications for lifestyle, metabolism and preventive medicine.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {7},
pages = {1685-1691},
doi = {10.36740/WLek/226612},
pmid = {42748320},
issn = {0043-5147},
mesh = {Humans ; *Alzheimer Disease/metabolism/prevention & control/therapy ; *tau Proteins/metabolism ; *Life Style ; *Amyloid beta-Peptides/metabolism ; Mitochondria/metabolism ; Preventive Medicine ; Microglia/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and remains a major global health challenge. Although current disease-modifying therapies primarily target amyloid-β and tau pathology, their clinical efficacy is limited. Increasing evidence indicates that AD is a multifactorial disorder involving neuroinflammation, mitochondrial dysfunction, impaired autophagy-lysosomal pathways, and dysregulated lipid metabolism. These interconnected mechanisms contribute to disease progression and represent promising therapeutic targets. This narrative review summarizes current evidence on emerging treatment strategies beyond the classical amyloid and tau paradigm, with particular emphasis on microglial activation, mitochondrial function, autophagy, and lipid homeostasis. Additionally, the translational potential of lifestyle-based interventions, including physical activity and metabolic regulation, is discussed. A broader understanding of AD pathogenesis may support the development of integrated therapeutic approaches combining pharmacological and non-pharmacological strategies to improve clinical outcomes.},
}

Humans
*Alzheimer Disease/metabolism/prevention & control/therapy
*tau Proteins/metabolism
*Life Style
*Amyloid beta-Peptides/metabolism
Mitochondria/metabolism
Preventive Medicine
Microglia/metabolism

@article {pmid42748401,
year = {2026},
author = {Tharwat, T and El-Nassan, HB and Adly, ME and Kamel, MM},
title = {Unlocking the Potential of Isatin Scaffolds in Acetylcholinesterase Inhibition.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {9},
pages = {e70336},
pmid = {42748401},
issn = {1521-4184},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; Humans ; *Isatin/pharmacology/chemistry/chemical synthesis ; *Acetylcholinesterase/metabolism ; Animals ; Structure-Activity Relationship ; *Alzheimer Disease/drug therapy/enzymology ; Molecular Structure ; Myasthenia Gravis/drug therapy/enzymology ; },
abstract = {The therapeutic significance of acetylcholinesterase (AChE) inhibition is most prominently observed in the management of various neurodegenerative and neuromuscular disorders, including Alzheimer's disease (AD), and myasthenia gravis (MG). The present review examines isatin-based compounds as a promising class of drugs for treating these conditions, focusing on their ability to inhibit AChE. While AD is characterized by a significant loss of cholinergic neurons leading to a deficiency in acetylcholine (ACh), MG is an autoimmune disease where the body produces antibodies that block or destroy ACh receptors at the neuromuscular junction. By inhibiting AChE, therapeutic agents increase the availability of ACh, thereby enhancing cholinergic neurotransmission and improving muscle strength or cognitive function. The underlying issue in MG is the reduced number of functional receptors rather than a primary decrease in AChE production. However, inhibition of the enzyme remains a vital strategy for symptom management. Accordingly, this review provides a systematic overview of the various synthetic strategies reported in the literature over the last decade for enhancing isatin-based AChE inhibitory activity. These strategies include modifications of the isatin nitrogen, such as N-alkylation, N-acylation, or N-arylation. Another strategy is aromatic ring substitution, where various substituents (e.g., halogens, nitro, amino, and alkyl groups) are introduced typically at the C5, C6, and/or C7 positions. C3-carbonyl functionalization is also reported, exemplified by the formation of Schiff bases, hydrazones, or spirocyclic derivatives. Our findings highlight the exceptional potential and adaptability of isatin derivatives in medicinal chemistry, highlighting the major advances within the last 10 years and the future directions.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
Humans
*Isatin/pharmacology/chemistry/chemical synthesis
*Acetylcholinesterase/metabolism
Animals
Structure-Activity Relationship
*Alzheimer Disease/drug therapy/enzymology
Molecular Structure
Myasthenia Gravis/drug therapy/enzymology

@article {pmid42748403,
year = {2026},
author = {Jeon, B and Noh, CH and Noh, SR and Shim, Y and Cho, SB and Cho, S},
title = {Scenario-Based Serious Game for Screening Mild Cognitive Impairment in Older Adults: Cross-Sectional Preliminary Validation Study.},
journal = {JMIR serious games},
volume = {14},
number = {},
pages = {e92334},
pmid = {42748403},
issn = {2291-9279},
abstract = {BACKGROUND: Many existing digital cognitive assessments rely on isolated or abstract tasks, and primarily use accuracy-based outcome measures, despite recent advances in the field. Few have been culturally adapted to reflect the familiar daily-life experiences of Korean older adults. Integrating culturally meaningful scenarios with task-specific accuracy and reaction time (RT) measures may provide a more ecologically grounded approach to mild cognitive impairment (MCI) screening.

OBJECTIVE: This study aimed to develop and preliminarily evaluate a tablet-based, scenario-based serious game for community-based MCI screening among Korean older adults.

METHODS: In this cross-sectional diagnostic accuracy study, community-dwelling adults aged 60-84 years were recruited through convenience sampling from a senior welfare center in Daejeon, South Korea, between July 2024 and June 2025. Of 87 participants who underwent eligibility assessment, 67 participants were included in the analysis: 47 cognitively normal participants, and 20 participants with MCI. Clinical classification was determined according to Petersen criteria based on the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease battery, second edition, structured clinical interviews, and clinician judgment blinded to the serious game results. The serious game initially comprised 5 culturally familiar and ecologically grounded daily-life tasks, from which task-specific accuracy and RT features were extracted. A reduced 4-task model informed by exploratory misclassification analysis served as the primary classification model and was evaluated using random forest classification with out-of-bag validation. A full 5-task model and a demographic-adjusted model were also evaluated. Convergent validity and perceived workload were assessed.

RESULTS: The group with MCI was older (77.3 vs 74.5 y; P=.002) and had fewer years of education (9.4 vs 11.2 y; P=.04). The primary 4-task model achieved an overall accuracy of 82.1% (55/67), balanced accuracy of 80.1%, sensitivity of 75% (15/20), specificity of 85.1% (40/47), and an area under the receiver operating characteristic curve of 0.787 (95% CI 0.643-0.932). The demographic-adjusted model showed broadly comparable discrimination (area under the receiver operating characteristic curve 0.794, 95% CI 0.654-0.934). Accuracy and RT measures from the sale items task ranked among the most important predictors. Digital composite scores were significantly correlated with the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease battery, second edition total score (r=.655 and r=.447; both P<.001). Perceived workload did not significantly differ between groups (P=.97).

CONCLUSIONS: This study provides preliminary evidence for the diagnostic utility and feasibility of a tablet-based serious game integrating culturally familiar daily-life scenarios with task-specific accuracy and RT measures, thereby capturing both performance accuracy and potential differences in processing efficiency. The automated format may offer a scalable and accessible screening option for community settings without specialized equipment. Independent, multisite, and longitudinal validation is required to establish its generalizability and predictive utility.},
}

@article {pmid42748589,
year = {2026},
author = {Buron, B and Killian, T and Wayland, C},
title = {Biologic personhood in advanced dementia: An integrative review to guide ethical and evidence-based care in long-term care settings.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {74},
number = {Pt A},
pages = {104305},
doi = {10.1016/j.gerinurse.2026.104305},
pmid = {42748589},
issn = {1528-3984},
abstract = {This integrative review synthesizes evidence on biologic care interventions for individuals with advanced dementia in long-term care settings. Biologic personhood, as defined by Buron[1], affirms that individuals remain sentient and emotionally expressive even when words and memory are lost, making this dimension of care essential as cognitive and communicative abilities decline. Guided by Whittemore and Knafl's[2] integrative review methodology, this study synthesized 28 peer-reviewed studies published between 2010 and 2025 examining biologic care interventions. Interventions were categorized into five domains: comfort and symptom relief, functional and sensory support, restorative rhythms of daily life, communication and attunement, and environmental safety and autonomy. Across studies, biologic interventions reduce distress, improve comfort, and affirm personhood through relational presence and attuned response. Several studies reframed behaviors often labeled as disruptive into signals of unmet needs requiring understanding rather than control. Despite its clinical and ethical importance, biologic personhood remains systemically underrepresented in person-centered care frameworks that typically emphasize autonomy or memory-based identity. This manuscript, the first in a three-part series, argues that biologic care is foundational to sustaining dignity and comfort when the narrative self is inaccessible. By grounding care in presence, sensation, and attuned nonverbal connection, clinicians uphold human dignity and demonstrate that personhood endures even when language and memory do not.},
}

@article {pmid42748650,
year = {2026},
author = {Nolt, GL and MacLean, SM and Golden, LR and Thorpe, SP and Stephens, IO and Funnell, JL and Brock, CR and Lucido, CC and Smith, L and Hernandez, G and Arbones-Mainar, JM and Wood, C and Morganti, JM and Johnson, LA},
title = {Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement.},
journal = {Neurobiology of aging},
volume = {169},
number = {},
pages = {13-26},
doi = {10.1016/j.neurobiolaging.2026.08.005},
pmid = {42748650},
issn = {1558-1497},
abstract = {Apolipoprotein E (APOE) genotype is the strongest genetic determinant of late-onset Alzheimer's disease (AD) risk. Of its three common isoforms, E4 increases AD risk and promotes inflammatory and metabolic dysregulation, whereas E2 is protective and is associated with altered lipid handling and immune function. Microglia express APOE in response to stress or injury and exhibit isoform-dependent transcriptional profiles, but the specific contribution of microglial APOE to these phenotypes remains unclear. Here, we used an inducible APOE "switch" model to selectively replace microglial E4 with E2 in older adult mice while maintaining E4 expression in other CNS and peripheral cells. Following a Western diet, microglial E2 replacement was associated with fewer phago-lysosomal microglia and decreased apoE localization within these phago-lysosomal microglia. Following a peripheral inflammatory stimulus (LPS), microglial E2 replacement was linked with increased expression of metabolic and immune-related pathways. Together, these findings indicate that microglial E2 expression is associated with selective cellular and transcriptional changes while E4 continues to be expressed by other cell types.},
}

@article {pmid42748655,
year = {2026},
author = {Shkirkova, K and Sta Maria, NS and Anson, H and Aghaei, Y and Badami, MM and Chakhoyan, A and Godoy-Lugo, JA and Chung, C and Durra, S and Tang-Tan, A and Zhao, L and Demetriou, A and Morales, M and Daggupati, S and Bent, I and Park, H and Franklin, C and Chen, S and Chahine, G and Dodds-Lewis, S and Morishita, M and Jacobs, RE and Gout, JF and Mack, WJ and Forman, HJ and Benayoun, BA and Vermulst, M and Cohen, MD and Campen, M and Sioutas, C and Mack, WJ and Finch, CE and Thorwald, MA},
title = {Induction of ferroptotic and amyloidogenic signatures linked to Alzheimer's disease by chemically distinct air pollutants.},
journal = {Redox biology},
volume = {97},
number = {},
pages = {104390},
doi = {10.1016/j.redox.2026.104390},
pmid = {42748655},
issn = {2213-2317},
abstract = {Air pollution (AirP) exposure is associated with increased risk of Alzheimer's disease (AD), yet AirP is chemically heterogeneous, complicating identification of shared pathogenic drivers. We compared acute cortical responses to two chemically distinct but metal-rich AirP sources, diesel exhaust particles (DEP) and World Trade Center (WTC) dust, and contrasted them with woodsmoke (WS), a particulate exposure containing substantially lower metal content. Despite major differences in particle composition and size, DEP and WTC elicited highly convergent transcriptomic responses, sharing more than 1200 differentially expressed genes associated with oxidative stress, interferon signaling, ferroptosis, neuronal remodeling, and amyloid processing. These transcriptional changes were accompanied by disrupted glutathione synthesis, altered ferritin-mediated iron storage and heme metabolism, and selective impairment of lipid raft antioxidant defenses, resulting in a 40% increase in lipid raft 4-hydroxynonenal (HNE) with WTC dust with DEP trending similarly, and at least a 65% reduction in phospholipid hydroperoxide detoxification capacity, and 36% increase in the aggregation-prone Aβ42 peptide for both pollution sources. Notably, both exposures produced acute white-matter abnormalities within the corpus callosum despite the absence of bulk brain iron accumulation, indicating that redistribution of bioactive iron rather than total iron burden may be sufficient to promote oxidative injury. In contrast, WS produced a distinct transcriptional profile, lacked coordinated ferroptotic priming, failed to induce lipid peroxidation or Aβ42 accumulation, and showed minimal effects on iron metabolism. Together, these findings identify metal-associated oxidative mechanisms as a convergent pathway linking chemically distinct forms of AirP to ferroptotic vulnerability, amyloidogenic processing, and AD-relevant pathology.},
}

@article {pmid42748769,
year = {2026},
author = {Kolobaric, A and Sinrich, JH and Schirda, C and Gujral, S and Butters, MA and Karim, HT and Andreescu, C},
title = {Hippocampal magnetic resonance spectroscopy markers in late life anxiety - a preliminary report.},
journal = {Psychiatry research. Neuroimaging},
volume = {364},
number = {},
pages = {112318},
doi = {10.1016/j.pscychresns.2026.112318},
pmid = {42748769},
issn = {1872-7506},
abstract = {Severe worry and anxiety in late life are linked to increased risk of Alzheimer's disease (AD), but underlying neural mechanisms remain unclear. Severe worry is associated with reduced hippocampal volume. One proposed mechanism is stress-related glutamate excitotoxicity, which may contribute to hippocampal atrophy and cognitive decline. This pilot study examined whether anxiety, worry, and cognitive function are associated with markers of glutamate excitotoxicity, specifically hippocampal glutamate and N-acetyl aspartate (NAA). Eighteen older adults with varying worry underwent 7T magnetic resonance spectroscopy of left and right hippocampus and clinical and cognitive assessments. Linear regression analyses examined associations between anxiety, cognitive performance, and hippocampal metabolites, controlling for volume. Exploratory analyses assessed additional metabolites, including creatine, gamma-aminobutyric acid (GABA), glutathione, and myo-inositol. Greater worry severity and lower overall cognitive function were associated with reduced hippocampal NAA levels. Higher global anxiety was associated with lower hippocampal glutamate. Exploratory analyses revealed additional relationships between other metabolites and both mood symptoms and cognition. These preliminary findings suggest hippocampal metabolic markers may play a role in late-life anxiety and worry. However, results provide only partial support for glutamate excitotoxicity as a mechanism linking anxiety to cognitive impairment, highlighting the need for larger studies.},
}

@article {pmid42748981,
year = {2026},
author = {Zhang, C and Yang, Z},
title = {The Double-Edged Sentinel: cGAS-STING as a Context-Dependent Regulator of Microglial Senescence and Neuronal Genotoxic Stress in Neurodegeneration.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112118},
doi = {10.1016/j.brainresbull.2026.112118},
pmid = {42748981},
issn = {1873-2747},
abstract = {BACKGROUND: Neurodegenerative diseases may continue to progress even when a pathogenic protein aggregate is reduced, suggesting that downstream inflammatory and genotoxic circuits can become partly autonomous. This narrative review examines cGAS-STING as a context-dependent regulator of DNA-stress responses in the ageing and proteinopathic brain.

METHODS: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for mechanistic, translational, and human-tissue studies of cGAS-STING, DNA damage, mitochondrial quality control, neuroinflammation, and major neurodegenerative diseases. Evidence was separated into biochemical or cellular, animal, and human observations, and contradictory findings were retained.

RESULTS: Mitochondrial DNA leakage is a recurrent candidate trigger, while activity-induced nuclear DNA breaks, defective repair, retrotransposon-derived cDNA, and micronuclear rupture provide conditional inputs. Microglial evidence is currently more extensive and causally developed than neuron-specific evidence; neuronal STING is most firmly supported in selected contexts such as excitotoxic or ischemic stress. Across Alzheimer disease, Parkinson disease, ALS/FTD, multiple sclerosis, and Huntington disease, cGAS-STING-associated inflammation is plausible but not uniform, and human validation remains limited. Therapeutic strategies therefore require cell-, source-, and stage-aware modulation rather than indiscriminate pathway ablation.

CONCLUSION: cGAS-STING is best regarded as a testable kinetic-bottleneck model, not a universal driver of neurodegeneration. Longitudinal human studies and cell-resolved biomarkers are needed to determine when recalibration can suppress pathological inflammation while preserving antiviral and homeostatic functions.},
}

@article {pmid42749078,
year = {2026},
author = {Wu, B and Jiang, Z and Lv, J and Zou, L},
title = {Adaptive hypergraph learning reveals high-order functional network alterations in mild cognitive impairment.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.09.015},
pmid = {42749078},
issn = {1873-7544},
abstract = {Mild cognitive impairment (MCI) is an important prodromal stage of Alzheimer's disease, and its early identification is critical for risk assessment and timely intervention. Resting-state functional magnetic resonance imaging (rs-fMRI) can noninvasively characterize brain functional activity and connectivity. However, most existing methods rely on static second-order functional connectivity, limiting their ability to capture dynamic coordination and high-order interactions among multiple brain regions. To address these limitations, we propose a brain functional network analysis framework integrating multi-scale temporal feature fusion with adaptive high-order hypergraph convolution. Specifically, the multi-scale temporal fusion module captures functional dynamics at different temporal resolutions, while the adaptive hypergraph convolutional network learns high-order associations among brain regions in an end-to-end manner. Spatiotemporal feature encoding is further incorporated to facilitate automatic MCI identification. The proposed framework was evaluated using rs-fMRI data from the ADNI dataset, with regional BOLD time series extracted based on the AAL atlas. Under five-fold cross-validation, the proposed method achieved an accuracy of 82.66%, a sensitivity of 82.07%, and a specificity of 83.07% on ADNI-2, while maintaining an accuracy of 81.50% on ADNI-3, outperforming existing methods on both datasets. Further analysis identified abnormal high-order coordination patterns involving the default mode network, limbic system, and hippocampus-related memory circuits in patients with MCI. These findings provide methodological support for the early identification of MCI and the discovery of potential neuroimaging biomarkers.},
}

@article {pmid42749181,
year = {2026},
author = {Zhu, H and Wang, X and Shao, J},
title = {Unlocking the role of fungal peptide cytotoxin candidalysin in candidiasis and non-candidiasis diseases.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.09.004},
pmid = {42749181},
issn = {1638-6183},
abstract = {Candida albicans is a commonly encountered opportunistic fungus that can cause both superficial discomforts and life-threatening invasive fungal infections. Ever-increasing reports have shown that C. albicans is also readily implicated in a set of metabolic and autoimmune diseases. Yeast-to-hypha transition is a hallmark of increased virulence and invasion of C. albicans, and candidalysin is the first peptide toxin secreted by C. albicans hyphae. Candidalysin contributes to fungal penetration across epithelial barrier via cytolytic activity, as well as the maintenance of commensalism and pathogenicity of Candida albicans. To specifically depict the role of candidalysin in multiple candidiasis and C. albicans associated infections, in this review, we focus on the recent advancements of candidalysin in oropharyngeal candidiasis (OPC), vulvovaginal candidiasis (VVC), disseminated candidaemia and sepsis. Meanwhile, we also pay close attention to the potential pathogenic mechanism of candidalysin in several C. albicans associated diseases including inflammatory bowel disease (IBD), asthma, Alzheimer's disease (AD) and alcohol-associated liver diseases (ALD). Based on these achievements, we propose a list of unresolved questions of interest for future investigation on biological functions and therapeutic potential of candidalysin in fungal infections caused by C. albicans. Unlocking the mode of action of candidalysin is beneficial for deep understanding of how C. albicans breaks through mucosal or blood brain barrier to colonize the niche via candidalysin and for rational design of fungal vaccine against candidalysin for clinical applications. Q1: Revision based on the comment 1 by Reviewer 1.},
}

@article {pmid42749199,
year = {2026},
author = {Radeen, KR and Hao, C and Wei, Z and Fan, X},
title = {β-Amyloid and Glutathione Dysregulation Cooperatively Drive Lipid Peroxidation and Ferroptosis in Neuron-Like Cells.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.09.008},
pmid = {42749199},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and oxidative stress, with aging being its greatest risk factor. Age-related glutathione (GSH) depletion may increase neuronal vulnerability to Aβ toxicity, but the underlying mechanisms remain unclear. Here, we investigated how impaired GSH homeostasis influences Aβ-associated neuronal injury. Human SH-SY5Y cells expressing either wild-type APP695 or the familial AD-associated APPSwe/Ind mutant were subjected to GSH depletion using complementary pharmacological (buthionine sulfoximine and dimethyl fumarate) and genetic (GCLC knockout) approaches. GSH depletion markedly sensitized APPSwe/Ind-expressing cells to ferroptotic cell death, characterized by increased lipid peroxidation, elevated malondialdehyde and 4-hydroxynonenal levels, enhanced lactate dehydrogenase release, increased transferrin receptor-1 expression, and intracellular iron accumulation. Cell death was prevented by ferrostatin-1, liproxstatin-1, and the iron chelator deferoxamine, but not by the pan-caspase inhibitor Z-VAD-FMK, confirming an iron-dependent ferroptotic mechanism. Similar findings were observed following co-treatment with Aβ oligomers and GSH depletion. Mechanistically, combined Aβ stress and GSH depletion were associated with increased chaperone-mediated autophagy (CMA) activity and reduced GPX4 protein levels. A photoactivatable CMA reporter demonstrated enhanced CMA activity and increased colocalization of GPX4 with CMA-associated puncta. Pharmacological inhibition of lysosomal function with bafilomycin A1 or treatment with the CMA inhibitor polyphyllin D rescued cell viability under these conditions. Collectively, these findings suggest a potential association among CMA activation, reduced GPX4 abundance, and increased susceptibility to ferroptotic cell death, providing new insight into how age-related redox imbalance may contribute to neuronal vulnerability in AD.},
}

@article {pmid42749235,
year = {2026},
author = {Knezovic, A and Krsnik, A and Homolak, J and Babic Perhoc, A and Deskin, A and Virag, D and Salkovic-Petrisic, M and Osmanovic Barilar, J},
title = {From systems to cells: Metabolic mechanisms underlying risk divergence in Alzheimer's disease and amyotrophic lateral sclerosis.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {106982},
doi = {10.1016/j.neubiorev.2026.106982},
pmid = {42749235},
issn = {1873-7528},
abstract = {Epidemiological studies show an inverse relationship between metabolic disorders and two major neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Obesity, type 2 diabetes (T2DM), and reduced physical activity increase AD risk, whereas in ALS cardiometabolic factors, particularly T2DM, show inverse, age-dependent associations with disease risk. This review integrates epidemiological, clinical, and experimental evidence to suggest that cell-type-specific energy metabolism underlies these contrasting risk profiles. Neurons and skeletal muscle differ in metabolic organization, substrate use, and redox capacity. Neurons rely mainly on glucose and lactate and have limited fatty acid oxidation, making them vulnerable to lipid overload, insulin resistance, and oxidative stress, hallmarks of AD. In contrast, skeletal muscle is metabolically flexible, efficiently oxidizes fatty acids, and has strong antioxidant defenses, which may protect against ALS. These cell-type-specific metabolic profiles are proposed to causally shape disease susceptibility: neuronal lipid overload and impaired redox homeostasis promote amyloid and tau pathology in AD, whereas preserved muscle fatty acid oxidation and antioxidant capacity support neuromuscular junction stability and delay motor neuron degeneration in ALS. Hypermetabolism, hypothalamic dysfunction, glial-neuronal coupling and lactate shuttling may further shape disease susceptibility. Overall, these patterns likely reflect distinct cellular responses to metabolic stress.},
}

@article {pmid42749285,
year = {2026},
author = {De Strooper, B and Karran, E},
title = {Inflection points and transitions in Alzheimer's disease.},
journal = {Nature},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41586-026-11110-5},
pmid = {42749285},
issn = {1476-4687},
abstract = {Alzheimer's disease is widely depicted as a linear cascade from amyloid-β accumulation to Tau pathology and neurodegeneration. We propose instead that the disease unfolds through discrete molecular, cellular and network phases organized around biological inflection points. At these thresholds, stress-driven loss of homeostasis produces qualitative shifts in cellular behavior that alters disease progression. These altered states spread across local tissue-domains, accumulate as a mosaic across the brain, and progressively engage vulnerable centres of information processing that control cognitive performance. The induction of amyloid-associated Tau phosphorylation marks a pivotal inflection point, separating amyloid-dominated tissue states from domains in which neuronal Tau stress responses have emerged. This framework helps reconcile the dissociation between pathology and symptoms, clarifies the shared architecture of familial and sporadic disease and reframes Alzheimer's disease as a disorder shaped by biological thresholds, timing, and progressive erosion of homeostatic resilience.},
}

@article {pmid42749375,
year = {2026},
author = {Wang, Y and Qin, Q and Yang, K and Yu, M and Yao, Y and Gong, C and Guo, J and Yang, L and Tang, Y},
title = {Alzheimer's disease burden in China (ABC) study: protocol for a nationwide multicentre cross-sectional and prospective cohort study.},
journal = {BMJ open},
volume = {16},
number = {9},
pages = {e122035},
pmid = {42749375},
issn = {2044-6055},
mesh = {Humans ; *Alzheimer Disease/economics/epidemiology ; China/epidemiology ; *Cost of Illness ; Prospective Studies ; Cross-Sectional Studies ; *Quality of Life ; *Caregivers/economics/psychology ; Health Care Costs ; Research Design ; Female ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is imposing an increasing public health and socioeconomic burden. In China, rapid population ageing is sharply increasing disease burden. Previous studies have shown that AD-related costs are mainly driven by long-term informal care. However, evidence in China remains limited by an incomplete cost framework and insufficient consideration of caregivers' burden and indirect costs. Notably, the National Dementia Action Plan (2024-2030), issued by the Chinese government, marks a major shift to early detection and comprehensive care of AD, highlighting the urgent need for nationally representative economic evidence to support policy implementation. This study aims to evaluate the economic burden and quality of life of patients with AD and their caregivers in mainland China, and is the first nationwide study to include individuals with amnestic mild cognitive impairment, providing foundational data for future health technology assessment of early AD interventions.

METHODS AND ANALYSIS: Baseline characteristics will be presented and compared using t-tests or χ[2] tests. Economic burden will be estimated by calculating the per capita cost and weighted national total based on provincial numbers of patients with AD. Indirect costs will be assessed using locally adapted replacement cost approach and forgone wages approach. The analysis will be stratified by disease severity and age. Future burden will be projected by linking data from China Statistical Yearbook 2025 and the UN World Population Prospects 2024. Unmet care needs, AD-related catastrophic health expenditure and AD dependency ratio (ADDR) will also be assessed.

ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of Xuanwu Hospital, Capital Medical University (No. 2023132). The study has been registered at ClinicalTrials.gov (NCT05995418) and the Chinese Clinical Trial Registry (ChiCTR2300074723). The results from this study will be actively disseminated through research articles and conference presentations.

TRIAL REGISTRATION NUMBERS: NCT05995418; ChiCTR2300074723.},
}

Humans
*Alzheimer Disease/economics/epidemiology
China/epidemiology
*Cost of Illness
Prospective Studies
Cross-Sectional Studies
*Quality of Life
*Caregivers/economics/psychology
Health Care Costs
Research Design
Female

@article {pmid42749382,
year = {2026},
author = {Conley, KB and Brown, KC and Christian, JC and Modi, KJ and Bender, CR and McGuffey, SE and Akter, S and Miles, SL and Gress, TW and Wolfer, RS and Antoniano, BD and Cummings, GH and Denning, KL and Valentovic, MA and Dasgupta, P},
title = {Memantine and its analogs: Potential applications in cancer therapy.},
journal = {Advances in cancer research},
volume = {172},
number = {},
pages = {1-74},
doi = {10.1016/bs.acr.2026.07.001},
pmid = {42749382},
issn = {2162-5557},
mesh = {Humans ; *Memantine/analogs & derivatives/therapeutic use/pharmacology ; *Neoplasms/drug therapy/pathology ; Animals ; *Antineoplastic Agents/therapeutic use ; *Drug Repositioning ; },
abstract = {Drug repurposing refers to the process of using an existing drug or drug candidate for a new treatment or medical condition for which it was not indicated before. The process of "drug repurposing" usually involves an FDA-approved entity which has undergone clinical development and have a with well-established safety and toxicity profile in patients. Several convergent studies show that repurposed drugs may present a promising strategy for the management and therapy of several human cancers. Memantine is used to combat dementia in moderate-to-severe Alzheimer's disease (AD) patients. Several convergent studies show that memantine (and its analogs) may have applications in multiple disease conditions associated with human cancers. Memantine and its related compounds have shown promise as neuroprotective agents, anti-fatigue agents and pain-relieving agents to alleviate the toxic side effects of radiation therapy and chemotherapy. Recent publications have revealed that memantine displays anti-cancer activity by exerting direct growth-suppressive activity on the primary tumor as modulating the genomic/cellular landscape of the tumor microenvironment. Currently, clinical trials are in progress, which aim to evaluate the potential applications of memantine in cancer treatment. The adamantane scaffold in memantine has proved to be a versatile tool for the discovery of synthetic memantine analogs with robust anti-cancer activity. The discovery of second-generation memantine analogs may have wider applications in combating cancer recurrence and addressing clinical challenges in the treatment of drug-resistant and metastatic cancers.},
}

Humans
*Memantine/analogs & derivatives/therapeutic use/pharmacology
*Neoplasms/drug therapy/pathology
Animals
*Antineoplastic Agents/therapeutic use
*Drug Repositioning

@article {pmid42749410,
year = {2026},
author = {Hossain, MM and Shammi, SS and Sarwar, G and Ahmed, S and Fardous, J and Morshed, MM and Sarker, MA and Asaduzzaman, M},
title = {Computational identification of Ginkgo biloba phytochemicals as dual inhibitors of herpes simplex virus type 1 glycoproteins gB and gD targeting its entry and Alzheimer's disease pathogenesis.},
journal = {Journal, genetic engineering & biotechnology},
volume = {24},
number = {3},
pages = {100728},
doi = {10.1016/j.jgeb.2026.100728},
pmid = {42749410},
issn = {2090-5920},
abstract = {Herpes simplex virus type 1 (HSV-1) causes severe neurological complications such as herpes simplex encephalitis and Alzheimer's disease (AD). Its entry is mediated by glycoproteins gD and gB, which regulate receptor binding and membrane fusion. Targeting these entry glycoproteins represents a promising therapeutic strategy to limit HSV-1 infection and its contribution to AD pathogenesis. Therefore, this study aimed to identify natural dual inhibitors of HSV-1 glycoproteins gB and gD from Ginkgo biloba using an integrated computational approach involving molecular docking, pharmacokinetic, toxicity, and bioactivity profiling, molecular dynamics simulations, and MM-GBSA binding free energy analyses to evaluate binding stability and therapeutic potential. A total of 39 phytochemicals were retrieved from IMPPAT 2.0 and PubChem databases and docked against HSV-1 glycoproteins gB and gD. Pharmacokinetics and toxicity were assessed using admetSAR 3.0, SwissADME, Deep-PK, and pKCSM. Molecular docking revealed several phytochemicals with strong binding affinities to HSV-1 glycoproteins gB and gD, compared to docosanol. Among these, β-sitosterol and ginkgolide A exhibited favorable drug-likeness, acceptable oral bioavailability, no mutagenic and hepatotoxic effects, and biologically active. Molecular dynamic simulation confirmed their greatest binding stability compared to docosanol. MM-GBSA binding free energy analysis further validated their strong and stable interactions within the active sites of HSV-1 glycoproteins gB and gD. These findings identify β-sitosterol and ginkgolide A as promising dual-target inhibitors of HSV-1 glycoproteins gB and gD in context of HSV-1-associated AD pathogenesis. However, experimental validation is required to confirm their antiviral efficacy and potential relevance to AD.},
}

@article {pmid42749454,
year = {2026},
author = {Amukti, DP and Kusumawardani, N and Pratami, RI and Purwanto, BD and Rukhama, RA and Akbar, I and Sarwadhamana, RJ and Aditya, RA and Yuliani, S},
title = {Genetic susceptibility of Alzheimer's disease associated with APOE polymorphism: systematic review and bibliometric study.},
journal = {Journal, genetic engineering & biotechnology},
volume = {24},
number = {3},
pages = {100785},
doi = {10.1016/j.jgeb.2026.100785},
pmid = {42749454},
issn = {2090-5920},
abstract = {INTRODUCTION: Alzheimer's disease is a progressive neurodegenerative disorder that is the leading cause of dementia worldwide. Genetic factors, particularly Apolipoprotein E (APOE) polymorphisms, are known to play a significant role in increasing susceptibility to Alzheimer's disease. The increasing number of publications related to APOE and Alzheimer's disease has prompted the need for bibliometric analysis and systematic reviews to comprehensively understand research developments and their genetic relationships. This study aims to analyze the global development of research on APOE polymorphisms in Alzheimer's disease through a bibliometric study and systematic review approach.

METHODS: The study used a combined bibliometric and systematic review design. Data were obtained from the Scopus database for the period 2000-2025 using keywords Title-Abs-Key (("APOE" Or "APOE E4" Or "Apolipoprotein E4") And ("Alzheimer's disease"And ("Genetic Susceptibility"Or"Risk Factor")) And (Limit-To (Doctype,"Ar")) And (Limit-To(Language,"English")) And Pubyear > 1999 And Pubyear < 2026. Bibliometric analysis was performed using VOSviewer and Microsoft Excel to evaluate publication trends, countries, institutions, journals, author collaborations, and co-occurrence keywords . A systematic review was conducted on 26 articles that met the inclusion criteria to evaluate the association of APOE polymorphisms with Alzheimer's risk.

RESULTS: A total of 3824 articles from 718 publication sources were identified with an average citation of 51.51 per document. The United States was the country with the highest publication contribution. Keyword co-occurrence analysis showed that APOE4, genetics, and biomarkers were the main research themes. The results of the systematic review showed that APOE polymorphisms, especially rs429358 and rs7412, had a significant association with an increased risk of Alzheimer's disease in various ethnic populations with a very low p-value of up to 1E-320.

CONCLUSION: APOE polymorphisms play an important role in the genetic susceptibility of Alzheimer's disease and have the potential to be key biomarkers in early detection and the development of precision medicine in neurodegenerative diseases.},
}

@article {pmid42749536,
year = {2026},
author = {Sun, Y and Cao, Y and Ma, J and Li, W and Li, H and Tan, Z},
title = {Neuropsychiatric symptoms as predictors of progression to Alzheimer's disease in mild cognitive impairment: A comparative meta-analysis of apathy, depression, and anxiety.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100275},
doi = {10.1016/j.inpsyc.2026.100275},
pmid = {42749536},
issn = {1741-203X},
abstract = {BACKGROUND: Identifying mild cognitive impairment (MCI) patients at high risk for Alzheimer's disease (AD) is a priority. The independent prognostic utility of neuropsychiatric symptoms (NPS) remains debated.

METHODS: We systematically searched longitudinal cohort studies that evaluated the predictive role of baseline apathy, depression, and anxiety for progression from MCI to clinical AD dementia. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using random-effects models with Hartung-Knapp adjustment.

RESULTS: Twenty-two studies (346,185 MCI patients) were included. Apathy demonstrated a statistically significant predictive association with progression (HR = 2.57, 95% CI: 1.58-4.17, p = 0.003). Depression was not significantly associated with progression overall (HR = 1.32, 95% CI: 0.69-2.50). In pre-specified subgroup analyses, a significant association was observed only among studies with follow-up ≥ 3 years (HR = 2.20, 95% CI: 1.08-4.46), although the test for subgroup differences did not reach conventional significance. Anxiety was not significantly associated with progression risk (HR = 1.27).

CONCLUSION: Apathy is a robust and consistent behavioral predictor of progression from MCI to clinical AD dementia. Depression may represent a potential long-term risk pattern, whereas anxiety requires further validation. Domain-specific neuropsychiatric assessment may improve future risk stratification.},
}

@article {pmid42749732,
year = {2026},
author = {Schwarck, S and Behrenbruch, N and Schumann-Werner, B and Molloy, EN and Garcia-Garcia, B and Hochkeppler, A and Fischer, L and Büchel, AT and Incesoy, EI and Bernal, J and Coello, RD and Valdés-Hernández, MDC and Wardlaw, JM and Vockert, N and Müller, P and Behnisch, G and Morgado, B and Esselmann, H and Seidenbecher, CI and Schott, BH and Barthel, H and Sabri, O and Wiltfang, J and Kreissl, MC and Düzel, E and Maass, A},
title = {Associations of physical fitness with brain structure, pathology and cognition in cognitively normal older adults.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42749732},
issn = {2731-6068},
support = {425899996//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 362321501//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; },
abstract = {The role of physical fitness in cognitive reserve and brain maintenance remains unclear. We investigated the associations of muscular and aerobic fitness (VO2max) with markers of brain health and cognition in 353 cognitively unimpaired older adults (mean age = 72.77 ± 7.95 years; 177 females). Muscular fitness comprised handgrip strength, appendicular skeletal muscle mass, and Timed-Up-and-Go performance. Blood biomarkers of Alzheimer's pathology (Aβ1-42/Aβ1-40, p-tau217, GFAP) and neuroplasticity (BDNF, VEGF, Cathepsin-B), gray matter (GM) volume and thickness, medial temporal lobe (MTL) tau burden ([[18]F]PI-2620 PET), white matter hyperintensities, and perivascular spaces (PVS) were assessed. Higher muscular capacity was associated with lower basal ganglia PVS volume, whereas aerobic fitness was related to greater MTL thickness and GM volume. Although fitness did not moderate pathology-cognition associations, VO2max explained additional variance in verbal memory beyond tau. These findings indicate distinct associations of fitness with brain health, while providing limited support for cognitive reserve. Trial Registration: The study was registered in the German Clinical Trials Register (DRKS00032449; date of registration: 2025-05-07; recruiting ongoing).},
}

@article {pmid42749735,
year = {2026},
author = {Cuní-López, C and Root, JT and Hao, Y and Blomberg, N and Koppes-den Hertog, SJ and Sacks, D and Trujillo, AE and Ghirlando, R and Kowal, I and Epstein, J and Yang, LG and Cookson, MR and Marsan, E and van der Kant, R and Giera, M and Qi, YA and Narayan, PS},
title = {APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42749735},
issn = {2041-1723},
support = {1ZIADK075158//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Astrocytes/metabolism ; *Lipid Droplets/metabolism ; *Proteome/metabolism/genetics ; Genotype ; Apolipoprotein E4/genetics/metabolism ; Alzheimer Disease/genetics/metabolism ; Autophagy ; Apolipoprotein E3/genetics/metabolism ; *Apolipoproteins E/genetics/metabolism ; Apolipoprotein E2/genetics/metabolism ; Oleic Acid/pharmacology ; Induced Pluripotent Stem Cells/cytology/metabolism ; Lipid Metabolism ; },
abstract = {Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer's disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer's disease and exists in common variants that confer decreased, neutral, or increased risk. Here we show that APOE genotype shapes the lipid droplet proteome, lipidome, and degradation dynamics in human induced pluripotent stem cell-derived astrocytes. By comparing oleic acid-treated astrocytes carrying APOE2, APOE3, or APOE4, we find that each variant is associated with distinct lipid droplet proteins and lipids. These molecular differences correspond to genotype-dependent changes in lipophagy, an autophagy-mediated pathway for lipid droplet clearance. Lipid droplets in APOE2 astrocytes undergo efficient autophagic turnover, whereas those in APOE4 astrocytes resist degradation. These findings identify impaired lipid droplet clearance as a potential mechanism linking APOE4 to Alzheimer's disease risk.},
}

Humans
*Astrocytes/metabolism
*Lipid Droplets/metabolism
*Proteome/metabolism/genetics
Genotype
Apolipoprotein E4/genetics/metabolism
Alzheimer Disease/genetics/metabolism
Autophagy
Apolipoprotein E3/genetics/metabolism
*Apolipoproteins E/genetics/metabolism
Apolipoprotein E2/genetics/metabolism
Oleic Acid/pharmacology
Induced Pluripotent Stem Cells/cytology/metabolism
Lipid Metabolism

@article {pmid42749769,
year = {2026},
author = {Naddaf, M},
title = {Map of brain 'microproteins' could offer new clues to Alzheimer's disease.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42749769},
issn = {1476-4687},
}

@article {pmid42749775,
year = {2026},
author = {Liu, J and Zhang, F and Zhong, T and Wang, J and Lei, H and Zhao, J and Lin, F and Fan, T and He, T and Xiong, R and Wang, X and Wei, L and Sun, F and Xiao, Y and Pi, G and Kang, D and Bian, Y and Li, H and Wang, Q and Ke, D and Wang, JZ and Yang, X and Wang, ZH and Yang, Y},
title = {Targeting C/EBPβ/ Calbindin 1 pathway bolsters the neural resilience to tau pathology and improves tau-impaired episodic memory.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42749775},
issn = {1476-5578},
support = {82371436//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82071219//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Intracellular accumulation of tau protein is a defining feature of Alzheimer's disease (AD) and is closely associated with episodic memory loss. In our previous report, we highlighted the high susceptibility of ventral hippocampal Calbindin1[-] neurons in the dorsal part of ventral hippocampal CA1 (dvCA1[Calb1-] neurons) to tau pathology in AD. However, it remains unclear whether and how dvCA1[Calb1+] neurons are also vulnerable during the chronic and progressive process of AD. In this study, we characterized dvCA1[Calb1+] neurons in terms of circuit connections and behavioral phenotypes under physiological conditions. Postmortem examination of AD patients' brains and P301L mice revealed a preferential reduction of Calb1 in the dvCA1, accompanied by heightened susceptibility of the dvCA1[Calb1+] neurons to phospho-tau mislocalization. Mechanistically, C/EBPβ was found to bind to the promoter regions of CALB1, resulting in the inhibition of CALB1 transcription. Knockdown of Calb1 accelerated, while overexpression of Calb1 impeded the AD-like tau pathology in dvCA1[Calb1+] neurons. As tau accumulated, dvCA1[Calb1+] neurons lost their firing patterns, leading to contextual social memory deficits. Ursolic acid, by promoting the degradation of C/EBPβ, modified the C/EBPβ-Calb1 pathway, ultimately enhancing the resilience of dvCA1[Calb1+] neurons against tau pathology and improving contextual social memory in AD. Our findings underscore the critical role of the C/EBPβ-Calb1 pathway in controlling the susceptibility of dvCA1[Calb1+] neurons to tau pathology. Furthermore, targeting the C/EBPβ-Calb1 pathway and UA administration could be promising strategies for treating AD in the future.},
}

@article {pmid42749851,
year = {2026},
author = {Garduño, BM and Melgarejo, T and Cogram, P and Holmes, TC and Xu, X},
title = {Unconventional animal models of Alzheimer's disease and aging: key insights from the UAMAA 2026 conference.},
journal = {Lab animal},
volume = {},
number = {},
pages = {},
pmid = {42749851},
issn = {1548-4475},
support = {R24AG073198//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; F31AG082485//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
}

@article {pmid42749890,
year = {2026},
author = {, and Song, Z and Feng, D and Rahman, NA and Duggan, MR and Tian, Q and Zeng, J and Zhou, X and Zou, C and Rafii, MS and Shen, L and Thompson, P and Simonsick, EM and Walker, KA and Zalesky, A and Davatzikos, C and Aisen, P and Ferrucci, L and Resnick, SM and Wen, J},
title = {Sex-specific biological aging clocks across organs and omics.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42749890},
issn = {1546-170X},
abstract = {Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.},
}

@article {pmid42749937,
year = {2026},
author = {Wang, M and Bi, S and Xue, H and Guan, L and Wang, Y and Zhang, X and Liu, X and Xu, X and Zhang, C and Qi, Z and Zhao, Z and Yan, S and Lu, J},
title = {Cerebellar cortical amyloid deposition biases [18]F-Florbetapir PET quantification with whole cerebellum as reference region.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42749937},
issn = {1619-7089},
support = {82394434//National Natural Science Foundation of China/ ; G202522130//Beijing High level Innovative and Entrepreneurial Youth Top notch Talent Program/ ; HZ2025PYDTR006//Xuanwu Hospital Talent Convergence Program/ ; },
abstract = {OBJECTIVE: To investigate whether cerebellar cortical amyloid-beta (Aβ) deposition biases [18]F-Florbetapir Aβ PET quantification when the whole cerebellum (WC) is used as the reference region, and to identify a stable reference region for quantification. Additionally, to establish an optimal diagnostic threshold for the detection of cerebellar cortical Aβ deposition.

METHODS: This retrospective cohort study enrolled 359 Aβ-positive participants including 52 with and 307 without cerebellar cortical Aβ deposition. All participants underwent [18]F-Florbetapir Aβ PET imaging, structural MRI, and cerebrospinal fluid biomarker analysis. Standardized uptake value ratio (SUVR) was derived from the standardized uptake value (SUV) by normalizing to WC, pons, and white matter (WM). Centiloid (CL) values were derived following standardized procedures. Bootstrap resampling was employed for group comparisons. Receiver operating characteristic (ROC) analysis was performed to determine the optimal SUVR threshold for identifying cerebellar cortical Aβ deposition, with validation conducted in an internal validation subset (n = 30). Two patients treated with lecanemab underwent longitudinal Aβ PET follow-up.

RESULTS: Individuals classified as cerebellar cortical Aβ-positive exhibited significantly lower CL values than Aβ‑negative individuals (bootstrap P < 0.001). The cerebellar cortical Aβ‑positive group showed elevated SUVWC (bootstrap P = 0.012) and reduced SUVcortex (bootstrap P = 0.008), whereas SUVpons showed no significant differences between groups (bootstrap P = 0.110). SUVWM exhibited a significant intergroup difference (bootstrap P < 0.001), while SUVRWM showed no significant between-group difference (bootstrap P = 0.288). An optimal cerebellar SUVRWM threshold of 0.428 yielded excellent diagnostic performance for identifying cerebellar cortical Aβ deposition, with an area under the curve (AUC) = 0.931, sensitivity 86.5%, specificity 86.3%. Substantial agreement between quantitative and visual assessment was confirmed in the validation subset (Cohen's kappa = 0.856). In the two cerebellar cortical Aβ-positive lecanemab-treated patients, CL values decreased over time, SUVRWM showed modest alterations, while cerebellar SUVRWM remained above the 0.428 threshold throughout follow-up.

CONCLUSION: Cerebellar cortical Aβ deposition raises WC reference signals and interferes with CL-based [18]F-Florbetapir Aβ PET quantification, which systematically underestimates true cerebral Aβ burden. The WM represents a robust reference region, and the cerebellar SUVRWM threshold of 0.428 is reliable and practical for identifying cerebellar cortical Aβ status.},
}

@article {pmid42749965,
year = {2026},
author = {Begum, MY and Rajkumar, M and Govindaraj, P and Velmani, S and Rajkumar, P and Sudha, PN and Alhamod, M and Alotaibi, H},
title = {Quercetin-Based Nanotherapeutics for Targeted Drug Delivery in Alzheimer's Disease: Comparative Insights into Molecular Mechanisms, Blood-Brain Barrier Targeting and Therapeutic Perspectives.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42749965},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Quercetin/administration & dosage/therapeutic use/chemistry ; *Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Drug Delivery Systems/methods ; *Nanoparticles/chemistry ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by interconnected pathological processes, including amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, cholinergic impairment, and chronic neuroinflammation. Quercetin, a naturally occurring flavonoid, exhibits pleiotropic neuroprotective activities by modulating oxidative stress, inflammatory signaling, pathological protein aggregation, mitochondrial function, and cholinergic pathways. However, poor aqueous solubility, rapid metabolism, limited systemic bioavailability, and restricted brain exposure constrain its therapeutic translation. Nanotechnology-based drug delivery approaches have therefore been explored to improve quercetin's physicochemical and pharmacokinetic properties and facilitate brain delivery. This review critically evaluates recent advances in quercetin-loaded polymeric nanoparticles, lipid-based nanocarriers, liposomes, inorganic systems, and biomimetic nanocarriers for AD. Particular emphasis is placed on the association between nanocarrier composition and drug-loading capacity, release behavior, stability, route of administration, and brain delivery. The review discusses BBB-targeting approaches, including receptor-mediated and adsorptive-mediated transport, alongside targeted drug-delivery strategies and the underlying molecular pathways, with particular attention to the distinction between evidence for BBB transport and actual brain exposure. The review further compares therapeutic outcomes across cellular, transgenic AD models, biodistribution, translational barriers, and regulatory considerations. Collectively, this review provides a mechanistic and comparative perspective on the potential and limitations of nanotechnology-enabled quercetin delivery and identifies priorities for developing clinically translatable nanotherapeutic strategies for AD.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Quercetin/administration & dosage/therapeutic use/chemistry
*Blood-Brain Barrier/metabolism/drug effects
Animals
*Drug Delivery Systems/methods
*Nanoparticles/chemistry

@article {pmid42749976,
year = {2026},
author = {Mathew, S and Seiden, D and Ingram, DK and Smith, WK},
title = {The TyrRS cascade: circadian gating of neuronal DNA repair and its collapse in aging.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42749976},
issn = {2509-2723},
abstract = {Age-related neurodegenerative diseases are characterized by progressive DNA damage in post-mitotic neurons against a backdrop of deteriorating circadian rhythms, yet the molecular link between these conjoined features of brain aging remains unclear. We propose the TyrRS cascade as that link: a signaling architecture in which the noncanonical nuclear functions of tyrosyl-tRNA synthetase (TyrRS/YARS1) schedule neuronal genome maintenance across the day through three coregulated streams, PARP1-mediated damage sensing, TRIM28/NuRD heterochromatin maintenance, and LIN9/DREAM control of a 67-gene repair archive. The model's central commitment is that the operative variable is oscillation amplitude rather than mean activity. We argue that as serum tyrosine rises with age and circadian amplitude flattens, these insults compound into a double-hit collapse that traps the cascade in a frozen-intermediate state, which bulk-tissue assays misread as elevated mean activity when the oscillation has merely lost its excursion. Placed in dialogue with oscillatory-clearance models of sleep, the cascade and the glymphatic system emerge as complementary, compartment-separated arms of a single sleep-dependent maintenance program that fail together through amplitude collapse, yielding a signature of preserved phase architecture with reduced dynamic range. Reframing neurodegeneration as a scheduling failure rather than a capacity failure carries three translational consequences: Pulsatile, phase-aligned dosing should outperform sustained-release pharmacology, which is predicted to flatten the rhythm it aims to restore; demonstrating target engagement will require phase-resolved rather than single-timepoint measurement; and because both arms fail together, combined restoration of intracellular repair and extracellular clearance should outperform single-arm intervention.},
}

@article {pmid42749977,
year = {2026},
author = {Krogstad, LS and Teppen, MA and Mjønes, HS and Brewer, JR and Park, T and Geiseler, S and Morland, C},
title = {Age-dependent changes in lipid droplet distribution and vascularization in naked mole rat vs. mouse hippocampus.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42749977},
issn = {2509-2723},
support = {2201647//National Science Foundation/ ; },
abstract = {The accumulation of lipid droplets in microglia has been reported to increase in response to ageing and age-related diseases like Alzheimer's disease. The present study investigates changes in lipid droplet dynamics with increasing age in the mouse and the similarly sized long-lived rodent, the naked mole rat (Heterocephalus glaber). We show that the naked mole rat contains large amounts of microglial lipid droplets in the CA1 and CA3 region of the hippocampus with an age-dependent increase in the CA3 region. Neuronal lipid droplet size is unaffected by age in the naked mole rat. The mouse hippocampus contains fewer microglial lipid droplets and shows no age-dependent change. However, neuronal lipid droplet size increases with age in the CA3 region in mice. These results could indicate two different ways of regulating lipid accumulation in the brain, where the naked mole rat shuttles their lipids from neurons to microglia to prevent neuronal lipotoxicity and neurodegeneration, while this does not seem to happen in mice. This shuttling of lipids between cells could be a protective mechanism contributing to the high resilience against diseases and damages to the brain seen in the naked mole rat. Additionally, we show that the brain of the naked mole rat has a lower vascularization than the mouse in the dentate hilus, stratum radiatum, and sensory/motor cortex. This could be coupled to the naked mole rats' low metabolism and conforms with its ability to live with low concentrations of oxygen without damage to the brain.},
}

@article {pmid42750145,
year = {2026},
author = {Ciaccio, M and Agnello, L},
title = {Alzheimer's Disease Beyond Amyloid: Lessons From Atherosclerosis.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70533},
pmid = {42750145},
issn = {2328-9503},
}

@article {pmid42750155,
year = {2026},
author = {Ekundayo, BE and Ekundayo, MC and Alonge, SA and Obafemi, BA and Obafemi, TO and Lebelo, SL and Ntwasa, MM},
title = {Neuroprotective Effect of Morin Against Chemical-Induced Neurotoxicities and Neurodegenerative Disease Models.},
journal = {The European journal of neuroscience},
volume = {64},
number = {6},
pages = {e70692},
doi = {10.1111/ejn.70692},
pmid = {42750155},
issn = {1460-9568},
mesh = {Animals ; Flavones ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Flavonoids/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/chemically induced/metabolism ; Humans ; *Neurotoxicity Syndromes/drug therapy ; },
abstract = {Morin (3,5,7,2',4'-pentahydroxyflavone) is a dietary flavonol with broad neuroprotective, anti-inflammatory, and antioxidant actions across central and peripheral nervous system models. This synthesis consolidates evidence from in vitro and rodent studies-covering neurodegenerative proteinopathies (Alzheimer's, Parkinson's, and Huntington's), neuropathic pain, epilepsy, stress- and schizophrenia-like phenotypes, and chemo-/toxicant-induced neurotoxicity-to evaluate morin's consistent benefits on survival, motor/cognitive performance, and biochemical normalization. Morin mitigated neurotoxicity induced by doxorubicin, ifosfamide, vincristine, acrylamide, heavy metals, and endocrine disruptors. Context-specific effects included modulation of disease-defining pathways (GSK3β/CDK5, mTORC1, PARP, and AMPK-ULK1-TFEB), microglial polarization, and normalization of neurotransmission (dopamine, GABA, 5-HT, and reduced AChE). Core mechanisms included the following: restoration of redox and mitochondrial homeostasis via Nrf2/HO-1 activation; replenishment of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH); decreased reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO); and preserved mitochondrial potential/fusion; suppression of innate immune and inflammasome signaling through downregulation of TLR4/NF-κB and ERK-p65, reduced TNF-α, IL-1β/IL-6, iNOS/COX-2; inhibition of NLRP3/caspase-1; and rebalancing of cell-death programs (↓Bax/caspase-3, ↑Bcl-2; attenuation of RIPK1/RIPK3/MLKL-mediated necroptosis). Formulation strategies (intranasal microemulsions, pluronic micelles, and more soluble derivatives) have enhanced brain exposure and efficacy, but translation now warrants optimized delivery, pharmacokinetic-pharmacodynamic mapping, target engagement biomarkers, and rigorously controlled trials to define dose, route, and indications as adjunctive to standard care in neurodegeneration, neuropathic pain, and toxicant-related brain injury. Collectively, morin emerges as a multitarget neuroprotective scaffold with reproducible functional and mechanistic benefits.},
}

Animals
Flavones
*Neuroprotective Agents/pharmacology/therapeutic use
*Flavonoids/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/chemically induced/metabolism
Humans
*Neurotoxicity Syndromes/drug therapy

@article {pmid42750195,
year = {2026},
author = {Pillai, JA and Alladi, S and Appleby, BS and Brosch, JR and Frederiksen, KS and Galasko, D and Lopez, OL and Leverenz, JB and Saykin, AJ and Schott, JM and Seshadri, S and Tousi, B and Wolk, DA},
title = {Operationalizing Alzheimer's disease trials in the era of targeted therapies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71829},
doi = {10.1002/alz.71829},
pmid = {42750195},
issn = {1552-5279},
support = {P30AG072979/AG/NIA NIH HHS/United States ; P30AG066468/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; P30AG72959/AG/NIA NIH HHS/United States ; P30AG062429/AG/NIA NIH HHS/United States ; P30AG066546/AG/NIA NIH HHS/United States ; U01NS100610/NS/NINDS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy/therapy ; Humans ; *Clinical Trials as Topic/methods ; *Antibodies, Monoclonal/therapeutic use ; Biomarkers ; Amyloid beta-Peptides ; },
abstract = {The therapeutic landscape of Alzheimer's disease (AD) is rapidly evolving with the clinical adoption of anti-amyloid monoclonal antibodies (mAbs) despite an incomplete understanding of disease mechanisms, progression, and heterogeneity. Designing both observational longitudinal cohorts and clinical trials with novel mAbs in mind is imperative. These studies should capture mAb type, dosing, duration, degree of amyloid clearance, and downstream effects on neurodegeneration to interpret outcomes. Observational cohorts can compare treated and untreated populations, track biomarker trajectories, assess co-pathologies, and evaluate social determinants of health. Future trials must address variability in treatment response, identify resistant subgroups, and include long-term follow-up to assess durability and post-treatment effects. Combination therapy trials should be stage specific, pairing novel agents with mAbs and incorporating broader stratification beyond traditional biomarkers to reflect clinical and pathological heterogeneity. Integrating biological and clinical outcomes, with digital biomarkers and responder-enrichment strategies will enable more precise, mechanism-driven, and individualized therapeutic approaches in AD.},
}

*Alzheimer Disease/drug therapy/therapy
Humans
*Clinical Trials as Topic/methods
*Antibodies, Monoclonal/therapeutic use
Biomarkers
Amyloid beta-Peptides

@article {pmid42750203,
year = {2026},
author = {Teunissen, CE and Pini, L and Imbimbo, BP},
title = {Rethinking tau-targeted therapy in Alzheimer's disease: Toward a dual biomarker strategy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71867},
doi = {10.1002/alz.71867},
pmid = {42750203},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/therapy ; *tau Proteins/metabolism ; Biomarkers/metabolism/cerebrospinal fluid ; Animals ; Positron-Emission Tomography ; },
abstract = {Tau pathology is more closely associated with cognitive deterioration than amyloid burden in symptomatic Alzheimer's disease (AD), yet tau-targeted trials have often interpreted decreases in soluble phosphorylated tau (p-tau) as evidence of therapeutic success. Emerging data argue for a more biology-informed framework. P-tau262 and p-tau356 identify sites within soluble pre-tangle tau assemblies, and cerebrospinal (CSF) p-tau262 may decline as neurofibrillary pathology advances. Conversely, marked p-tau217 lowering with posdinemab was not accompanied by clinical benefit. The amyloid field offers a useful but incomplete analogy. Amyloid plaques are extracellular whereas tau misfolding and fibrillization occur predominantly intracellularly, so equivalent relationships among imaging, fluid biomarkers, and clinical outcomes should not be assumed. A recent preprint describing a functional plasma assay of pathologically active tau reported high discrimination of tau positron emission tomography (PET) positivity, particularly at early tau PET stages, illustrating how seeding-related activity may add information beyond p-tau concentration. We propose a dual-domain framework in which tau-targeted therapies are evaluated using complementary measures of aggregated tau burden and biologically defined soluble tau states. P-tau262 is one candidate within the soluble domain, but treatment-induced increases should be considered favorable only when they accompany aggregate reduction and evidence of a less pathogenic soluble state. This framework applies across antibodies, antisense oligonucleotides, and other biologic tau-directed strategies. Future trials should test joint biomarker-clinical response functions rather than importing thresholds from anti-amyloid therapy, and should prespecify adequately powered analyses of sex, population background, disease stage, and other potential modifiers.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/therapy
*tau Proteins/metabolism
Biomarkers/metabolism/cerebrospinal fluid
Animals
Positron-Emission Tomography

@article {pmid42750204,
year = {2026},
author = {Böken, D and Lobo, PB and Wu, Y and Rowe, LA and Fertan, E and Croft, CL and Jimenez-Sanchez, M and Cox, D and Klenerman, D},
title = {Temporal Trajectories of the Tau Aggregate Interactome Reveal Stage-Specific Vulnerabilities in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77822},
doi = {10.1002/advs.77822},
pmid = {42750204},
issn = {2198-3844},
support = {//Royal Society funded Professorship/ ; DRI-PRO202332//UK Dementia Research Institute/ ; (Cox971-799)//MND Association UK/ ; DE240100707//Australian Research Council/ ; ARUK-RADF2019A-003//Race Against Dementia Alzheimer's Research UK fellowship/ ; MR/V036947/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Tau aggregation is a central pathological feature of Alzheimer's disease, yet how different forms of tau-ranging from monomers to small soluble aggregates and mature fibrils-interact with the cellular environment remains poorly understood. Here, we combine immunoaffinity proteomics with single-molecule techniques and super-resolution microscopy to systematically map the tau interactome across defined aggregation states, spanning monomeric tau, nanoscopic soluble aggregates, and fibrillar species. Using post-mortem Alzheimer's disease brain tissue, we identify distinct functional modules associated with different aggregation states: while proteostasis factors and immune-related proteins preferentially associate with nanoscopic aggregates (oligomers), cytoskeletal, metabolic, and RNA-binding proteins are enriched for mature fibrillar tau. Single-molecule microscopy directly confirms this conformation-dependent recruitment for key interactors including Hsp70-2, ENO1, hnRNPA1, APP, EAAT4, and ubiquitin. A primary-neuron system with accelerated tau aggregation is used to model these findings in a controlled system, showing striking similarities to the brain samples. Finally, pseudotime analysis reconstructs a progressive remodelling of the tau interactome across disease progression, revealing stage-specific pathway vulnerabilities. Together, these results establish a temporally resolved framework for tau pathology shaped by protein interactions and identify potential therapeutic intervention points for investigation across stages of disease.},
}

@article {pmid42750750,
year = {2026},
author = {Noguchi-Shinohara, M and Ono, K},
title = {Effective amyloid clearance with lecanemab in a female with Alzheimer's disease: A case report.},
journal = {Radiology case reports},
volume = {21},
number = {12},
pages = {5973-5977},
pmid = {42750750},
issn = {1930-0433},
abstract = {Anti-amyloid monoclonal antibodies, including lecanemab, have been approved for patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (AD). Further clarification of the long-term safety and effectiveness of these disease-modifying therapies is essential in patients treated outside the setting of clinical trials. We report an 81-year-old woman with amnestic MCI due to AD who was treated with lecanemab for 18 months in a clinical setting. At baseline, she had mild memory impairment without functional decline (Mini-Mental State Examination-Japanese version [MMSE-J], 29; Clinical Dementia Rating global score [CDR-GS], 0.5), extensive cortical amyloid deposition on [11]C-Pittsburgh compound B positron emission tomography (PET; centiloid [CL], 107.1), and elevated cerebrospinal fluid phosphorylated tau 181; she received 36 biweekly intravenous lecanemab (10 mg/kg). During treatment, surveillance magnetic resonance imaging revealed no amyloid-related imaging abnormalities, no adverse events occurred, and cognitive and functional status remained stable at 18 months (MMSE-J 28; CDR-GS 0.5), while amyloid PET demonstrated marked amyloid clearance (CL 21.3). This case illustrates substantial amyloid clearance with preserved cognitive and functional status after 18 months of lecanemab treatment without treatment-related safety concerns. Continued lecanemab therapy beyond 18 months may be feasible in carefully selected patients with early-stage AD, although further real-world data are needed to establish its long-term benefits and risks.},
}

@article {pmid42750836,
year = {2026},
author = {Lv, C and Liu, T and Chen, H and Huang, W and Huang, M and Zang, L and Shen, C and Guo, Y and Chen, F},
title = {Interpretable multimodal MRI fusion in Alzheimer's disease classification using extended parallel multilink joint ICA and 3D ResNet.},
journal = {iScience},
volume = {29},
number = {9},
pages = {117313},
pmid = {42750836},
issn = {2589-0042},
abstract = {Accurate identification of Alzheimer's disease (AD) stages is important for improving clinical understanding and supporting early-stage assessment. In this study, two multimodal MRI fusion strategies were developed to integrate structural MRI, resting-state functional MRI, and diffusion tensor imaging for pairwise binary classification among four groups: normal cognition (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD dementia (ADD). The extended parallel multilink joint independent component analysis (Epml-jICA) combined with a support vector machine (SVM) approach (machine learning) and the ensemble 3D ResNet model (deep learning) were evaluated on 664 participants with multimodal MRI. The results demonstrated that the optimal area under the receiver operating curve (AUROC) values for ADD vs. NC and SCD vs. NC were 95.68% and 81.25%, respectively. Furthermore, systematic interpretability analyses using SHAP, Grad-CAM, and anatomical localization of cross-modal important components were conducted, identifying model-associated imaging patterns that were consistent with prior AD-related findings and may provide insights into different disease stages.},
}

@article {pmid42751187,
year = {2026},
author = {Guo, Y and Liu, Z and Lu, W and Zhuo, H and Wang, Z and Wang, X},
title = {Platelet factor 4 in cognitive, immune and hematopoietic aging: emerging evidence and translational challenges.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1883921},
pmid = {42751187},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Platelet Factor 4/metabolism/immunology ; *Aging/immunology ; *Cognition ; *Hematopoietic Stem Cells/metabolism/immunology ; *Hematopoiesis ; },
abstract = {Platelet Factor 4 (PF4) is a CXC chemokine abundantly sequestered within platelet α-granules. Its modulatory roles in age-related dysfunction across cognitive, immune, and hematopoietic systems have garnered increasing research attention in recent years. PF4 modulates an array of biological pathways associated with the attenuation of aging-related cellular defects; these pathways are activated by physical activity, young plasma exposure, and Klotho-related signaling cascades. Mechanistically, PF4 engages CXCR3 and LDLR to activate downstream PI3K/Akt and MAPK signaling axes, exerting neuroprotective and immunomodulatory effects and restoring function in aged hematopoietic stem cells (HSCs). Collectively, these actions exert multifaceted effects on aging-associated cellular dysfunction. Within the central nervous system, PF4 mitigates hippocampal neuroinflammation, enhances synaptic plasticity, and promotes adult hippocampal neurogenesis to ameliorate age-dependent learning and memory deficits. In the peripheral immune system, PF4 restores balanced T-cell subset distribution and reduces circulating levels of pro-senescent inflammatory mediators. Within the bone marrow hematopoietic niche, PF4 preserves HSC quiescence, facilitates DNA damage repair, and maintains lymphoid differentiation potential. Clinical observational studies have identified correlations between circulating PF4 levels and multiple age-associated pathologies, including Alzheimer's disease, sarcopenia, stroke, and coronary artery disease, suggesting its potential as an adjunct diagnostic biomarker. Nevertheless, published findings regarding age-related changes in PF4 levels remain inconsistent, largely due to heterogeneous sample preparation protocols and detection methodologies. Furthermore, PF4 carries inherent thrombotic, profibrotic, and autoantigenic risks. Unresolved questions surrounding long-term safety, standardized dosing regimens, and tissue-targeted delivery systems represent major barriers to clinical translation. This review systematically delineates the multilayered modulatory mechanisms of PF4 in age-related cognitive, immune, and hematopoietic dysfunction, as well as its translational prospects, unresolved discrepancies, and key research gaps. We further outline prospective research directions, including protein structural optimization, refined targeted delivery strategies, and combinatorial intervention regimens, to establish a theoretical framework for future preclinical studies of PF4 as a modulator of discrete aging-related cellular phenotypes.},
}

Humans
Animals
*Platelet Factor 4/metabolism/immunology
*Aging/immunology
*Cognition
*Hematopoietic Stem Cells/metabolism/immunology
*Hematopoiesis