@article {pmid43014985,
year = {2027},
author = {Verma Saluja, K and Jindal, S and Benzinger, TLS},
title = {Molecular Neuroimaging in Alzheimer's Disease.},
journal = {Neuroimaging clinics of North America},
volume = {37},
number = {1},
pages = {51-67},
doi = {10.1016/j.nic.2026.07.003},
pmid = {43014985},
issn = {1557-9867},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Neuroimaging/methods ; *Molecular Imaging/methods ; Positron-Emission Tomography/methods ; Brain/diagnostic imaging ; Biomarkers/metabolism ; tau Proteins/metabolism ; },
abstract = {Molecular neuroimaging in Alzheimer's disease has shifted from a confirmatory diagnostic adjunct to a decision-defining clinical tool that informs diagnosis, treatment eligibility, and longitudinal therapeutic monitoring. Driven by global therapeutic approvals of anti-amyloid monoclonal antibodies and high-precision fluid biomarkers, molecular imaging now adjudicates diagnostic certainty and governs progression to disease-modifying therapy. While high-precision plasma biomarkers increasingly serve as scalable screening tools, they frequently require adjudication by amyloid or tau PET to resolve indeterminate results and enable treatment decisions. 18F-FDG PET remains an important diagnostic tool for patients with more advanced dementia presenting with complex syndromes.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Neuroimaging/methods
*Molecular Imaging/methods
Positron-Emission Tomography/methods
Brain/diagnostic imaging
Biomarkers/metabolism
tau Proteins/metabolism

@article {pmid43014987,
year = {2027},
author = {Minoshima, S and Anzai, Y and Thientunyakit, T and Ngam, PI and Cliatt Brown, CJ and Drzezga, A},
title = {Dementia and Neurodegenerative Disease: Emerging Neurodegenerative Diseases-Limbic-predominant age-related TDP-43 encephalopathy/Hippocampal Sclerosis, Argyrophilic Grain Disease, Primary Age-Related Tauopathy, and Frontotemporal Dementia Fused in Sarcoma.},
journal = {Neuroimaging clinics of North America},
volume = {37},
number = {1},
pages = {89-101},
doi = {10.1016/j.nic.2026.07.005},
pmid = {43014987},
issn = {1557-9867},
mesh = {Humans ; *Tauopathies/diagnostic imaging/pathology ; Hippocampal Sclerosis/diagnostic imaging ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; *Frontotemporal Dementia/diagnostic imaging ; *TDP-43 Proteinopathies/diagnostic imaging ; *Dementia/diagnostic imaging ; Brain/diagnostic imaging ; Diagnosis, Differential ; Magnetic Resonance Imaging/methods ; },
abstract = {Limbic-predominant age-related TAR DNA-binding protein 43 encephalopathy, hippocampal sclerosis-aging, primary age-related tauopathy, argyrophilic grain disease, and frontotemporal lobar degeneration fused in sarcoma are increasingly recognized neurodegenerative disorders that frequently mimic Alzheimer's disease (AD) and commonly coexist with AD pathology in older adults. As disease-modifying therapies emerge, accurate identification of these non-AD and mixed pathologies has become clinically important. This article reviews current clinicopathologic concepts and highlights the role of MR imaging and molecular PET imaging in differentiating limbic-predominant and frontotemporal neurodegeneration, estimating concurrent AD pathology, and interpreting complex multietiology dementia patterns.},
}

Humans
*Tauopathies/diagnostic imaging/pathology
Hippocampal Sclerosis/diagnostic imaging
*Neurodegenerative Diseases/diagnostic imaging/pathology
*Frontotemporal Dementia/diagnostic imaging
*TDP-43 Proteinopathies/diagnostic imaging
*Dementia/diagnostic imaging
Brain/diagnostic imaging
Diagnosis, Differential
Magnetic Resonance Imaging/methods

@article {pmid43015086,
year = {2026},
author = {Rivera-Ramirez, N and O'Malley, JJ and Jagirdar, R and Campbell, JR and Silva-Pérez, M and Stephens, GS and Chin, J and Beierlein, M},
title = {Thalamic Reticular Nucleus Excitability and Cholinergic Signaling are Disrupted in a Mouse Model of Alzheimer's Disease Neuropathology.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1320-26.2026},
pmid = {43015086},
issn = {1529-2401},
abstract = {The thalamic reticular nucleus (TRN) forms powerful GABAergic connections with thalamic nuclei that regulate sleep, attention, and sensory processing. TRN neurons receive dense cholinergic innervation from the basal forebrain and brainstem, dynamically shaping TRN function across brain states. We previously showed reduced TRN activity and sleep deficits in amyloid precursor protein transgenic mice (APP mice), implicating TRN dysfunction as an early contributor to Alzheimer's disease (AD) pathophysiology. Here, using slice electrophysiology in mice of both sexes, we determined whether changes in intrinsic membrane properties or cholinergic synaptic transmission contribute to TRN hypoactivity in APP mice. We found that TRN neurons located in the inner core and outer shell regions undergo substantial increases in excitability after the first postnatal month. In mature animals, core neurons exhibited higher firing rates and diverse firing patterns, including persistent firing, whereas shell neurons fired at lower rates and displayed more homogeneous firing patterns without persistent activity. Firing diversity in core neurons was mediated in part by low-threshold T-type Ca[2+] channels. Cholinergic synaptic activation, mediated predominantly by basal forebrain afferents, produced biphasic excitatory-inhibitory postsynaptic responses in both core and shell neurons, with the ratio of postsynaptic excitation and inhibition varying across postsynaptic targets. Overall, cholinergic activation suppressed TRN firing. In APP mice, core neurons showed reduced intrinsic excitability and cholinergic afferents evoked postsynaptic responses with a larger muscarinic receptor-mediated inhibitory component, leading to delayed TRN firing. Together, these findings identify both intrinsic and cholinergic synaptic mechanisms that may contribute to TRN dysfunction during early AD.Significance Statement Alzheimer's disease (AD) is typically diagnosed after cognitive symptoms emerge when treatments are less effective, highlighting the need to understand preclinical disease mechanisms. Cholinergic signaling and slow-wave sleep are disrupted before symptom onset, but the mechanisms underlying these changes remain poorly understood. Because the thalamic reticular nucleus (TRN) receives strong cholinergic input and mediates sleep-related rhythms, it is well positioned to contribute to early AD pathophysiology. We previously found reduced TRN activity and disrupted sleep in an AD mouse model. Here, we show that intrinsic excitability and cholinergic synaptic signaling are altered in TRN neurons during preclinical AD. These changes may contribute to thalamic dysfunction and sleep disturbances, providing a potential circuit mechanism linking early AD pathology to disease progression.},
}

@article {pmid43015247,
year = {2026},
author = {Xie, Z and Yang, Q and Liu, L and Chu, M and Quan, Z and Yang, L and Bai, Z and Yang, K and Nakanishi, H and Wu, L and Qing, H and Ni, J},
title = {Targeting peripheral cathepsin E restricts CD8[+] T-cell neuroinvasion and ameliorates Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {43015247},
issn = {1552-5279},
support = {8260053790//National Natural Science Foundation of China/ ; 82230042//National Natural Science Foundation of China/ ; 32070954//National Natural Science Foundation of China/ ; 2026JJ60267//Natural Science Foundation of Hunan Province/ ; 2026JJ50069//Natural Science Foundation of Hunan Province/ ; 25B0375//Research Foundation of Education Bureau of Hunan Province/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/immunology/metabolism ; *CD8-Positive T-Lymphocytes/metabolism/immunology ; Mice ; Humans ; *Cathepsin E/metabolism/antagonists & inhibitors ; Disease Models, Animal ; Mice, Transgenic ; Brain/pathology/metabolism ; Cell Movement ; Adoptive Transfer ; },
abstract = {BACKGROUND: CD8[+] T-cell-mediated neuroimmune activation increases with aging and contributes to Alzheimer's disease (AD), yet the molecular cues that drive their recruitment into the brain remain largely undefined.

METHODS: We quantified Cathepsin E (CatE) expression in CD8[+] T cells from 5×FAD mice and clinical samples from patients with AD. The functional necessity of CatE in T-cell trafficking was assessed through 4D-data-independent acquisition (4D-DIA) proteomics, microfluidic migration assays under physiological flow, and adoptive transfer experiments. Finally, we evaluated the therapeutic efficacy of a brain-impermeable CatE inhibitor in mitigating AD-related pathology.

RESULTS: CatE is selectively and age-dependently upregulated in peripheral CD8[+] T cells in both AD mice and patients. Adoptive transfer of AD-derived CD8[+] T cells significantly accelerated promoted soluble Aβ₁- 4 2 accumulation, glial activation, and memory deficits in 5-month-old recipient mice. Mechanistically, CatE is associated with elevated expression of vinculin and fibronectin in CD8[+] T cells, accompanied by enhanced activation of β1-integrins that stabilizes adhesion to brain endothelial cells. Pharmacological suppression of peripheral CatE effectively restricted T-cell infiltration, attenuated neuroinflammation, and restored cognitive function in AD models.

DISCUSSION: These results identify CatE as a key cell-intrinsic regulator of CD8[+] T-cell migratory competence. Targeting the peripheral CatE-integrin axis offers a promising immunotherapeutic strategy to limit pathogenic neuroinflammation in AD while circumventing the challenges of blood-brain barrier penetration.},
}

Animals
*Alzheimer Disease/pathology/immunology/metabolism
*CD8-Positive T-Lymphocytes/metabolism/immunology
Mice
Humans
*Cathepsin E/metabolism/antagonists & inhibitors
Disease Models, Animal
Mice, Transgenic
Brain/pathology/metabolism
Cell Movement
Adoptive Transfer

@article {pmid43015270,
year = {2026},
author = {Feng, Y and Chen, X and Song, W and Yang, X and Dou, L and Bonakdarpour, B and Jamshidi, P and Castellani, RJ and Mao, Q and Chu, X and Gao, H and Liu, Y and Xu, J and Hou, Y and Martin, W and Nelson, PT and Leverenz, JB and Hu, M and Li, YE and Pieper, AA and Cummings, J and Flanagan, ME and Cheng, F},
title = {A single-nucleus multiome map of the human cerebellum with Alzheimer's disease and related dementias.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43015270},
issn = {2041-1723},
support = {R01AG082118//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U24 AG021886/AG/NIA NIH HHS/United States ; RF1 AG048083/AG/NIA NIH HHS/United States ; R56 AG057478/AG/NIA NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG092591/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; R33 AG083003/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; R01 AG092462/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 NS133812/NS/NINDS NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; U01 NS093334/NS/NINDS NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Cerebellum/metabolism/pathology ; Female ; *Cell Nucleus/metabolism/genetics ; Male ; Purkinje Cells/metabolism ; *Dementia/genetics/metabolism/pathology ; Transcriptome ; Multiomics ; Aged ; Frontal Lobe/metabolism/pathology ; Gene Regulatory Networks ; },
abstract = {Although cerebellum is neuropathologically affected in Alzheimer's disease (AD) and AD-related dementia (ADRD), the cell type-specific genomic and epigenomic changes remain poorly understood. Here, we present single-nucleus multiome (RNA-seq and ATAC-seq) analysis of 103,861 nuclei isolated from both the cerebellum and frontal cortex of diseased individuals and cognitively healthy controls. We identify 431,834 significant peak-to-gene linkages across cell subtypes, revealing cis-regulatory elements linked to cell type-specific and disease-associated transcriptomic and regulatory network changes. Differential trajectory analysis pinpoints disease-associated genes in cerebellar granule cells, such as STMN1 and CLU. Integrating epigenomic, genetic, and three-dimensional genome data, we pinpoint two likely causal variants linked to SEZ6L2 in Purkinje cells and KANSL1 in granule cells. Through CRISPR interference in patient-derived cerebellar organoids, we show that silencing the variant-containing regulatory elements suppresses SEZ6L2 and KANSL1 expression, which perturbs neurodegeneration-associated gene programs. This cell type-specific regulatory landscape provides genomic and epigenomic insights into the pathological role of the cerebellum in AD/ADRD.},
}

Humans
*Alzheimer Disease/genetics/metabolism/pathology
*Cerebellum/metabolism/pathology
Female
*Cell Nucleus/metabolism/genetics
Male
Purkinje Cells/metabolism
*Dementia/genetics/metabolism/pathology
Transcriptome
Multiomics
Aged
Frontal Lobe/metabolism/pathology
Gene Regulatory Networks

@article {pmid43015435,
year = {2026},
author = {Basu, M},
title = {New culprit in early Alzheimer's: Blood-brain barrier blocks protective proteins.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {43015435},
issn = {1476-4687},
}

@article {pmid43015511,
year = {2026},
author = {Daly, T},
title = {Broadening the scope of multimodal precision prevention in Alzheimer's disease research.},
journal = {Discover mental health},
volume = {6},
number = {1},
pages = {},
pmid = {43015511},
issn = {2731-4383},
abstract = {INTRODUCTION: Within the last decade, translational research into Alzheimer's disease and related dementias (ADRD) has embraced the complexity of disease mechanisms and pluralistic approaches to therapeutics. As part of this broader shift, the "multimodal precision prevention paradigm" has emerged as an actionable approach to reduce the public health burden of ADRD.

OBJECTIVE: To provide an overview of the definitions, scope, and limitations of the multimodal precision prevention paradigm for ADRD and propose a broader definition of translational research in ADRD research and policy.

METHODS: This article performs a critical analysis of leading proposals by different international research initiatives working on multimodal precision medicine for ADRD prevention.

MAIN RESULTS: Within the multimodal precision prevention paradigm, two overlapping approaches are distinguished on a continuum: on one hand, researchers predominantly from the global North propose a multimodal therapy approach. On the other hand, authors from the global South are proposing a "multimodal diversity" approach stressing the need for a deeper understanding of, and action against, broader contributors to risk of ADRD. It is argued that the complexity of multimodal diversity requires extending the scope of what is typically called "translational research" beyond the "bench-to-bedside" metaphor to include broader policy entry points for prevention (such as action against the social determinants of ADRD).

CONCLUSIONS: Translational research into ADRD faces a choice between narrow and broader policy entry points. This article suggests a broader definition of translational research as follows: translational research in Alzheimer's disease and Alzheimer's disease-related dementias should promote a multi-directional interaction between, and multimodal integration of, laboratory-based and diverse population research to achieve a robust, global understanding of brain health and disease that can inspire equitable public health policy and advance precision medicine.},
}

@article {pmid43015644,
year = {2026},
author = {Liu, X and Guo, Z and Fu, B and Jia, X and Mao, C and Zhang, Z and , },
title = {An impaired excitatory-inhibitory balance in the right inferior temporal gyrus of patients with Alzheimer's disease correlated with executive function.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {43015644},
issn = {1471-2318},
support = {U19 AG024904/AG/NIA NIH HHS/United States ; 2020KY182//the General Project of the Department of Science and Technology of Zhejiang Province/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/psychology/metabolism ; Female ; *Temporal Lobe/physiopathology/diagnostic imaging ; Male ; Aged ; *Executive Function/physiology ; Magnetic Resonance Imaging/methods ; Cognitive Dysfunction/physiopathology/psychology ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: Preliminary research indicates that an imbalance between excitation and inhibition may be an early pathological feature of Alzheimer's disease. However, the relevant brain networks, neurotransmitters and genetic mechanisms are still unclear.

METHODS: This study enrolled 27 patients with Alzheimer's disease (AD), 86 patients with mild cognitive impairment MCI, and 85 healthy controls (HC), all aged 65 or older, from the ADNI3 cohort in May 2024. We employed analysis of covariance to compare abnormalities in the excitation-inhibition balance across the three groups. We performed a transcriptomic analysis of abnormal excitation-inhibition imbalance. To elucidate the characteristics of the underlying brain networks, we extracted brain regions exhibiting differences in the balance of excitation and inhibition for seed-based functional connectivity analysis.

RESULTS: Compared to the HC group, AD exhibits a significant putative excitatory-inhibitory imbalance in the right inferior temporal gyrus and superior orbital frontal gyrus. The Hurst exponent of the right inferior temporal gyrus was significantly correlated with executive function. Transcriptomic analysis revealed that the abnormal excitation-inhibition imbalance observed in AD patients is significantly associated with GABA and mGluR5 receptors, as well as with genes that are enriched in the GABAergic synapse pathway. Functional connectivity analysis using the right inferior temporal gyrus as a seed point revealed significant abnormalities in the frontoparietal control network in AD patients.

CONCLUSIONS: Our findings suggest that an imbalance between excitation and inhibition in the inferior temporal gyrus is a potential pathological mechanism underlying AD. This imbalance also leads to functional abnormalities in the frontoparietal control network associated with executive functions.},
}

Humans
*Alzheimer Disease/physiopathology/psychology/metabolism
Female
*Temporal Lobe/physiopathology/diagnostic imaging
Male
Aged
*Executive Function/physiology
Magnetic Resonance Imaging/methods
Cognitive Dysfunction/physiopathology/psychology
Aged, 80 and over
Cohort Studies

@article {pmid43015714,
year = {2026},
author = {Pérez-de la Cruz, S},
title = {From technique to sensitivity: the transformation of clinical and ethical reasoning in physiotherapy students in the context of chronic neurodegenerative diseases.},
journal = {BMC medical education},
volume = {26},
number = {1},
pages = {},
pmid = {43015714},
issn = {1472-6920},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Physical Therapy Specialty/education/ethics ; Qualitative Research ; *Clinical Reasoning ; Male ; Female ; Spain ; *Physical Therapists/education ; Attitude of Health Personnel ; Chronic Disease ; Curriculum ; },
abstract = {BACKGROUND: The evolution of Physiotherapy requires a shift from the biomedical model towards bioethical and humanistic approaches. This study explores how final-year students perceive their professional role when dealing with patients with complex neurodegenerative conditions, where traditional technical success is challenged by the irreversibility of the deterioration.

METHODS: Qualitative research based on interpretative description. Thirty final-year students from the University of Almería (Spain) took part, divided into five working groups. Three training sessions and discussions were held on Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, stroke and Rett syndrome. The data were analysed using thematic analysis and triangulation by researchers external to the study, with reflexivity ensured through logbooks.

RESULTS: A shift in clinical reasoning was identified, with sensitivity taking precedence over technique. Students redefined therapeutic success in terms of "comfort" and support, valuing "microscopic achievements" such as the preservation of dignity and the alleviation of distress. Of particular note is the ability to adapt ethical principles according to the patient's cognitive integrity (autonomy in ALS versus protection in Alzheimer's) and the integration of the carer as an inseparable part of the therapeutic process.

CONCLUSION: Future physiotherapists perceive humanization and the empathetic interpretation of non-verbal cues as essential therapeutic tools. Unlike previous studies focused on clinical experience, this research explores pre-clinical ethical maturation, offering a unique perspective on the educational foundation and humanistic predisposition of future graduates prior to their immersion in the healthcare system. It is imperative that academic curricula formally integrate competencies in bioethics, palliative care and emotional management to prepare graduates for extreme vulnerability and prevent early professional burnout.},
}

Humans
*Neurodegenerative Diseases/therapy
*Physical Therapy Specialty/education/ethics
Qualitative Research
*Clinical Reasoning
Male
Female
Spain
*Physical Therapists/education
Attitude of Health Personnel
Chronic Disease
Curriculum

@article {pmid43015837,
year = {2026},
author = {Capdevila-Bayo, M and Rossi, R and de Rojas, I and Puerta, R and Guzmán, L and Carrasco, M and Muñoz-Morales, Á and Olivé, C and Montrreal, L and García-González, P and Bayón-Buján, P and Miguel-Romero, A and Calm, B and Sotolongo-Grau, O and Tatinya, N and Alegret, M and Sanz-Cartagena, P and Fernández, V and Marquié, M and Valero, S and Montalban, X and Camins, A and Ramírez, A and Martí, M and Pividori, MI and Boada, M and Sánchez-Luengo, MÁ and Mañes, S and Ruiz, A and Ettcheto, M and Cano, A},
title = {A peripheral proteomic signature of Alzheimer's disease is identified in the plasma extracellular vesicles of mild cognitive impairment patients from a memory clinic: the BIOPEXAL study.},
journal = {Journal of nanobiotechnology},
volume = {24},
number = {1},
pages = {},
pmid = {43015837},
issn = {1477-3155},
support = {Projectes de recerca jove i emergent 2024 grant 24S05876-001//Barcelona City Council/ ; Predocs-UB grant//University of Barcelona/ ; Pre-doctoral grant FI24/00029//Instituto de Salud Carlos III (ISCIII)/ ; Sara Borrell grant CD22/00125//Instituto de Salud Carlos III (ISCIII)/ ; STAR Award, the Keith M. Orme and Pat Vigeon Orme Endowed Chair in Alzheimer's and Neurodegenerative Diseases (2024-2025) and Patricia Ruth Frederick Distinguished Chair for Precision Therapeutics in Alzheimer's and Neurodegenerative Diseases (2025-2028)//University of Texas, National Institute of Aging, National Institutes of Health/ ; Assistant professor Serra Hunter contract (UB-LE-9115)//Generalitat de Catalunya/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/metabolism/diagnosis ; *Cognitive Dysfunction/blood/metabolism ; *Extracellular Vesicles/metabolism ; Female ; Male ; *Proteomics/methods ; Aged ; Biomarkers/blood ; *Proteome/analysis ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Middle Aged ; },
abstract = {AIMS: Alzheimer's disease (AD) is commonly diagnosed when neuronal damage is already established and irreversible. Achieving an accurate differential diagnosis in the preclinical and mild cognitive impairment (MCI) stage is one of the greatest challenges nowadays. Nanotechnological analysis of plasma extracellular vesicles (pEVs) are gaining attention as a promising tool for the early detection of AD pathology. This study aims to evaluate the proteomic profile of pEVs from patients with MCI and AD dementia to explore their potential as AD screening tools.

METHODS: pEVs were isolated by ultracentrifugation from 144 patients with MCI A-T-, MCI A+T+, and AD dementia. Nanoparticle tracking analysis and cryo-TEM were used to characterize the pEVs. CSF, serum and pEVs proteomics were carried out by using the multiplex PEA technology of Olink® proteomics, Inflammation and Neurology Explore 384 panels (768 proteins).

RESULTS: Characterization results showed that isolated plasma fraction corresponded in shape, size and concentration to EVs. Many pEVs neurology proteins involved in AD pathology significantly correlated (r > ± 0.30, p < 0.05) with their CSF homonyms, but not with their serum's. pEVs' proteome correlated with common AD signatures (CSF Aβ42 and pTau181, plasma pTau181, MMSE, NBACE, and Qalb) showing similar patterns to those observed with CSF biomarkers. Several pEVs neurology proteins didn't exhibit differences between the MCI A+T+ and AD dementia groups, whilst they did with MCI A-T-. Proteins in pEVs showed strong correlations with several measures of brain atrophy in MRI. Several neurology pEV proteins predicted conversion from MCI to AD dementia. Moreover, some of these showed a significant diagnostic accuracy of AD pathology.

CONCLUSION: Preliminary results suggest that EVs biomarker signature could reflect AD pathology in the prodromal stages of AD continuum. However, further experiments are still needed for a better understanding of EVs' role in AD development and pathology dissemination.},
}

Humans
*Alzheimer Disease/blood/metabolism/diagnosis
*Cognitive Dysfunction/blood/metabolism
*Extracellular Vesicles/metabolism
Female
Male
*Proteomics/methods
Aged
Biomarkers/blood
*Proteome/analysis
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
Middle Aged

@article {pmid43015898,
year = {2026},
author = {Millar, PR and Doering, S and Adeyemo, B and Jindal, S and McKay, NS and Strain, JF and Wisch, JK and An, GZ and Canfield, P and Flores, S and Metcalf, NV and Roman, J and Cruchaga, C and Hassenstab, JJ and Holtzman, DM and Morris, JC and Gordon, BA and Ances, BM and Benzinger, TL},
title = {Network connectivity and amyloid-β align with tau in atypical Alzheimer disease subtypes.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {43015898},
issn = {1758-9193},
support = {K01-AG090753/AG/NIA NIH HHS/United States ; P01-AG026276/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P30-AG066444/AG/NIA NIH HHS/United States ; AARF-22-972678/ALZ/Alzheimer's Association/United States ; K01 AG090753/AG/NIA NIH HHS/United States ; A2022014F//BrightFocus Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology/classification ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/metabolism/pathology ; Female ; Aged ; Male ; Magnetic Resonance Imaging ; Neural Pathways/diagnostic imaging/metabolism ; Aged, 80 and over ; Retrospective Studies ; },
abstract = {BACKGROUND: Spatiotemporal patterns of tau accumulation differ between Alzheimer disease (AD) subtypes in brain networks related to clinical manifestations. Converging evidence suggests that accumulation may be driven by spreading through network connections and/or interactions with amyloid-β (Aβ). Persons with atypical AD presentations might carry pre-existing network-specific vulnerabilities, which might predispose these areas to tau pathology. However, it is unknown if regional patterns of Aβ and network connectivity differ between tau-defined subtypes and whether these patterns precede tau accumulation.

METHODS: We used Subtype-and-Stage-Inference (SuStaIn) to identify subtypes in 919 tau-PET scans from 709 participants in the Knight ADRC. We tested group differences between tau-defined subtypes in regional Aβ-PET and resting-state-functional-connectivity (RSFC) seed maps to early-stage tau epicenter regions using retrospective imaging data preceding the tau-PET scans by up to 14 years, including across stages of AD progression.

RESULTS: Most participants were tau-negative (N = 522). Among tau-positive participants, we identified three tau-PET subtypes. Limbic tau was the most common subtype (N = 136, 73.9%), resembling amnestic AD. Participants with the posterior tau subtype (N = 25, 13.6%) had specific cognitive deficits on visuospatial-dominant tasks, resembling posterior cortical atrophy. Participants with the medial-temporal-lobe-sparing (MTL-sparing) tau subtype (N = 23, 12.5%) were younger and more severely impaired, resembling early-onset dysexecutive AD. Subtype-specific Aβ-PET elevations colocalized with regions of tau accumulation, including in preliminary retrospective analyses of scans preceding tau positivity. RSFC was elevated between subtype-specific regions of tau spreading. Specifically, connectivity was elevated between occipital regions in the posterior tau subtype and was elevated between temporal and frontal regions in the MTL-sparing subtype. In preliminary retrospective analyses, these patterns were detectable in small subsets of scans acquired when participants were Aβ-negative or cognitively unimpaired, before they would later exhibit atypical tau patterns, and extended with disease progression.

CONCLUSIONS: Regional patterns of Aβ, tau, and functional connectivity align in subtype-specific brain networks. Elevated connectivity between tau spreading regions might indicate network-specific vulnerabilities that predispose these regions to tau aggregation, possibly preceding Aβ positivity. These results suggest a temporal sequence of disease progression in brain networks, which might inform explanations of clinico-pathological heterogeneity and the development of precision medicine tools for early detection, prognosis, and treatment of atypical AD.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology/classification
*tau Proteins/metabolism
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/metabolism/pathology
Female
Aged
Male
Magnetic Resonance Imaging
Neural Pathways/diagnostic imaging/metabolism
Aged, 80 and over
Retrospective Studies

@article {pmid43016032,
year = {2026},
author = {Liu, J and Li, Y and Xia, D},
title = {Association between urinary flow rate and cognition in the elderly: a cross-sectional study.},
journal = {The Canadian journal of urology},
volume = {33},
number = {5},
pages = {1313-1325},
pmid = {43016032},
issn = {1488-5581},
support = {2024C03198//"Pioneer" and "Leading Goose" R&D Program of Zhejiang/ ; },
mesh = {Humans ; Female ; Cross-Sectional Studies ; Aged ; Male ; *Cognition/physiology ; Nutrition Surveys ; *Cognitive Dysfunction/physiopathology/epidemiology ; Middle Aged ; *Urination/physiology ; United States ; },
abstract = {BACKGROUND: Urinary abnormalities and cognitive impairment are common in older adults, but their relationship remains incompletely understood. We examined the association between urinary flow rate (UFR) and cognitive performance in this population.

METHODS: We analyzed data from 2700 participants aged ≥60 years in the 2011-2014 U.S. National Health and Nutrition Examination Survey (NHANES). Cognitive performance was assessed using the Digit Symbol Substitution Test (DSST), Animal Fluency Test (AFT), and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) immediate- and delayed-recall tests. Multivariable linear regression evaluated associations between UFR and cognitive scores, and segmented regression assessed potential nonlinear threshold effects.

RESULTS: The mean age was 69.58 years, and 51.48% were women. In the fully adjusted model, higher UFR was associated with higher DSST scores (β = 1.77, 95% CI: 0.74-2.81; p = 0.0008). Participants in the highest UFR tertile had a 2.41-point higher DSST score than those in the lowest tertile (β = 2.41, 95% CI: 0.90-3.92; p = 0.0018; p for trend = 0.0051). Segmented regression identified inflection points of 1.46 mL/min for AFT, 1.30 mL/min for DSST, 0.69 mL/min for CERAD immediate recall, and 0.80 mL/min for CERAD delayed recall. Below these points, higher UFR was significantly associated with better cognitive scores, whereas no significant associations were observed above them. The UFR-DSST association was stronger among participants with BMI ≤30 kg/m2 (p for interaction = 0.0106).

CONCLUSIONS: Lower UFR was associated with poorer cognitive performance in older adults, with a nonlinear pattern. Prospective longitudinal and mechanistic studies are needed to confirm these findings and clarify their clinical relevance.},
}

Humans
Female
Cross-Sectional Studies
Aged
Male
*Cognition/physiology
Nutrition Surveys
*Cognitive Dysfunction/physiopathology/epidemiology
Middle Aged
*Urination/physiology
United States

@article {pmid43016101,
year = {2026},
author = {Bhardwaj, M and Singh, AP and Sharma, BM},
title = {Cyclovirobuxine D: Pharmacological and Bioanalytical Perspectives and Therapeutic Insights.},
journal = {Drug metabolism and bioanalysis},
volume = {19},
number = {3},
pages = {234-245},
pmid = {43016101},
issn = {3117-3861},
mesh = {Humans ; Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use/pharmacokinetics/chemistry ; Signal Transduction/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use/pharmacokinetics ; Antineoplastic Agents/pharmacology/therapeutic use/pharmacokinetics ; },
abstract = {Cyclovirobuxine D (CVB-D) is a steroidal alkaloid extracted from Buxus microphylla, widely used in traditional Chinese medicine for cardiovascular diseases. It has demonstrated significant pharmacological activities, including anti-arrhythmic, cardioprotective, neuroprotective, antiinflammatory, and anti-cancer effects. CVB-D modulates key signaling pathways, such as PI3K/Akt, NF-κB, MAPK, and calcium channel regulation, contributing to its therapeutic potential. Studies indicate that CVB-D induces apoptosis, inhibits cell proliferation, and suppresses tumor metastasis, particularly in lung, gastric, colorectal, and hepatocellular cancers. Additionally, its neuroprotective properties suggest potential applications in neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Beyond its benefits, CVB-D poses challenges related to toxicity, bioavailability, and long-term safety. Reported side effects include hepatotoxicity, nephrotoxicity, and cardiovascular risks, necessitating further clinical investigations. Despite its promising pharmacological profile, preclinical and clinical trials are essential to determine its optimal dosage and therapeutic window. This review provides a comprehensive analysis of CVB-D, including its mechanisms of action, pharmacokinetics, therapeutic potential, and limitations. A deeper understanding of its molecular interactions and safety profile will help guide future drug development and clinical applications.},
}

Humans
Animals
*Drugs, Chinese Herbal/pharmacology/therapeutic use/pharmacokinetics/chemistry
Signal Transduction/drug effects
Neuroprotective Agents/pharmacology/therapeutic use/pharmacokinetics
Antineoplastic Agents/pharmacology/therapeutic use/pharmacokinetics

@article {pmid43016150,
year = {2026},
author = {Al-Jehani, H and Al-Kuraishy, HM and Eliwa, D and Batiha, GE},
title = {Platelets in Alzheimer's disease: pathogenic mechanisms and therapeutic implications.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/01616412.2026.2762288},
pmid = {43016150},
issn = {1743-1328},
abstract = {OBJECTIVES: This review examines the role of platelets, the primary peripheral source of amyloid precursor protein (APP) and amyloid-beta (Aβ), in Alzheimer's disease (AD) pathogenesis, focusing on the bidirectional feedback loop between peripheral platelet over-activation and central neuropathology, alongside potential antiplatelet therapies.

METHODS: A narrative review was conducted evaluating literature on platelet biological functions, pathological shifts in platelet APP processing in AD, mechanisms of blood-brain barrier (BBB) breakdown, and the therapeutic potential of antiplatelet agents (e.g. aspirin, clopidogrel) and adenosine A2A receptor modulators.

RESULTS: In AD patients, platelet APP expression is markedly upregulated, shifting toward amyloidogenic processing via decreased α-secretase and increased β-secretase activity. Activated platelets breach the BBB, release pro-inflammatory mediators into the brain parenchyma, and promote cerebral Aβ deposition. Reciprocally, central AD pathology further drives systemic platelet activation, creating a self-reinforcing disease loop.

CONCLUSIONS: A clear, bidirectional relationship may exist between activated platelets and AD neuropathology. Because peripheral platelets actively fuel central amyloid accumulation and neuroinflammation, targeting platelet activation may be a viable strategy to mitigate AD risk and slow disease progression.},
}

@article {pmid43016267,
year = {2026},
author = {Afridi, S and Choudhary, F and Sharma, P and Mustafa, M and Farooqi, H},
title = {Ubiquitin-Proteasome System: Key Insights into Neurological Disorder Mechanisms.},
journal = {Current aging science},
volume = {19},
number = {4},
pages = {406-420},
pmid = {43016267},
issn = {1874-6128},
mesh = {Humans ; *Proteasome Endopeptidase Complex/metabolism ; *Ubiquitin/metabolism ; Animals ; Ubiquitin-Protein Ligases/metabolism ; *Neurodegenerative Diseases/drug therapy/enzymology/physiopathology/pathology/metabolism ; Autophagy ; Proteostasis ; Proteolysis ; Proteotoxic Stress ; Signal Transduction ; },
abstract = {The ubiquitin-proteasome system (UPS) is crucial for maintaining protein homeostasis in the central nervous system. Dysfunction of the UPS leads to the accumulation of neurotoxic aggregates, including amyloid, tau, alpha-synuclein, SOD1, and TDP-43, which are hallmark features of various neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Agerelated decline in the UPS and autophagy-lysosomal pathways results in compromised proteostasis and progressive neuronal damage. Current literature from diverse databases provides insights emphasizing the clinical relevance of UPS-targeted interventions. Strategies such as targeted degradation of misfolded proteins, modulation of PINK1/Parkin-mediated mitophagy, and the use of enzyme activators or allosteric modulators show potential in restoring brain homeostasis. This review discusses UPS-mediated proteolytic mechanisms, molecular disruptions associated with disease progression, and emerging therapeutic approaches aimed at enhancing protein clearance.},
}

Humans
*Proteasome Endopeptidase Complex/metabolism
*Ubiquitin/metabolism
Animals
Ubiquitin-Protein Ligases/metabolism
*Neurodegenerative Diseases/drug therapy/enzymology/physiopathology/pathology/metabolism
Autophagy
Proteostasis
Proteolysis
Proteotoxic Stress
Signal Transduction

@article {pmid43016268,
year = {2026},
author = {Rejitha, C and Babu, L},
title = {Animal and Cell Models in Alzheimer's and Parkinson's Disease: Current Innovations Reviewed.},
journal = {Current aging science},
volume = {19},
number = {4},
pages = {448-463},
pmid = {43016268},
issn = {1874-6128},
mesh = {Animals ; *Parkinson Disease/genetics/metabolism/pathology/physiopathology/drug therapy ; *Disease Models, Animal ; Humans ; *Alzheimer Disease/genetics/metabolism/pathology/physiopathology/drug therapy ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) remain major global health challenges due to their complex pathology and lack of curative therapies. Advancing therapeutic strategies requires reliable experimental models that recapitulate disease mechanisms. This review summarizes recent developments in animal and in vitro models for AD and PD, with emphasis on their translational relevance and applications. Transgenic mice (APP/PS1, 3xTg-AD), α-synuclein and LRRK2-based models for PD, rat 6- OHDA systems, zebrafish, and non-human primates provide valuable insights into amyloid deposition, tau aggregation, synaptic dysfunction, and motor impairment, though each presents limitations in faithfully mimicking human disease. Complementary in vitro approaches using neuronal and glial cell lines enable targeted studies on oxidative stress, inflammation, amyloid-beta (Aβ) toxicity, tau pathology, and dopaminergic degeneration. Emerging platforms such as CRISPR/Cas9-based editing, induced pluripotent stem cell (iPSC)-derived organoids, and artificial intelligence-driven drug discovery are further expanding the preclinical landscape. Together, these integrated strategies enhance understanding of neurodegenerative processes and hold promise for the development of effective disease-modifying therapies.},
}

Animals
*Parkinson Disease/genetics/metabolism/pathology/physiopathology/drug therapy
*Disease Models, Animal
Humans
*Alzheimer Disease/genetics/metabolism/pathology/physiopathology/drug therapy
Amyloid beta-Peptides/metabolism

@article {pmid43016269,
year = {2026},
author = {Mehrabadi, S and Samarghandian, S},
title = {Glymphatic Dysfunction in Alzheimer's Disease: Mechanisms, Biomarkers, and Emerging Therapeutic Perspectives.},
journal = {Current aging science},
volume = {19},
number = {4},
pages = {464-472},
pmid = {43016269},
issn = {1874-6128},
mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy/metabolism/cerebrospinal fluid ; *Glymphatic System/physiopathology/metabolism ; Animals ; Biomarkers/metabolism/cerebrospinal fluid ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Sleep ; Cognition ; *Brain/metabolism/physiopathology/pathology ; Sleep Wake Disorders/physiopathology/therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, with hallmark pathological features including amyloid-beta plaques, tau tangles, and neuronal loss. The glymphatic system, a recently discovered network responsible for brain waste clearance, plays a crucial role in maintaining cerebral homeostasis by facilitating the removal of neurotoxic metabolites, including amyloid-beta. Disruption of glymphatic function has emerged as a key factor in AD pathophysiology, contributing to the accumulation of toxic proteins and accelerating neurodegenerative processes. This narrative review explores the complex interplay between glymphatic dysfunction and AD. We discuss the mechanisms of the glymphatic system, emphasizing its reliance on cerebrospinal fluid (CSF) and interstitial fluid flow to clear metabolic waste, and how this process is closely linked to sleep cycles. In AD, impaired glymphatic function, exacerbated by aging and sleep disturbances, accelerates the buildup of amyloid-beta and tau, driving neurodegeneration. Furthermore, sleep disturbances commonly observed in AD patients further hinder glymphatic activity, creating a vicious cycle that exacerbates cognitive decline. Emerging therapeutic approaches aimed at enhancing glymphatic function-including sleep regulation, pharmacological agents, and lifestyle interventions-are promising, but most findings remain preliminary and largely based on animal studies or early clinical observations. These strategies should therefore be considered exploratory until validated in large-scale human trials. By restoring efficient waste clearance, such interventions may offer novel avenues for slowing or preventing AD progression.},
}

Humans
*Alzheimer Disease/physiopathology/therapy/metabolism/cerebrospinal fluid
*Glymphatic System/physiopathology/metabolism
Animals
Biomarkers/metabolism/cerebrospinal fluid
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Sleep
Cognition
*Brain/metabolism/physiopathology/pathology
Sleep Wake Disorders/physiopathology/therapy/metabolism

@article {pmid43016645,
year = {2026},
author = {Zhong, J and Li, J and Mo, Z and Zeng, Y and Peng, J and Zhu, P and Wang, H and Mo, C and Liu, Y and Tu, Y},
title = {Cerebrospinal fluid MMP-2 and TIMP-2 reflect blood-cerebrospinal fluid barrier dysfunction in Guillain-Barré syndrome and CIDP.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1993595},
pmid = {43016645},
issn = {1664-2295},
mesh = {Humans ; *Guillain-Barre Syndrome/cerebrospinal fluid/blood/physiopathology ; Female ; *Matrix Metalloproteinase 2/cerebrospinal fluid/blood ; Male ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/cerebrospinal fluid/blood/physiopathology ; *Tissue Inhibitor of Metalloproteinase-2/cerebrospinal fluid/blood ; Middle Aged ; Aged ; Prospective Studies ; Biomarkers/cerebrospinal fluid/blood ; *Blood-Brain Barrier/physiopathology/metabolism ; Matrix Metalloproteinase 9/cerebrospinal fluid/blood ; Adult ; },
abstract = {BACKGROUND: This study aimed to investigate patterns of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). It also examined how these patterns relate to dysfunction of the blood-cerebrospinal fluid barrier (BCB).

METHODS: This prospective observational study enrolled 86 participants: 33 patients with GBS, 34 with CIDP, and 19 with Alzheimer's disease (AD) as controls. Enzyme-linked immunosorbent assay (ELISA) quantified MMP-2, MMP-9, TIMP-1, and TIMP-2 levels in blood and cerebrospinal fluid (CSF). Analyses included group comparisons, multivariable logistic regression, ROC curve analysis, and multivariable linear regression to assess classification value and association with CSF protein (CSF-Pro).

RESULTS: Compared to controls, patients with immune-mediated peripheral neuropathies had lower blood MMP-2 and TIMP-2 levels and higher blood MMP-9 levels. CSF MMP-2 and TIMP-2 levels were higher in CIDP than in GBS. Multivariable logistic regression showed CSF MMP-2 was associated with disease classification. ROC analysis revealed CSF MMP-2 moderately distinguished CIDP from GBS (AUC = 0.700). Multivariable linear regression showed CSF TIMP-2 was independently and negatively associated with CSF-Pro levels.

CONCLUSION: The MMP-2/TIMP-2 axis may contribute to BCB dysfunction in immune-mediated peripheral neuropathies. CSF MMP-2 levels are associated with disease classification, while elevated CSF TIMP-2 levels may alleviate barrier damage. These biomarkers may serve as potential reference indicators for assessing barrier dysfunction and could provide a basis for differentiating GBS from CIDP.},
}

Humans
*Guillain-Barre Syndrome/cerebrospinal fluid/blood/physiopathology
Female
*Matrix Metalloproteinase 2/cerebrospinal fluid/blood
Male
*Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/cerebrospinal fluid/blood/physiopathology
*Tissue Inhibitor of Metalloproteinase-2/cerebrospinal fluid/blood
Middle Aged
Aged
Prospective Studies
Biomarkers/cerebrospinal fluid/blood
*Blood-Brain Barrier/physiopathology/metabolism
Matrix Metalloproteinase 9/cerebrospinal fluid/blood
Adult

@article {pmid43016785,
year = {2026},
author = {Shir, D and Piura, YD and Graff-Radford, NR and Aduen, P and Jain, MK and Schecter, L and Vemuri, P and Day, GS and Lachner, C},
title = {Modifiable dementia risk factors and socioeconomic differences in a diverse aging cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70493},
pmid = {43016785},
issn = {2352-8729},
abstract = {BACKGROUND: Black and Hispanic/Latino Americans experience higher risk of Alzheimer's disease and related dementias (ADRD). Modifiable biological and social risk factors may contribute to this risk but remain underrecognized.

METHODS: In this cross-sectional study, we evaluated 105 cognitively normal Black and Hispanic/Latino-White adults in a Northeast Florida longitudinal cohort. Assessments included clinical exams, objective cardiometabolic/laboratory testing, brain magnetic resonance imaging, and amyloid and tau positron emission tomography (PET) imaging. We compared subjective versus objective risk factors and explored potential associations with prespecified neuroimaging biomarkers.

RESULTS: Participant median age was 64.2 years, and 63% were female. Nearly all participants (98%) had at least one modifiable ADRD risk factor; 58% had at least three. Objective testing identified higher prevalence of abnormal hemoglobin A1C and vitamin B12 deficiency than self-report. Black participants had greater white matter hyperintensity burden than Hispanic-White participants, whereas PET measures were similar. Measured risk factors were not clearly associated with neuroimaging biomarkers.

DISCUSSION: Potentially modifiable ADRD risk factors were common and underrecognized in this modest-sized cohort of Black and Hispanic/Latino Americans. These findings reinforce the importance of objective assessment of modifiable risk factors to inform early prevention strategies while emphasizing the need to validate these preliminary findings in larger, representative cohorts.},
}

@article {pmid43016791,
year = {2026},
author = {Cáceres-Palomo, L and Alfonso-Triguero, M and Belloso-Iguerategui, A and Santiago-Mujika, E and Mirón-Alcalá, M and Arranz, AM},
title = {Chimeric models of neurodegenerative diseases: from disease mechanisms to regenerative therapies.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {51},
pmid = {43016791},
issn = {3059-4944},
abstract = {Human-rodent chimeric CNS models provide a unique platform for investigating human-specific aspects of neurodegeneration within the physiological environment of the living CNS. These models are generated by transplanting human pluripotent stem cell-derived neurons, astrocytes, microglia, oligodendrocytes, or neural or glial progenitor cells into the CNS of permissive host animals. Following transplantation, human cells mature, functionally integrate within host tissue, and retain key species-specific molecular and cellular features. Here, we review recent advances in the use of chimeric models to investigate disease mechanisms in Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and demyelinating disorders. We highlight the unique insights these models have provided into human-specific cellular vulnerabilities, genotype-dependent phenotypes, glial responses, and neuroimmune interactions in vivo. We also discuss emerging translational applications, including cell replacement therapies, engineered glial delivery platforms, and remyelination strategies, some of which have progressed toward clinical translation. Finally, we outline the current limitations and future directions for developing next-generation multi-lineage humanized models with enhanced disease fidelity and translational potential.},
}

@article {pmid43017153,
year = {2026},
author = {Feng, Y and Sha, Y and Xu, L and Tian, J and Gao, Y and Zhou, R and Liu, G},
title = {Integrated gut microbiome and fecal metabolome profiling identifies taurine-associated microbial dysbiosis across the Alzheimer's disease clinical spectrum.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1981076},
pmid = {43017153},
issn = {1663-4365},
abstract = {BACKGROUND: Gut microbiome alterations have been associated with Alzheimer's disease (AD), but how microbial composition, fecal metabolites, and cognitive function relate across the cognitive impairment spectrum-from subjective cognitive decline (SCD) through mild cognitive impairment (MCI) to AD-remains unclear. We integrated microbiome and metabolome profiles across this clinical spectrum.

METHODS: Fecal samples from 84 participants [10 healthy controls (HC), 22 SCD, 23 MCI, 29 AD] underwent 16S rRNA V3-V4 sequencing and untargeted LC-MS metabolomics. Profiles were integrated via Procrustes analysis, sparse canonical correlation, MIMOSA2 community-metabolism modeling, and mediation analysis. Differential abundance was assessed by Kruskal-Wallis, ANCOM-BC2, and LinDA.

RESULTS: Microbial composition differed across groups (ANOSIM R = 0.111, p = 0.001; Adonis R [2] = 0.070, p = 0.002). Cross-method validation confirmed 8 differentially abundant genera in AD vs. HC with 100% directional concordance between ANCOM-BC2 and LinDA, including depletion of butyrate-producing Lachnospiraceae (Blautia, Dorea, Fusicatenibacter) and enrichment of opportunistic pathobionts (Klebsiella, Escherichia-Shigella). Taurine showed the highest MIMOSA2 community-prediction R [2] (0.129; n = 62) and was positively associated with MMSE scores (r = 0.45, BH-FDR Q = 0.0005). A multi-omic random forest model (5 genera + 5 metabolites + age + sex) discriminated AD-clinical spectrum participants from HC with AUC = 0.86 (95% CI 0.82-0.90), although pairwise differences from the age + sex baseline (AUC = 0.75) did not reach statistical significance. Statistical mediation analysis was consistent with a Blautia → taurine → MMSE statistical mediation [ACME = 0.21, p = 0.008; 54% proportion mediated, bootstrap 95% CI (9%, 58%)].

CONCLUSION: Integrated multi-omic profiling reveals coordinated microbiome-metabolome dysregulation across the AD clinical spectrum, with taurine as a candidate microbial-metabolic node linking gut dysbiosis to cognitive performance. Microbial and metabolic alterations are detectable at the SCD stage, before objective cognitive impairment. These findings warrant validation in larger, age-matched cohorts and higher-resolution metagenomic studies.},
}

@article {pmid43017199,
year = {2026},
author = {Gan, X and Zhou, X and Yan, S and Yang, S and Li, Z},
title = {Sleep and circadian disturbances in Alzheimer's disease: clinical assessment, treatable syndromes, and limits of biomarker inference.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1998439},
pmid = {43017199},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/complications/physiopathology ; *Sleep Wake Disorders/diagnosis/etiology/physiopathology/therapy ; Biomarkers ; Polysomnography ; Animals ; *Chronobiology Disorders/diagnosis/therapy/etiology/physiopathology ; Circadian Rhythm/physiology ; },
abstract = {Sleep and circadian disturbances in Alzheimer's disease (AD) affect patients and caregivers, but clinical action depends on the syndrome, measurement, and outcome under consideration. This narrative review links sleep assessment to indication-based care while distinguishing symptomatic benefit, physiological target engagement, and disease modification. A purposive literature search was supplemented by targeted checks of PubMed-indexed and original publisher records through 4 October 2026. Selected studies are described by population, AD ascertainment, comparator, and measured endpoint rather than assigned formal evidence-certainty grades. Actigraphy characterizes behavioral rest-activity patterns; melatonin timing and temperature rhythms address endogenous circadian physiology under controlled conditions. Polysomnography and quantitative electroencephalography characterize respiratory events, sleep architecture, and oscillatory activity. These measurements inform different questions and do not independently assign AD etiology or cognitive-functional stage. Clinical priorities include confirmed obstructive sleep apnea, cognition-adapted insomnia care, irregular sleep timing, medication-related effects, parasomnias, limb symptoms, and excessive daytime sleepiness. Interpretation incorporates hypoxemia, treatment exposure, comorbidity, caregiver support, and competing diagnoses. Randomized sleep benefits remain distinct from observational cognitive associations or exploratory imaging and cerebrospinal fluid changes. Human and animal studies of arousal circuits, protein dynamics, inflammation, and fluid transport provide mechanistic context, with conflicting results interpreted according to the actual experimental endpoint. The review provides a clinically organized account of selected evidence, not a comprehensive treatment ranking. Sleep care and cognitive-etiologic assessment should proceed in parallel, with follow-up matched to patient function, safety, and the specific treatment goal.},
}

Humans
*Alzheimer Disease/complications/physiopathology
*Sleep Wake Disorders/diagnosis/etiology/physiopathology/therapy
Biomarkers
Polysomnography
Animals
*Chronobiology Disorders/diagnosis/therapy/etiology/physiopathology
Circadian Rhythm/physiology

@article {pmid43017209,
year = {2026},
author = {Bai, X and Ji, Y and Ruan, H and Zhang, W and Ma, Y and Jiang, X and Liu, X and Wang, F},
title = {Acupuncture-related brain network findings across clinical stages of the Alzheimer's disease continuum: a critical review of functional MRI evidence.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1977763},
pmid = {43017209},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging/physiopathology ; *Magnetic Resonance Imaging ; *Acupuncture Therapy ; *Brain/diagnostic imaging/physiopathology ; *Cognitive Dysfunction/therapy/diagnostic imaging/physiopathology ; *Nerve Net/diagnostic imaging/physiopathology ; Disease Progression ; },
abstract = {Brain network abnormalities are observed across the Alzheimer's disease (AD) continuum, but the relationship between clinical stage, acupuncture-related functional brain changes, and cognitive outcomes remains unclear. This review examined clinical blood oxygen level-dependent functional MRI studies of acupuncture in subjective cognitive decline (SCD), mild cognitive impairment (MCI, including amnestic MCI [aMCI]), and AD dementia. PubMed, Web of Science Core Collection, and China National Knowledge Infrastructure (CNKI) were searched for relevant studies. The evidence was synthesized narratively by clinical stage, with attention to study design, acupuncture protocols, control conditions, imaging methods, brain-cognition associations, biomarker status, and possible cohort overlap. In SCD, the limited available evidence mainly involved changes in regional spontaneous activity, hippocampal connectivity, and network organization. In MCI, including aMCI, reported changes involved memory- and limbic-related regions, DLPFC-ACC connectivity, and locus coeruleus-related pathways. In AD dementia, reported changes mainly involved the hippocampus and posterior medial memory-related regions, with earlier studies mainly examining short-term responses and two longitudinal cohorts assessing changes over a treatment course. Across the reviewed literature, findings in MCI, including aMCI, involved a broader range of brain regions and networks, whereas those in AD dementia were more often centered on the hippocampus and posterior medial memory-related regions. These differences are difficult to attribute to clinical stage alone, given substantial differences across studies in acupuncture protocols, control conditions, imaging methods, sample size, biomarker confirmation, and follow-up. Larger longitudinal studies with biomarker confirmation where possible and complementary imaging modalities are needed to determine whether the observed differences are related to clinical stage and how the imaging changes relate to cognitive outcomes.},
}

Humans
*Alzheimer Disease/therapy/diagnostic imaging/physiopathology
*Magnetic Resonance Imaging
*Acupuncture Therapy
*Brain/diagnostic imaging/physiopathology
*Cognitive Dysfunction/therapy/diagnostic imaging/physiopathology
*Nerve Net/diagnostic imaging/physiopathology
Disease Progression

@article {pmid43017342,
year = {2026},
author = {Zhou, S and Chen, Y and Yang, X and Xiang, L and Li, B and Qiu, L and Liu, Z and Zhang, T and Liu, F and Zeng, L and Mao, G},
title = {Noncoding RNA control of neuroinflammation in Alzheimer's disease: from immune cell states to precision therapeutics.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1998588},
pmid = {43017342},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/genetics/therapy/metabolism ; Animals ; *Neuroinflammatory Diseases/genetics/immunology/therapy ; *RNA, Untranslated/genetics ; Precision Medicine ; MicroRNAs/genetics ; Microglia/immunology/metabolism ; },
abstract = {Neuroinflammation is an active and heterogeneous component of Alzheimer's disease, shaped by dynamic interactions among microglia, astrocytes, neurons, and brain-interface compartments. Noncoding RNAs, including microRNAs, long noncoding RNAs, circular RNAs, and emerging small-RNA species, regulate innate immune sensing, interferon responses, phagocytosis, metabolic adaptation, inflammasome activity, and neuronal stress. Their effects are strongly context dependent: the same noncoding RNA can exert different or even opposing functions according to cell identity, intracellular or extracellular localization, disease stage, and dose. Extracellular vesicles and extracellular RNA sensing further extend noncoding RNA activity beyond cell-autonomous regulation, creating intercellular circuits that couple neuronal stress to glial immune states. Noncoding RNA-regulated inflammation intersects with amyloid-β production and clearance, tau-associated stress, synaptic dysfunction, mitochondrial impairment, and regulated cell death. Rather than acting as isolated inflammatory switches, noncoding RNAs appear to tune the strength of pathological feedback networks that determine whether proteotoxic and inflammatory stress is contained or progressively amplified. The translational value of individual noncoding RNAs depends on the convergence of causal evidence, mechanistic resolution, human relevance, and therapeutic tractability. Human brain, cerebrospinal fluid, patient-derived extracellular vesicles, and induced pluripotent stem cell models are beginning to bridge experimental mechanism and human disease, while antisense oligonucleotides, engineered extracellular vesicles, targeted nanoparticles, and synthetic circular RNAs provide emerging therapeutic routes. Pleiotropy, cell-type specificity, disease-stage dependence, endosomal trafficking, and innate RNA sensing remain major barriers. Context-resolved noncoding RNA regulatory nodes that control defined neuroimmune states may ultimately enable precision neuroimmune reprogramming while preserving protective immune functions.},
}

Humans
*Alzheimer Disease/immunology/genetics/therapy/metabolism
Animals
*Neuroinflammatory Diseases/genetics/immunology/therapy
*RNA, Untranslated/genetics
Precision Medicine
MicroRNAs/genetics
Microglia/immunology/metabolism

@article {pmid43017368,
year = {2026},
author = {Luo, D and Lv, X and Mu, H and Tao, X and Chen, H and Cui, Z and Gao, P},
title = {The role of vascular factors in Alzheimer's disease: from cerebrovascular pathological mechanisms to blood biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1997082},
pmid = {43017368},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is the most common dementia, and post-mortem and imaging studies consistently demonstrate that vascular pathology coexists with plaques and tangles in most AD brains. Vascular risk factors-hypertension, diabetes, dyslipidaemia, and atrial fibrillation-damage the neurovascular unit, disrupt the blood-brain barrier, and induce chronic hypoperfusion, thereby promoting β-amyloid (Aβ) deposition, tau hyperphosphorylation, and neuroinflammation. Cerebral small vessel disease, amyloid angiopathy, and carotid stenosis are overrepresented in AD and accelerate cognitive decline. Ultrasensitive blood assays now enable plasma Aβ42/40, phosphorylated tau isoforms, glial fibrillary acidic protein, and neurofilament light chain to approach the diagnostic accuracy of cerebrospinal fluid and PET, while endothelial injury markers such as vascular endothelial-cadherin and soluble adhesion molecules are emerging. Against this background, this review contends that AD diagnostics must move beyond a single-pathology framework toward an integrated model that combines neurodegenerative and vascular injury biomarkers. Reliance on Aβ and tau alone cannot capture clinical heterogeneity nor guide vascular-targeted interventions. A multidimensional blood panel reflecting pericyte loss, endothelial dysfunction, and blood-brain barrier compromise may offer improved stratification and ultimately help identify whether a biomarker-defined subgroup could benefit from vascular interventions-a hypothesis that remains to be tested prospectively. This review traverses the entire cascade from risk factors through cerebrovascular mechanisms to surgical considerations and blood biomarkers, aiming to provide a clinically actionable reference for multidisciplinary dementia care.},
}

@article {pmid43017408,
year = {2026},
author = {Li, X and Gozes, I},
title = {AI-enabled drug repurposing in Alzheimer's disease: from computational nomination to pharmacological proof.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1999276},
pmid = {43017408},
issn = {1663-9812},
abstract = {Artificial intelligence (AI) has expanded the scale and speed of drug repurposing in Alzheimer's disease (AD). Transcriptomic signature matching, network-based systems pharmacology, real-world data pharmacoepidemiology and multi-omics machine learning have generated hundreds of candidate drugs, while repurposed agents account for 35% (56 of 158) of drugs and 42% (15 of 36) of Phase 3 agents in the 2026 AD pipeline. Clinical translation, however, remains unproven. Randomised trials of GLP-1 receptor agonists illustrate the gap between prioritisation and therapeutic proof: semaglutide did not slow clinical progression in evoke and evoke+, while liraglutide did not improve the primary FDG-PET endpoint in ELAD. We examine four complementary evidence domains, defining what each can and cannot establish, and position large language models as a cross-cutting tool for evidence synthesis and knowledge-graph reasoning rather than an independent source of biological evidence. Rather than cataloguing methods and candidates, we appraise leading drugs at the individual-molecule level and propose explicit criteria for progression from computational nomination to clinical testing. The framework defines seven requirements for clinical progression: disease-stage matching, adequate site-of-action exposure, including CNS exposure for central mechanisms, mechanistic validation in human-relevant models, biomarker-stratified trial design, convergence across independent evidence domains, causal inference with explicit boundary conditions, and mechanism-aligned endpoints with predefined stopping rules. AI has improved candidate prioritisation in AD, but clinical value will depend on converting ranked hypotheses into pharmacologically plausible and prospectively testable programmes.},
}

@article {pmid43017556,
year = {2026},
author = {Huang, X and Zhang, X and Zhu, Q},
title = {Microbiome-targeted strategies for Alzheimer's disease: multi-omics signatures, mechanistic links, and intervention evidence.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1828118},
pmid = {43017556},
issn = {1664-302X},
abstract = {Alzheimer's disease (AD) is increasingly studied in relation to gut microbial mechanisms because microbial metabolism, mucosal barrier function, and peripheral immune activation may influence neuroinflammation and host metabolic stress. This review evaluates microbiome-linked evidence in AD with emphasis on studies that combine metagenomics, metabolomics, inflammatory markers, neuroimaging, cerebrospinal fluid or blood biomarkers, and cognitive phenotyping. Current data support several recurring but not yet causal axes, including bile acid transformation, short-chain fatty acid (SCFA) production, trimethylamine N-oxide (TMAO), bacterial product-related inflammatory signaling, and barrier dysfunction. We also review microbiome-targeted interventions, including diet and prebiotics, strain-specified probiotics and synbiotics, oligosaccharide-based agents, gut-restricted antimicrobials, and fecal microbiota transplantation (FMT). The strength of evidence differs substantially across these strategies: sodium oligomannate has been tested in a phase 3 trial, whereas many probiotic, antimicrobial, and FMT approaches remain early clinical, preclinical, or mechanism-generating. Future trials should define a priori microbial, metabolite, immune, and brain biomarker endpoints; control diet, medication, and comorbidity confounding; and validate candidate signatures across independent cohorts before using microbiome profiles for screening or treatment selection.},
}

@article {pmid43017560,
year = {2026},
author = {Stellingwerf, A and Schreuder, FHBM and Kuiperij, HB and Van Der Kolk, AG and Backes, WH and Claassen, JAHR and Verbeek, MM},
title = {Longitudinal amyloid-beta measurements and blood-brain barrier dysfunction in cerebral amyloid angiopathy as part of the Mechanisms Of DEMentia project: protocol of the MODEM-LAMBDA-C study.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1949765},
pmid = {43017560},
issn = {1664-2295},
mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/physiopathology/metabolism/complications ; *Blood-Brain Barrier/metabolism/diagnostic imaging/physiopathology ; Female ; Longitudinal Studies ; Male ; Magnetic Resonance Imaging ; Aged ; Peptide Fragments/cerebrospinal fluid ; *Dementia/cerebrospinal fluid/etiology ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta (Aβ) peptides within the cerebral vasculature and is a major cause of lobar intracerebral haemorrhage, cognitive impairment, and dementia. Vascular Aβ aggregates are enriched in shorter peptides (Aβ38 and Aβ40) whereas neuritic plaques, as observed in Alzheimer's disease pathology, predominantly contain longer Aβ peptides (Aβ42 and Aβ43). These pathological signatures are reflected by reduced cerebrospinal fluid (CSF) Aβ levels. However, the longitudinal dynamics of CSF Aβ peptides in CAA and their relationship with blood-brain barrier (BBB) dysfunction remain poorly understood.

METHODS: The MODEM-LAMBDA-C study is a longitudinal observational study including participants with CAA and age- and sex-matched control participants. At baseline, participants undergo clinical assessment, cognitive testing, blood pressure measurement, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the brain, blood sampling, and lumbar puncture to obtain CSF. At 2 years of follow-up, all assessments except MRI are repeated. Longitudinal changes in CSF Aβ peptide concentrations will be examined and related to cognitive performance, baseline MRI markers of cerebral small vessel disease and DCE-MRI-derived measures of BBB leakage. Additionally, CSF biomarkers of BBB dysfunction will be quantified and correlated with DCE-MRI markers of BBB dysfunction.

CONCLUSION: By integrating biochemical and imaging markers of Aβ pathology and BBB dysfunction, the MODEM-LAMBDA-C study aims to provide a comprehensive understanding of disease mechanisms underlying CAA, potentially contributing to improved diagnosis and prognostic strategies.

CLINICAL TRIAL REGISTRATION: https://onderzoekmetmensen.nl/en, identifier: NL85709.091.23.},
}

Humans
*Amyloid beta-Peptides/cerebrospinal fluid
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/physiopathology/metabolism/complications
*Blood-Brain Barrier/metabolism/diagnostic imaging/physiopathology
Female
Longitudinal Studies
Male
Magnetic Resonance Imaging
Aged
Peptide Fragments/cerebrospinal fluid
*Dementia/cerebrospinal fluid/etiology

@article {pmid43017601,
year = {2026},
author = {Xiao, Z and Qin, Y and Dong, M and Wei, S and Ma, Q and Luo, C and Li, Y and Chen, F and Wu, G and Wei, P and Hu, R and Huang, Z and Liu, C},
title = {Multi-Omics Mendelian Randomization Identifies DDX17 as a Potential Mediator Linking Gut Microbiota-Immune-Metabolism Axis to Alzheimer's Disease.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {652037},
pmid = {43017601},
issn = {1178-7074},
abstract = {INTRODUCTION: The gut microbiota-immune-metabolism axis has been implicated in Alzheimer's disease (AD) pathogenesis; however, the key host molecular targets linking peripheral dysregulation to central neurodegeneration remain elusive.

METHODS: In this study, we systematically integrated large-scale GWAS data covering 1,903 gut microbiota taxa, 14,696 immune cell features, and 34,843 metabolite features with AD GWAS summary statistics, using two-sample Mendelian randomization (MR) to identify causal genes. These genes were intersected with differentially expressed genes from three GEO datasets, followed by protein-protein interaction network construction using four Cytoscape algorithms (MCC, EPC, DMNC, Degree) and feature selection via three machine learning methods (Support Vector Machine, Random Forest, LASSO). Single-cell transcriptomics (GSE188545) localized key gene expression, Support Vector Machine virtual knockout (scTenifoldKnk) analyzed downstream regulatory networks, with in vitro validation performed in okadaic acid-treated SH-SY5Y cells using RT-qPCR and Western blotting.

RESULTS: MR analysis revealed multiple causal associations among microbial taxa, immune phenotypes, metabolites, and AD. Integration of MR causal genes with DEGs, PPI network analysis, and machine learning refinement prioritized six key genes: BYSL, DDX17, HSPA6, RRN3, C4B, and NCKAP1L. Among them, only DDX17 showed robust expression in AD-associated neuronal populations in single-cell transcriptomics, whereas the other five genes showed low expression and may act through non-cell-autonomous mechanisms. Virtual knockout predicted that the PI3K/AKT pathway was the most significantly enriched downstream of DDX17 perturbation. In vitro, DDX17 was significantly upregulated in an OA-induced AD cell model, and siRNA-mediated knockdown partially reversed tau hyperphosphorylation (total P-tau and P-tau Thr217), while restoring AKT phosphorylation at Thr308 and Ser473.

CONCLUSION: These findings suggest that DDX17 is a potential downstream host candidate linking peripheral dysregulation to tau pathology in AD, partially through PI3K/AKT pathway modulation. However, these results are primarily hypothesis-generating, and direct mechanistic and in vivo validation remain essential.},
}

@article {pmid43017815,
year = {2026},
author = {Williams, DM and Mukadam, N and Davies, NM and Anderson, EL},
title = {Understanding apolipoprotein E as a predominant cause of Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag395},
pmid = {43017815},
issn = {1460-2156},
abstract = {The full contribution of apolipoprotein E (APOE) to Alzheimer's disease burden in populations may have been overlooked. This is due, in large part, to a lack of recognition that the most common allele of the APOE gene, ε3, increases risk of Alzheimer's disease relative to the ε2 allele. When the impact of both ε3 and ε4 alleles of APOE are considered, the majority of late-onset Alzheimer's disease appears to be attributable to differences in APOE function or expression in populations of European ancestry and in other ethnic groups for which we have reliable data. Moreover, most sporadic early-onset Alzheimer's disease might not occur without the contributions of APOE ε3 and ε4, and the two alleles may be component causes of most forms of Alzheimer's disease arising from highly penetrant genetic mutations and trisomy 21. Taken together, these lines of epidemiological evidence suggest that APOE is a predominant cause of Alzheimer's disease, spanning the aetiologies of many forms of the disease. Consequently, almost all prospective cases of Alzheimer's disease might benefit from the development of therapies to modulate APOE's role in the disease's pathophysiology.},
}

@article {pmid43017840,
year = {2026},
author = {Drapała, N and Barańska, I and Kliś-Kalinowska, A and Szczerbińska, K},
title = {Factors associated with self-reported stress by informal caregivers providing care for older adults.},
journal = {International journal of occupational medicine and environmental health},
volume = {},
number = {},
pages = {},
doi = {10.13075/ijomeh.1896.02855},
pmid = {43017840},
issn = {1896-494X},
abstract = {OBJECTIVES: The aim of this study was to assess the prevalence of self‑reported stress among informal caregivers of older adults living at home and to identify key factors associated with caregiving-related stress.

MATERIAL AND METHODS: Between April 2024 and May 2025, a cross-sectional survey was conducted among 338 informal caregivers of individuals aged ≥60 years. Data were collected using the interRAI-Self-Reported Carer Needs (SCaN) tool. Logistic regression analyses were used to identify key stress-related factors.

RESULTS: Factors that significantly increase the odds of experiencing stress associated with caregiving include: being employed while providing care (OR = 3.03, 95% CI: 1.61-5.70), caring for a person with Alzheimer's disease or other dementia (OR = 2.38, 95% CI: 1.24-4.54), lack of access to respite services (OR = 3.53, 95% CI: 1.92-6.49), spending >35 h/week on caregiving (OR = 2.27, 95% CI: 1.08-4.77), and the presence of mood-disorder symptoms in the carer (OR = 3.53, 95% CI: 1.92-6.49). Caregivers who felt their relatives' needs were unmet were nearly 6 times more likely to report stress compared to those who felt otherwise (OR = 5.84, 95% CI: 1.48-23.01).

CONCLUSIONS: Caregiver stress is a multifaceted phenomenon associated with numerous factors. This cross-sectional study identifies factors associated with the prevalence of caregiving stress, underscoring the need for a multidimensional approach to strengthen and optimize support systems for informal caregivers and the individuals they care for. Int J Occup Med Environ Health. 2026;39(6).},
}

@article {pmid43017915,
year = {2026},
author = {Singh, R and Reuben, S and Oyelami, M and Adeleye, A and Marshall, E},
title = {In vivo biomarkers for limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC): A scoping review of proposed measures.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261505301},
doi = {10.1177/13872877261505301},
pmid = {43017915},
issn = {1875-8908},
abstract = {BackgroundLimbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common cause of late-life amnestic dementia that mimics Alzheimer's disease but lacks a validated in vivo biomarker.ObjectiveThe authors sought to map the in vivo biomarker candidates for LATE-NC, characterize the type and quality of evidence for each, highlight their validation against postmortem TDP-43 staging and map their performance in both pure LATE-NC and mixed pathology.MethodsFive databases were searched (PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, Scopus). Eligible studies investigated in vivo biomarkers for LATE-NC in adults with mean age above 65. Two reviewers independently screened all records; a third adjudicated disagreements. Data were extracted across 24 fields and synthesized narratively.Results43 studies covering structural MRI (19), FDG-PET (8), plasma (7), diffusion MRI (4), multimodal MRI (1), CSF (2), TDP-43 PET (1), and linguistic markers (1) were reviewed. The most replicated signal was medial temporal lobe atrophy and hypometabolism. Several studies framed their candidate as a diagnostic validation against autopsy; yet only three reported formal performance metrics with stated cut-off values. A handful of studies (12%) tested in an independent cohort and the corpus contains only one study from outside North America and Europe (Japan).ConclusionsImaging evidence is well-anchored but mostly exploratory or surrogate validated at this stage. Plasma TDP-43 elevation is consistent but no commercial assay has a validated cut-point. Clinical translation requires external validation, cut-point-anchored diagnostic accuracy, and cohort diversification.},
}

@article {pmid43017921,
year = {2026},
author = {Wilson, L and Toomey, M and Pachana, NA and Dawes, P},
title = {Impact of Hearing and Vision Loss on Quality of Life in Older Adults Living With Cognitive Impairment: A Scoping Review.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261506165},
doi = {10.1177/14713012261506165},
pmid = {43017921},
issn = {1741-2684},
abstract = {Previous reviews have established that hearing and vision impairments are common among people living with cognitive impairment and that these comorbidities can exacerbate effects of cognitive impairments on cognitive, social and functional outcomes. This scoping review aimed to extend on this knowledge, by identifying and evaluating evidence regarding the effect of hearing and vision impairment on quality of life among older adults living with cognitive impairment, to: (i) determine if a compounding effect exists between hearing and/or vision and cognitive impairments; (ii) compare the effects on hearing, vision and health-related quality of life, and (iii) evaluate quality of life outcomes for hearing and vision interventions for this population. Seven electronic databases were searched systematically from inception to February 2026 for studies reporting quality of life outcomes among older adults living with cognitive impairment and hearing and/or vision impairment. Results were summarised then categorised by aim. Thirteen studies met inclusion criteria. The limited evidence suggests that (i) individuals living with comorbid vision and cognitive impairments may have substantially worse quality of life than those with either impairment alone, (ii) the effect is similar in size across different quality of life outcomes and (iii) sensory support interventions, involving counselling and assistance with device use, appear to be a more promising method of improving quality of life among this population. Further research is necessary to understand the relationship between hearing and vision impairments and quality of life among people living with cognitive impairment. Recommendations for future research include focusing on dual sensory impairment, utilising mixed methods approaches and inclusive selection criteria for people living with dementia. Further development and implementation of sensory support programs, codesigned with individuals with lived experience, is also recommended for improving the quality of life for people living with dementia globally.},
}

@article {pmid43018301,
year = {2026},
author = {Saha, G and Bandyopadhyay, S},
title = {Molecular Insights into the Aβ-42 Tetramer-Induced Disruptive Effects on a Model Phospholipid Membrane.},
journal = {The journal of physical chemistry. B},
volume = {130},
number = {45},
pages = {12014-12027},
doi = {10.1021/acs.jpcb.6c04108},
pmid = {43018301},
issn = {1520-5207},
support = {NA//Anusandhan National Research Foundation/ ; NA//Indian Institute of Technology Kharagpur/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Molecular Dynamics Simulation ; *Lipid Bilayers/chemistry ; *Peptide Fragments/chemistry/metabolism ; *1,2-Dipalmitoylphosphatidylcholine/chemistry ; *Phospholipids/chemistry ; Temperature ; Protein Multimerization ; },
abstract = {Formation of pores in neuronal membranes by amyloid-β (Aβ) oligomers is believed to be the origin behind neurotoxicity in Alzheimer's disease (AD). However, despite significant efforts, high-resolution characterizations of the pore-forming Aβ oligomers from experimental studies have been hindered due to structural heterogeneity of such aggregated oligomers. Consequently, efforts have been made to characterize the aggregated oligomers that develop within a membrane environment. Attempts have been made in this study to probe the microscopic properties of the three-dimensional structure of an Aβ oligomer, specifically an Aβ-42 tetramer present in a membrane-mimicking environment. The tetramer comprises of eight antiparallel β strands forming an Aβ-42 barrel. Atomistic molecular dynamics simulations at constant temperature and pressure (NPT) have been carried out on a fully hydrated liquid-crystalline lamellar phase of dipalmitoylphosphatidylcholine (DPPC) lipid bilayer with an Aβ-42 tetramer embedded into it forming a pore. The results were compared with that of a fully hydrated pure DPPC bilayer system. Based on the calculations, we have been able to successfully quantify the disruptions in the bilayer structure caused by the peptide tetramer through conformational rearrangements of the lipid hydrocarbon chains. We believe that the results presented can quantitatively provide fundamental molecular-level insights into the detrimental effects of pore-forming Aβ-42 on membrane environment, which in turn, may have important implications on Alzheimer's disease.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Molecular Dynamics Simulation
*Lipid Bilayers/chemistry
*Peptide Fragments/chemistry/metabolism
*1,2-Dipalmitoylphosphatidylcholine/chemistry
*Phospholipids/chemistry
Temperature
Protein Multimerization

@article {pmid43018660,
year = {2026},
author = {Wang, Y and Zhao, H and Kong, M and Qin, K and Teng, Y and Zhu, Z and Li, Y and Liu, D and Cui, L and Sun, Y},
title = {Epigenetic regulation of the complement system in age-related chronic inflammation: mechanisms and therapeutic prospects.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {43018660},
issn = {1573-4978},
support = {#82371153 and #82571317//the National Natural Science Foundation of China/ ; #ZR2022QH073 and #ZR2025MS1188//the Natural Science Foundation of Shandong Province/ ; #ZR2025LZ044//Natural Science Foundation of Yantai/ ; },
mesh = {Humans ; *Epigenesis, Genetic ; *Inflammation/genetics/immunology ; *Aging/genetics/immunology ; *Complement System Proteins/genetics/metabolism ; Animals ; DNA Methylation/genetics ; Alzheimer Disease/genetics/immunology ; Complement Activation/genetics ; Macular Degeneration/genetics ; Chronic Disease ; },
abstract = {Aging is accompanied by progressive changes in epigenetic regulation, immune function, and tissue homeostasis, which may contribute to chronic low-grade inflammation and age-related disease. The complement system is an important component of innate immunity and participates in immune surveillance, tissue homeostasis, and inflammatory regulation. Increasing evidence suggests that DNA methylation, histone modifications, and non-coding RNAs can influence the expression of complement components and regulatory proteins, while complement-associated inflammatory signaling may reciprocally affect cellular epigenetic states. In this review, we summarize current evidence linking epigenetic regulation with complement biology during aging and discuss how this relationship varies across tissues and disease contexts. Particular attention is given to the central nervous system, where complement-dependent synaptic remodeling can support physiological circuit refinement but may become excessive or dysregulated under pathological conditions. We further examine the epigenetic-complement relationship in Alzheimer's disease, age-related macular degeneration, and atherosclerosis, and consider age-associated clonal hematopoiesis as a potential modifier of myeloid and inflammatory states. Rather than proposing a uniform linear pathway from epigenetic aging to complement activation and disease, we propose a context-dependent framework in which age-associated epigenetic remodeling may coexist with physiological adaptation or, under specific genetic, metabolic, environmental, cellular, and tissue contexts, contribute to reduced regulatory reserve and persistent complement-associated inflammation. This framework highlights the potential of cell-, tissue-, and disease-stage-specific strategies targeting the epigenetic-complement axis while preserving physiological complement functions.},
}

Humans
*Epigenesis, Genetic
*Inflammation/genetics/immunology
*Aging/genetics/immunology
*Complement System Proteins/genetics/metabolism
Animals
DNA Methylation/genetics
Alzheimer Disease/genetics/immunology
Complement Activation/genetics
Macular Degeneration/genetics
Chronic Disease

@article {pmid43018803,
year = {2026},
author = {Jenkins, MR and Hickey, EJ and Greenlee, JL and Brothers, CE and Yoon, DM and Barry, AM and Schworer, EK and Handen, BL and Hom, CL and Bodde, AE and Ptomey, LT and Hartley, SL},
title = {Adverse life experiences, mood symptoms, and quality of life in adults with down syndrome.},
journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation},
volume = {35},
number = {12},
pages = {},
pmid = {43018803},
issn = {1573-2649},
mesh = {Humans ; *Down Syndrome/psychology ; *Quality of Life/psychology ; Adult ; Female ; Male ; Middle Aged ; *Mood Disorders/psychology ; *Life Change Events ; Affect ; },
abstract = {PURPOSE: Life expectancy for people with Down syndrome (DS) has increased, creating a need to understand how to optimize later-life quality of life (QOL). In the general population, adverse life experiences (ALES) are thought to alter QOL via several mechanisms, including the presence of mood disorders. Little is known about whether ALES predict later-life QOL in adults with DS and, if so, whether this association is driven by increased mood symptoms.

METHODS: Data came from 133 adults with DS (Mage = 38.58 years, SD = 8.61) without dementia enrolled in the Alzheimer Biomarker Consortium-Down Syndrome. We used hierarchical linear regression to predict the effect of ALES and mood symptoms on QOL. We conducted an ordinary least squares path analysis to quantify the direct effect of ALES on QOL and the indirect effect through mood symptoms using 5000 bootstrap samples.

RESULTS: ALES was not a significant predictor of QOL. Mood symptoms were significantly negatively associated with QOL. The path analysis indicated that adults with DS who experienced more ALES also had more mood symptoms, and mood symptoms were associated with lower QOL. The confidence interval for the indirect effect was below zero, indicating that mood symptoms significantly affected the relationship between ALES and QOL. The direct effect of ALES on QOL was not significant.

CONCLUSION: Mood symptoms are not simply a correlate of early adversity but an intervening variable through which the psychological and neurobiological effects of ALES may be expressed as poorer later-life QOL.},
}

Humans
*Down Syndrome/psychology
*Quality of Life/psychology
Adult
Female
Male
Middle Aged
*Mood Disorders/psychology
*Life Change Events
Affect

@article {pmid43018819,
year = {2026},
author = {Alsamman, AM and Ibrahim, MS and Mousa, KH and Ibrahim, SM and Mokhtar, MM and Saedwi, AM and Khaled, R and Allali, AE and Zayed, H},
title = {NeuroBase: A Web-Based Transcriptomic Resource and R Package for Cross-Disorder Analysis of Neurodegenerative and Neuropsychiatric Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {43018819},
issn = {1559-1182},
mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Internet ; *Mental Disorders/genetics ; *Transcriptome/genetics ; *Databases, Genetic ; Gene Expression Profiling ; Principal Component Analysis ; },
abstract = {Neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease, autism spectrum disorder, bipolar disorder, Parkinson's disease, and schizophrenia, are highly prevalent and biologically complex conditions that remain difficult to diagnose and treat. This study aimed to develop NeuroBase, a web-based transcriptomic resource that supports exploratory comparison of shared and disorder-specific gene expression features across these disorders. Fourteen human brain bulk RNA sequencing datasets (262 total samples) were processed using a standardized pipeline, followed by differential gene expression analysis with DESeq2, edgeR and limma-voom for broad exploratory discovery, complemented by a multi-method sensitivity analysis to define a method-concordant core gene set, protein-protein interaction network analysis using STRING with downstream exploration in Cytoscape, and functional enrichment analysis. Principal component analysis and clustering-based visualizations were used to summarize similarities and differences in transcriptomic patterns among disorders. Differential expression analysis identified dataset-level significant genes within each disorder using DESeq2 for one dataset per disorder (FDR ≤ 0.05), including 38 genes in Alzheimer's disease, 6,704 in autism spectrum disorder, 3,559 in bipolar disorder, 687 in Parkinson's disease, and 2,750 in schizophrenia; a stricter multi-method intersection analysis yielded method-concordant Core Intersection sets in the most informative datasets (983 core DEGs in autism spectrum disorder, 505 in bipolar disorder, 281 in schizophrenia, and 234 and 151 in two Parkinson's disease datasets; only two core genes (SPP1 and CHST3) were found in Alzheimer's disease). A unified strict-threshold reanalysis (FDR ≤ 0.05, |log2FC|≥ 1) revealed disorder-level DEG burdens ranging from 34 (Alzheimer's disease) to 2,812 (autism) deduplicated genes, but only 24 genes were reproducible across independent cohorts of the same disorder, highlighting the limited cross-cohort reproducibility characteristic of bulk brain transcriptomics. Enrichment analyses identified significantly enriched signaling pathways in autism spectrum disorder and nominally enriched synapse-related pathways in Alzheimer's disease. Representative high-signal genes included SPP1 in Alzheimer's disease, NRGN in one Parkinson's disease dataset, and BEST1 in autism spectrum disorder. Cross-disorder comparison identified 465 differentially expressed genes shared between the neurodegenerative and neuropsychiatric disorder groups, and principal component analysis showed that sample variation was dominated by dataset and tissue of origin. NeuroBase is a publicly accessible, web-based transcriptomic database and companion R package (neurobaseR) that enables standardized, cross-disorder exploration of bulk brain gene expression profiles across neurodegenerative and neuropsychiatric disorders, supporting comparative analysis, programmatic data access, and hypothesis generation through interactive visualization and pathway-level summaries.},
}

Humans
*Neurodegenerative Diseases/genetics
*Internet
*Mental Disorders/genetics
*Transcriptome/genetics
*Databases, Genetic
Gene Expression Profiling
Principal Component Analysis

@article {pmid43018845,
year = {2026},
author = {Chakraborty, W and Roy, KK},
title = {Precision Neurology in Alzheimer's Disease: Genomics to Drug Optimization for Effective Therapeutic Intervention.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {43018845},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/therapy ; *Genomics/methods ; *Precision Medicine/methods ; *Neurology/methods ; Pharmacogenetics ; Animals ; },
abstract = {Alzheimer's disease (AD) exhibits high clinical and biological heterogeneity, which complicates the development of one-size-fits-all therapeutic strategies. Standard trial designs can mask subgroup-specific effects, highlighting the need to move towards precision neurology entailing multisystem genomics, biomarkers, and artificial intelligence (AI) integrative signals. The aim of the study is to critically synthesize and evaluate emerging strategies for drug optimization and individual therapeutic algorithms informed by genomic architecture, pharmacogenomics (PGx), and polygenic risk scores (PRS) with the opinion to resolve the controversy and unanswered question. Amplify the convergence into amyloid processing, lipid metabolism, and innate immunity seen from monogenic mutations and over 80 GWAS risk loci. Genotyping of CYP2D6 and CYP2C19 variants permits pharmacogenomic stratifications for the optimization of cholinesterase inhibitor and psychotropic dosing, thereby reducing adverse events. Variants of the alleles APOE ε4 and immune-related factors (e.g., FCGR3A) are significant in predicting the effects of ARIA associated with amyloid on anti-amyloid immunotherapy outcomes. PRS and deep phenotyping (including digital and fluid-based biomarkers) allow for the identification of unique biological endotypes (e.g., tau-dominant vs. vascular-inflammatory) that improve clinical trial enrichment and prognostication. This framework delineates molecular endotypes and translates CYP2D6 or APOE stratification into drug dosing and ARIA risk predictions. These biomarker-driven strategies shift AD management from a passive, reactive therapeutic scheme to an active, personalized one. Utilization of high-dimensional data streams via AI-driven learning health systems converts AD management from a reactive, symptom-based model to that which is proactive and hallmark biomarker-driven precision.},
}

Humans
*Alzheimer Disease/genetics/drug therapy/therapy
*Genomics/methods
*Precision Medicine/methods
*Neurology/methods
Pharmacogenetics
Animals

@article {pmid43018890,
year = {2026},
author = {Moore, SJ and Murphy, GG},
title = {Acarbose ameliorates age-related spatial learning and memory deficits in a mouse model of normal aging but not Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {43018890},
issn = {2509-2723},
support = {AG081981/AG/NIA NIH HHS/United States ; AG074552/AG/NIA NIH HHS/United States ; AWD016559//Glenn Foundation for Medical Research/ ; },
abstract = {INTRODUCTION: Declines in function occur in both "normal" aging (in the absence of disease) and age-related pathological contexts, like Alzheimer's disease (AD). Whether "anti-aging" interventions (that extend lifespan) also promote cognitive function in aging and AD remains largely unexplored.

METHODS: We assessed the effect of acarbose (1000 ppm from 4 months of age) on spatial learning and memory using the Morris water maze in young adult (6 mo), mid-aged (12 mo), or aged (24 mo) cohorts of normal aging (Ntg-HET3) and AD-relevant (5xFAD-HET3) genetically heterogeneous mice.

RESULTS: In middle-aged and aged Ntg-HET3 mice, acarbose (ACA) treatment moderately improved age-related deficits in spatial learning and robustly ameliorated impairments in spatial memory, maintaining performance at levels equivalent to young adults, with a progressively greater effect at older ages. Conversely, ACA failed to improve progressively worsening AD-related cognitive impairments in 5xFAD-HET3 mice.

DISCUSSION: This work demonstrates that anti-aging interventions can also promote cognitive longevity in normal aging. Further, it highlights that AD does not simply reflect an accelerated aging process and requires therapies beyond anti-aging interventions that target its unique molecular and cellular drivers.},
}

@article {pmid43019091,
year = {2026},
author = {Iglesias, JE and Johnson, IP and Williams-Ramirez, J and Zemlyanker, D and Tian, L and Gopinath, K and Olchanyi, M and Farnan, AD and Demopoulos, A and Rosen, MS and Sheth, KN and de Havenon, A and Kimberly, WT and Sorby-Adams, A},
title = {On the accuracy of nonlinear image registration in portable low-field 3D brain MRI.},
journal = {Scientific reports},
volume = {16},
number = {},
pages = {34965},
pmid = {43019091},
issn = {2045-2322},
mesh = {*Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging ; Humans ; Algorithms ; *Imaging, Three-Dimensional/methods ; *Image Processing, Computer-Assisted/methods ; Signal-To-Noise Ratio ; Nonlinear Dynamics ; },
abstract = {Portable low-field MRI offers an affordable and mobile alternative to conventional high-field scanners, enabling imaging in point-of-care and resource-limited settings. However, its lower signal-to-noise ratio, reduced resolution, and acquisition artifacts raise concerns about the accuracy of standard image registration methods. Reliable nonlinear registration is critical for a wide range of emerging applications, including frequent brain monitoring, assessment of neurodegenerative disease progression, and evaluation of treatment effects such as those associated with Alzheimer's therapeutics. In this work, we systematically evaluated state-of-the-art registration approaches on simulated low-field scans (obtained by downsampling high-field images) and on real low-field brain MRI data. We compared three approaches that are representative of current registration methods: classical optimization (NiftyReg), learning-based registration (SynthMorph), and synthesis-based registration (SynthSR+NiftyReg). Using downsampled high-field scans, all methods performed well, achieving high Dice scores and smooth deformation fields, indicating that reduced resolution alone does not hinder registration. In contrast, real low-field data exhibited lower accuracy, primarily due to geometric distortion and other acquisition-specific artifacts. Among the tested approaches, the synthesis-based pipeline achieved the most robust performance across subjects and modalities. Overall, existing algorithms can accommodate resolution limitations, however, future methods could further enhance coregistration by explicitly addressing the distortions present in low-field MRI scans.},
}

*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging
Humans
Algorithms
*Imaging, Three-Dimensional/methods
*Image Processing, Computer-Assisted/methods
Signal-To-Noise Ratio
Nonlinear Dynamics

@article {pmid43019186,
year = {2026},
author = {De Francisci, M and Faggionato, E and Dalla Man, C and Lee, JJ and Metcalf, N and Raichle, ME and Morris, JC and Benzinger, TLS and Vlassenko, AG and Bertoldo, A and Goyal, MS},
title = {Full-compartmental modeling of [[18]F]FDG PET suggests divergent brain metabolism trajectories from healthy aging to early Alzheimer disease.},
journal = {Scientific reports},
volume = {16},
number = {},
pages = {35963},
pmid = {43019186},
issn = {2045-2322},
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging/pathology ; Humans ; *Positron-Emission Tomography/methods ; *Fluorodeoxyglucose F18 ; *Brain/metabolism/diagnostic imaging ; Female ; Glucose/metabolism ; Male ; *Aging/metabolism ; Aged ; Radiopharmaceuticals ; Aged, 80 and over ; },
abstract = {UNLABELLED: Within the Alzheimer disease (AD) spectrum, metabolic alterations occur in addition to proteinopathies. While hypometabolism is frequently observed in the late symptomatic stages, characterizing the metabolic changes during early AD stages might aid in both understanding its pathophysiology and in patient selection for future treatments. In this study, we conduct an exploratory, data-driven analysis aimed at better understanding the timing and specificity of the metabolic changes in early AD. Using kinetic analysis of [[18]F]FDG PET brain imaging data coming from 223 individuals, including 33 preclinical individuals and 19 symptomatic individuals, we find new evidence of a more complex spatiotemporal trajectory of glucose metabolism in early AD, which includes a paradoxical regional increase in glucose phosphorylation during preclinical AD. These findings suggest that the pathologic phases of AD parallel changes in brain glucose metabolism, which is readily assessable with [[18]F]FDG PET imaging. Moreover, they may indicate that metabolic interventions may work differently during preclinical AD as compared to the early symptomatic phase.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-64573-x.},
}

*Alzheimer Disease/metabolism/diagnostic imaging/pathology
Humans
*Positron-Emission Tomography/methods
*Fluorodeoxyglucose F18
*Brain/metabolism/diagnostic imaging
Female
Glucose/metabolism
Male
*Aging/metabolism
Aged
Radiopharmaceuticals
Aged, 80 and over

@article {pmid43019187,
year = {2026},
author = {Milicic, L and Vacher, M and Bourgeat, P and Doré, V and Shishegar, R and Maruff, P and Masters, CL and Rowe, CC and Villemagne, VL and Porter, T and Laws, SM and , and , },
title = {Peripheral DNA methylation of candidate Alzheimer's disease risk genes and its associations with cognition, brain volume and amyloid-β burden.},
journal = {Scientific reports},
volume = {16},
number = {},
pages = {35889},
pmid = {43019187},
issn = {2045-2322},
mesh = {Humans ; *DNA Methylation ; *Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging ; *Amyloid beta-Peptides/metabolism ; *Cognition ; *Brain/pathology/metabolism/diagnostic imaging ; Female ; Male ; Aged ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Magnetic Resonance Imaging ; CpG Islands ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {UNLABELLED: Alzheimer's disease (AD) is a growing major public health issue, affecting millions of people worldwide. Genome-wide association studies (GWAS) have identified over 50 loci associated with late-onset AD risk. However, most disease-associated variants are located in noncoding regions of the genome, making it difficult to elucidate exactly how disease risk is affected. Variants within noncoding regions can modulate disease risk through mechanisms such as gene expression regulation, which can be regulated by DNA methylation, which has, in recent years, been implicated in dementia and AD. This study utilised data from two well-characterised longitudinal studies, the Australian Imaging, Biomarker and Lifestyle (AIBL) study (n = 565) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 533), and aimed to investigate the association between peripheral blood DNA methylation at CpG sites located in previously implicated AD-risk genes and cognition, MRI volumetric measures and brain Aβ-amyloid (Aβ) burden. Analyses were undertaken across the preclinical to prodromal population as well as within subsets classified by clinical diagnosis and Aβ burden using two methods: all CpG sites within a candidate gene and a representative site from each gene region with the greatest variance (mean absolute deviation; MAD). We identified numerous associations in the AIBL cohort that remained significant after correction for the false discovery rate, although only one novel site was validated in the ADNI cohort. This was located within the gene body region of CR1 (cg00416522) and was associated with ventricle volume in cognitively unimpaired individuals with high brain Aβ burden. While this study's results contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related traits, they suggest that there are limited associations of peripheral DNA methylation with cognitive and neuroimaging traits in the a priori AD-risk genes that were screened in this study. Future meta-analyses across studies with larger cohort sizes and phenotypically rich datasets will help to confirm this finding and potentially elucidate further associations, while unbiased approaches are warranted and may uncover novel peripheral DNA methylation associations.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-64935-5.},
}

Humans
*DNA Methylation
*Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging
*Amyloid beta-Peptides/metabolism
*Cognition
*Brain/pathology/metabolism/diagnostic imaging
Female
Male
Aged
Genetic Predisposition to Disease
Genome-Wide Association Study
Magnetic Resonance Imaging
CpG Islands
Aged, 80 and over
Longitudinal Studies

@article {pmid43019193,
year = {2026},
author = {Park, J and Jeong, SY and Kim, JH},
title = {Hearing loss drives region-specific amyloid accumulation along the auditory pathway in female 5xFAD mice.},
journal = {Scientific reports},
volume = {16},
number = {},
pages = {34914},
pmid = {43019193},
issn = {2045-2322},
mesh = {Animals ; Female ; *Alzheimer Disease/metabolism/pathology ; Mice ; Male ; *Amyloid beta-Peptides/metabolism ; *Plaque, Amyloid/metabolism/pathology ; *Auditory Pathways/metabolism/pathology/physiopathology ; *Hearing Loss/metabolism/physiopathology/pathology ; Mice, Transgenic ; Microglia/metabolism/pathology ; Inferior Colliculi/metabolism/pathology ; Disease Models, Animal ; },
abstract = {UNLABELLED: Hearing loss is a major modifiable risk factor for Alzheimer's disease (AD), but how auditory deprivation engages specific neural circuits, particularly in a sex-dependent manner, to promote amyloid pathology remains unclear. We examined whether sound deprivation alters amyloid-beta (Aβ) deposition, auditory neural activity, and cognition in 5xFAD mice. Notably, sound deprivation using bilateral earplugging from 2 to 4 months selectively increased Aβ plaque burden in the inferior colliculus (IC) of female 5xFAD mice, with no comparable effect in males. This IC-selective pathology was accompanied by increased c-Fos expression in the IC. Microglial density was unchanged, but earplugging increased the fraction of plaque-associated microglia and reduced microglia-plaque distance specifically in the IC, suggesting local amplification of AD-related pathology at the plaque interface. 5xFAD mice without deprivation retained intact novel object recognition (NOR) at 6 months. In contrast, female 5xFAD mice with prior earplugging developed a selective NOR deficit despite no detectable increase in hippocampal plaque burden, whereas males remained unaffected. Together, these findings identify the IC as a female-vulnerable locus where transient sound deprivation drives persistent auditory-circuit hyperactivity, remodels microglia-plaque interactions, and accelerates region-specific amyloid pathology with extra-hippocampal cognitive consequences, highlighting sensory loss as modifiable risk factor in prodromal AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-64191-7.},
}

Animals
Female
*Alzheimer Disease/metabolism/pathology
Mice
Male
*Amyloid beta-Peptides/metabolism
*Plaque, Amyloid/metabolism/pathology
*Auditory Pathways/metabolism/pathology/physiopathology
*Hearing Loss/metabolism/physiopathology/pathology
Mice, Transgenic
Microglia/metabolism/pathology
Inferior Colliculi/metabolism/pathology
Disease Models, Animal

@article {pmid43019413,
year = {2026},
author = {Smith, JE},
title = {The sideshow.},
journal = {Science (New York, N.Y.)},
volume = {394},
number = {6825},
pages = {712-715},
doi = {10.1126/science.aeo0622},
pmid = {43019413},
issn = {1095-9203},
mesh = {Humans ; *Neurons/pathology ; *Alzheimer Disease/pathology/physiopathology ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {How an unpopular hypothesis linking Alzheimer's disease to the loss of crucial neurons made a comeback.},
}

Humans
*Neurons/pathology
*Alzheimer Disease/pathology/physiopathology
Animals
Amyloid beta-Peptides/metabolism

@article {pmid43019495,
year = {2026},
author = {Lalive, HM and Ribaldi, F and Mendes, AJ and Wang, C and Chicherio, C and Piazza, F and Frias, MA and Kern, I and Boccalini, C and Harput, E and Garibotto, V and Scheffler, M and Lovblad, KO and Frisoni, GB and Lathuiliere, A},
title = {Cerebral Amyloid Angiopathy in Alzheimer Disease Continuum: Prevalence and Clinical Relevance in a Biomarker-Defined Memory Clinic Cohort.},
journal = {Neurology},
volume = {107},
number = {11},
pages = {e218738},
doi = {10.1212/WNL.0000000000218738},
pmid = {43019495},
issn = {1526-632X},
mesh = {Humans ; Female ; *Cerebral Amyloid Angiopathy/epidemiology/diagnostic imaging/cerebrospinal fluid ; Male ; *Alzheimer Disease/epidemiology/diagnostic imaging/cerebrospinal fluid/complications ; Aged ; Biomarkers/cerebrospinal fluid ; Prevalence ; Retrospective Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; Positron-Emission Tomography ; Aged, 80 and over ; Cohort Studies ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy (CAA) frequently co-occurs with Alzheimer disease (AD), yet the prevalence and clinical significance of comorbid CAA among cognitively impaired individuals on the AD continuum remain unclear. We aimed to determine the frequency of probable CAA (Boston criteria v2.0) in a memory-clinic cohort of symptomatic amyloid-positive individuals and to compare demographic, clinical, cognitive, and biomarker profiles between those with and without comorbid probable CAA.

METHODS: We conducted a retrospective cohort study at the Geneva Memory Center including amyloid-positive patients confirmed by CSF or amyloid PET. Participants meeting the Boston criteria v2.0 for probable CAA were classified as AD-probable CAA, whereas those with possible or no CAA were classified as AD-nonprobable CAA. Group differences were assessed using standard parametric and nonparametric tests, linear mixed-effects models for cognitive trajectories, logistic regression for cerebral microbleed (CMB)-CSF biomarker associations, and voxel-wise Statistical Parametric Mapping for regional amyloid PET differences.

RESULTS: Among 533 participants (mean age 73.8 ± 6.7 years, 59% female), 148 (28%) met criteria for probable CAA. Demographic characteristics, baseline cognition (mini-mental state examination: rank-biserial r = -0.05, 95% CI -0.16 to 0.07, p = 0.410), and longitudinal cognitive decline (β = -0.02, 95% CI -0.05 to 0.02, p = 0.309; median follow-up 28.1 months) did not differ between groups. Lower CSF Aβ42 was associated with lobar CMB burden (odds ratio per 1 SD decrease = 1.48, 95% CI 1.14-1.92, p = 0.004). Voxel-wise PET analyses revealed higher cortical amyloid uptake in AD-probable CAA with tracer-dependent patterns (cluster-level family-wise error p < 0.05).

DISCUSSION: More than one-quarter of amyloid-positive patients fulfilled the Boston criteria v2.0 for probable CAA. Probable CAA was not associated with a distinct clinical presentation or trajectory of cognitive decline. Higher cortical amyloid PET uptake in probable CAA and the association of lower CSF Aβ42 with lobar CMB burden suggest more prominent cerebral amyloidosis in this population. The binary probable CAA label may therefore reflect greater amyloid burden without necessarily delineating a clinically distinct subgroup within the AD continuum. Marker-specific approaches targeting cortical superficial siderosis and high lobar CMB burden may prove more informative.},
}

Humans
Female
*Cerebral Amyloid Angiopathy/epidemiology/diagnostic imaging/cerebrospinal fluid
Male
*Alzheimer Disease/epidemiology/diagnostic imaging/cerebrospinal fluid/complications
Aged
Biomarkers/cerebrospinal fluid
Prevalence
Retrospective Studies
Amyloid beta-Peptides/cerebrospinal fluid
Positron-Emission Tomography
Aged, 80 and over
Cohort Studies
Peptide Fragments/cerebrospinal fluid

@article {pmid43019496,
year = {2026},
author = {Oliveira, TG},
title = {Cerebral Amyloid Angiopathy Brain MRI Boston Criteria v2.0: Are We Ready to Implement Them in the Study of Patients With Alzheimer Disease?.},
journal = {Neurology},
volume = {107},
number = {11},
pages = {e218815},
doi = {10.1212/WNL.0000000000218815},
pmid = {43019496},
issn = {1526-632X},
}

@article {pmid43019701,
year = {2026},
author = {Dai, L and Chen, SX and Yang, ZC},
title = {Clinical application progress of neural stem cells.},
journal = {Current opinion in pharmacology},
volume = {91},
number = {},
pages = {102683},
doi = {10.1016/j.coph.2026.102683},
pmid = {43019701},
issn = {1471-4973},
abstract = {Neural stem cells (NSCs) possess self-renewal capacity and multipotent differentiation potential. While endogenous NSC function declines in neurodegenerative diseases, exogenous NSC transplantation exhibits therapeutic efficacy against brain disorders, such as Alzheimer's, Parkinson's, stroke, and traumatic brain injury, via cell replacement, promoting neurotrophic factor secretion, and immunomodulation. Furthermore, combining NSCs with nanoparticles or traditional medicines enhances therapeutic outcomes, while their inherent tumor tropism enables targeted anticancer drug delivery. However, clinical translation faces significant hurdles, including safety risks (tumorigenicity and immune rejection), sourcing constraints, ethical concerns, and microenvironmental sensitivity. Optimizing cryopreservation technology to establish high-quality NSC banks and constructing sound regulatory frameworks represent critical solutions. This review systematically summarizes the therapeutic mechanisms, clinical progress, and translational barriers of NSC-based therapies. Moving forward, accelerating clinical translation requires elucidating underlying mechanisms, optimizing isolation, culture, and preservation protocols, strengthening safety evaluations, and refining regulatory governance.},
}

@article {pmid43020013,
year = {2026},
author = {Zhou, J and Wang, Y and Li, M and Ma, S},
title = {Mapping primate brain aging across cell types, regions, and sexes.},
journal = {Cell},
volume = {189},
number = {23},
pages = {7256-7258},
doi = {10.1016/j.cell.2026.10.021},
pmid = {43020013},
issn = {1097-4172},
mesh = {Animals ; *Brain/physiology/metabolism ; *Aging ; Female ; Male ; Humans ; Brain Mapping ; Alzheimer Disease ; Macaca ; },
abstract = {Aging is the major risk factor for neurodegenerative disease, yet how it affects different cells in the primate brain remains unclear. In this issue of Cell, Yang et al. present a single-nucleus atlas of the aging macaque brain that, together with recent work by Zhang et al., reveals context-dependent aging programs, sex-biased transcriptional aging, and molecular links to Alzheimer's disease.},
}

Animals
*Brain/physiology/metabolism
*Aging
Female
Male
Humans
Brain Mapping
Alzheimer Disease
Macaca

@article {pmid43020032,
year = {2026},
author = {Yang, W and Watkins, KL and DeCasien, AR and O'Neill, MB and Bohlen, MO and O'Day, DR and Smith, EA and Duran, M and Qiu, C and Meleshko, A and Vo, A and Menke, M and Calderon, D and , and Sallet, J and Higham, JP and Martínez, MI and Trapnell, C and Starita, LM and Montague, MJ and Platt, ML and Chiou, KL and Shendure, J and Snyder-Mackler, N},
title = {Single-cell, multi-region profiling of the macaque brain across the lifespan.},
journal = {Cell},
volume = {189},
number = {23},
pages = {7571-7592.e7},
doi = {10.1016/j.cell.2026.09.014},
pmid = {43020032},
issn = {1097-4172},
mesh = {Animals ; *Brain/metabolism ; Male ; *Aging/genetics ; Female ; *Single-Cell Analysis/methods ; Macaca mulatta ; Transcriptome/genetics ; Neurons/metabolism ; Neuroglia/metabolism ; *Longevity/genetics ; Alzheimer Disease/genetics/metabolism/pathology ; Single-Cell Gene Expression Analysis ; },
abstract = {Brain aging is a complex process with profound health and societal consequences. However, the molecular and cellular pathways that govern its progression, and inter- and intra-individual variation, remain poorly defined. We present a transcriptomic atlas of 5.3 million cells from 582 samples spanning 11 brain regions of 55 rhesus macaques (aged 0.5-21 years). We identify age-depleted and vulnerable neuronal populations and subtle, age-associated compositional differences in glia-detectable only at single-cell resolution. We chart convergent and divergent age-associated molecular signatures across regions and cell types, which include sex-specific signatures that could underlie biases in neurological disorders. These signatures overlap those of Alzheimer's disease (AD), which suggests that aging and AD share molecular roots that emerge at different ages and in region- and sex-specific windows of vulnerability. This work provides a temporal, regional, and sex-stratified atlas of the aging primate brain, offering insights into cell-type-specific vulnerabilities and regional heterogeneity with translational human relevance.},
}

Animals
*Brain/metabolism
Male
*Aging/genetics
Female
*Single-Cell Analysis/methods
Macaca mulatta
Transcriptome/genetics
Neurons/metabolism
Neuroglia/metabolism
*Longevity/genetics
Alzheimer Disease/genetics/metabolism/pathology
Single-Cell Gene Expression Analysis

@article {pmid43020054,
year = {2026},
author = {Kana, OZ and Postupna, N and Agrawal, A and Long, B and Travaglini, KJ and Gabitto, MI and Lai, HY and Mahoney, JT and Xiao, M and Bajwa, T and Hulsey-Vincent, H and Oyaizu, SL and Mena, GE and Hong, J and Gelfand, EC and Kaplan, ES and Ariza, J and Smith, KA and McMillen, DA and Chakka, AB and Goldy, J and Melief, EJ and Barta, S and Oyama, A and Ruiz, A and Pom, CA and Ayala, A and Bixby, M and Huang, A and Martin, N and Cuevas, NV and Olsen, P and Nagra, J and Chakrabarty, R and Tieu, M and Cardenas, T and Torkelson, A and Bertagnolli, D and Guzman, J and Ferrer, R and Waters, J and Grabowski, TJ and Crane, PK and Gatto, NM and Miller, JA and Hodge, RD and Hawrylycz, M and Keene, CD and Lein, ES and Close, JL},
title = {Amyloid and tau display distinct patterns across Alzheimer's in anterior caudate.},
journal = {Cell genomics},
volume = {},
number = {},
pages = {101427},
doi = {10.1016/j.xgen.2026.101427},
pmid = {43020054},
issn = {2666-979X},
abstract = {The anterior caudate shows a pattern of Alzheimer's disease pathology that differs from the more extensively studied cortex. Across 41 donors, we found mostly diffuse amyloid beta plaques in gray matter and phosphorylated tau threads associated with white matter. Combining digital pathology with single-nucleus and spatial gene expression data, we detected no significant loss or gain in neuronal cell-type abundance with increasing pathology. However, we did observe increases in an FLT1+/IL1B+ microglial population with tau burden. Fast-spiking PTHLH-PVALB interneurons showed changes in genes related to ion channels, cellular trafficking, and phosphorylation. These findings offer a cellular-resolution reference for investigating how Alzheimer's disease affects subcortical brain regions.},
}

@article {pmid43020055,
year = {2026},
author = {Liu, T and Ko, E and Yang, Y and Wu, H and Unjitwattana, T and Wang, S and Kang, J and Li, Y and Garmire, LX},
title = {Population-scale integration of spatial omics networks for clinical prediction and biological discovery by SPIN.},
journal = {Cell genomics},
volume = {},
number = {},
pages = {101420},
doi = {10.1016/j.xgen.2026.101420},
pmid = {43020055},
issn = {2666-979X},
abstract = {Spatial omics enables the integration of high-dimensional molecular organization with clinical outcomes, yet incorporating spatial single-cell information into predictive models at the population scale remains challenging. We introduce SPIN (spatial predictive integration network), which integrates subject-specific, cell-type level, spatially informed co-expression or co-abundance networks for population-scale clinical prediction. Current implementation of SPIN includes three key modules: network construction, molecular-to-clinical prediction by Bayesian scalar-on-network regression with manifold learning (BSNMani), and visualization & interpretation module. In the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) multiplexed error-robust fluorescence in situ hybridization (MERFISH) transcriptomics cohort, SPIN achieved an accuracy of 0.81 for dementia-status prediction and revealed co-expression subnetworks with clear biological relevance. SPIN also achieved robust survival prediction in a breast cancer single-cell proteomics cohort (C-index = 0.78), identifying two survival-associated spatial proteomic subnetworks. In summary, SPIN is an interpretable tool for spatial-omics-based clinical outcome prediction at the population scale.},
}

@article {pmid43009035,
year = {2026},
author = {Muskan, A and Khan, AU and Malik, I},
title = {Neuroprotective effects of remdesivir in ICV-STZ induced Alzheimer-like pathology: Potential involvement of ACE2-associated signaling.},
journal = {European journal of pharmacology},
volume = {1040},
number = {},
pages = {179539},
doi = {10.1016/j.ejphar.2026.179539},
pmid = {43009035},
issn = {1879-0712},
abstract = {Alzheimer's disease involves interacting metabolic, oxidative, and inflammatory disturbances, with accumulating evidence implicating dysregulation of the brain renin-angiotensin system in disease-related pathology. This study investigated the neuroprotective effects of remdesivir against intracerebroventricular streptozotocin (ICV-STZ)-induced Alzheimer-like pathology and examined the potential involvement of ACE1/ACE2-associated signaling. Following ICV-STZ administration on Days 1 and 3, remdesivir treatment was initiated on Day 4 and continued once daily through Day 31. Remdesivir was evaluated using molecular docking, molecular dynamics simulation, behavioral testing, cholinesterase inhibition assays, biochemical analyses, ELISA, immunohistochemistry, qRT-PCR, Western blotting, and histopathology. ICV-STZ induced memory-related and affective-like behavioral impairments, altered exploratory activity, reduced ACE2 expression, increased ACE1 expression, oxidative stress, NLRP3/NF-κB-associated neuroinflammation, amyloid/tau-related alterations, and neuronal degeneration. Remdesivir dose-dependently improved behavioral and biochemical outcomes, increased ACE2 expression, reduced ACE1 expression, and attenuated neuroinflammation, oxidative injury, and neurodegeneration, with the most pronounced effects observed at 30 mg/kg. Pharmacological modulation with DX600 and diminazene aceturate altered the protective effects of remdesivir, providing supportive but not definitive evidence for the involvement of ACE2-associated signaling. However, ACE2 enzymatic activity and downstream Ang-(1-7)/Mas receptor signaling were not directly assessed. Remdesivir also inhibited AChE and BChE, with IC50 values of 237.4 μM and 535.7 μM, respectively. These findings demonstrate that early remdesivir intervention attenuates the development of ICV-STZ-induced Alzheimer-like pathology and suggest that modulation of the ACE1/ACE2 expression balance may be associated with its antioxidant, anti-inflammatory, and neuroprotective effects.},
}

@article {pmid43009349,
year = {2026},
author = {Wei, M and Zhang, J and Liu, X and Liu, R and Yao, L and Ni, J and Li, T and Li, F and Shi, J and Tian, J and , },
title = {Plasma p-tau217 as a biomarker mapping cognitive impairment in Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100311},
doi = {10.1016/j.inpsyc.2026.100311},
pmid = {43009349},
issn = {1741-203X},
abstract = {OBJECTIVE: Plasma p-tau217 is a well-established biomarker of Alzheimer disease (AD) pathology, but its relationship with cognitive status and longitudinal cognitive change remains less well characterized. We investigated the clinical relevance of plasma p-tau217 as a blood-based biological correlate of cognitive status and change in AD.

METHODS: We included 1147 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available plasma biomarkers and amyloid-β (Aβ) status determined by amyloid PET or cerebrospinal fluid Aβ42. Cross-sectional associations between plasma p-tau217 and cognitive performance were evaluated across clinical stages and by Aβ status. Longitudinal associations between baseline plasma p-tau217 and subsequent cognitive change, as well as between changes in p-tau217 and changes in cognition, were assessed using linear mixed-effects models and correlation analyses. Baseline to last follow-up change correlations and separated within-person from between-person associations were also analyzed.

RESULTS: Plasma p-tau217 were higher at more advanced clinical stages, particularly among Aβ+ participants. In the Aβ positive group, higher p-tau217 was associated with poorer baseline MMSE, CDR-SB, and ADAS-Cog13 scores (partial ρ = -0.46, 0.52, and 0.55, respectively). Higher baseline p-tau217 was associated with greater subsequent worsening on all three measures at nominal P < 0.05. Increases in p-tau217 were associated with concurrent worsening in ADAS-Cog13 and CDR-SB (P = 0.001 and P = 0.011, respectively, but not MMSE. Exploratory analyses identified a within-person association between p-tau217 increases and ADAS-Cog13 worsening. Associations were less consistent among Aβ- participants.

CONCLUSION: Plasma p-tau217 was associated with cognitive impairment and longitudinal cognitive change, particularly among Aβ+ participants. These findings support plasma p-tau217 as a potential blood-based biological correlate of cognitive status and longitudinal cognitive change in AD.},
}

@article {pmid43009422,
year = {2026},
author = {Zhao, T and Levey, AI and Liang, SH},
title = {[18]F-Florquinitau PET for imaging tau pathology in Alzheimer's disease.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2026.10.001},
pmid = {43009422},
issn = {1873-3735},
}

@article {pmid43009438,
year = {2026},
author = {Pourbarkhordar, V and Rahmani, S and Hosseinzadeh, H and Mehri, S},
title = {The Effect of Natural Compounds on Cognitive Impairment Through BDNF/TrkB/CREB Pathway: A Review.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70517},
pmid = {43009438},
issn = {1099-1573},
abstract = {Considering the global prevalence of Alzheimer's disease (AD) and the restrictions of current treatment procedures, natural compounds (such as curcumin, hesperidin, and rutin) have been evaluated as multifaceted therapeutic agents. This review demonstrated that these compounds employ neuroprotective effects primarily through upregulating the brain-derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element binding protein (BDNF/TrkB/CREB) pathway. After inducing this pathway, they subsequently decrease apoptosis through the regulation of B-cell lymphoma protein 2-associated X/B-cell lymphoma 2 protein (Bax/Bcl2) ratio and the inhibition of apoptosis signal-regulating kinase 1 (ASK1) (e.g., icariin). They also modulate oxidative stress via increasing superoxide dismutase, catalase, and glutathione peroxidase (e.g., hesperidin), and suppress neuroinflammation through the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (Nf-κB) and proinflammatory cytokines (e.g., curcumin). These compounds enhance the level of postsynaptic density protein (PSD-95), a key enhancer of neuronal plasticity, improve synaptic signaling (e.g., oleanolic acid), and reduce cognitive disorders by reducing the formation of amyloid beta (Aβ) plaques (e.g., rutin). The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway is modulated (e.g., icariin), and cholinergic neurons are restored (e.g., maslinic acid). Despite the beneficial potential of natural compounds, the extrapolation of their findings to clinical application requires more precise preclinical studies and validated biomarkers.},
}

@article {pmid43009540,
year = {2026},
author = {Lee, HJ and Lee, SJ},
title = {The neuro-inflammaging triangle: a self-amplifying circuit of protein pathology, senescence-associated secretory phenotype and innate immunity in neurodegenerative disease.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {43009540},
issn = {2092-6413},
support = {RS-2024-00336045//National Research Foundation of Korea (NRF)/ ; RS-2023-00266536//Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs)/ ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis, share common pathological features, including abnormal protein aggregation, chronic neuroinflammation and progressive neuronal loss. Ageing is the strongest risk factor, accompanied by a chronic, mild inflammatory state called 'inflammaging,' partly due to senescent cells producing senescence-associated secretory phenotype (SASP) factors. Innate immune DNA- and danger-sensing pathways, most notably the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes, convert cellular injury into chronic neuroinflammation. Here, we propose that protein pathology, SASP, and innate immune activation form a self-amplifying triangular circuit leading to age-related neurodegeneration. We present the cellular and molecular basis of each part and how microglia, astrocytes, oligodendrocyte precursor cells and neurons contribute. We outline treatment strategies, including senolytics, senomorphics, innate immune pathway inhibitors and metabolic restoration, and identify unresolved questions, including the reversibility of post-mitotic neuronal senescence, the relative contribution of each cell type and the translational challenge of interrupting the cycle. Collectively, the neuro-inflammaging triangle theory shifts focus from individual pathogenic entities to the self-amplifying circuit that sustains them, offering a unified mechanistic model to advance our understanding and treatment of age-related neurodegeneration.},
}

@article {pmid43009562,
year = {2026},
author = {Abbott, A},
title = {Some people are resistant to dementia - here's what their genes can teach us.},
journal = {Nature},
volume = {659},
number = {8140},
pages = {290-292},
pmid = {43009562},
issn = {1476-4687},
}

@article {pmid43009615,
year = {2026},
author = {Li, Y and Xia, X and Sun, Y and Jia, K and Yuan, P and Wei, R and Liang, Z and Shi, M and Li, C and Kleemann, K and Wang, S and Qi, X and Zhang, X and Zhu, J and Zhang, Y and Zhu, B and Liu, J and Wang, Y and Zheng, JC},
title = {Mitochondria-derived extracellular vesicles mediate Alzheimer's disease pathology through transmitting microglial Ggt1.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {43009615},
issn = {2662-8465},
support = {82271477//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82530039//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Extracellular vesicles (EVs) can modify pathological progression in Alzheimer's disease (AD), the most common neurodegenerative disease in older adults, by spreading pathogenic factors. However, the function of mitovesicles (mtVs)-a recently identified subset of EVs-in AD remain unknown. Here we show that release of mtVs is enriched in brain tissue from patients with AD and 5×FAD mice. Administration of 5×FAD mouse brain-derived mtVs (ADmtVs) induced AD-like behavioral and pathological changes in wild-type mice and accelerated disease progression of AD mice. Moreover, the release of mtVs was regulated by mitochondrial respiratory metabolism, and blocking the release of mtVs significantly alleviated AD-like phenotypes. Proteomic analysis identified Ggt1 as a highly enriched protein in ADmtVs. Inhibiting Ggt1 expression and activity mitigated AD-like phenotypes of 5×FAD mice and delayed ADmtV-induced disease progression, suggesting Ggt1 as a pathological cargo of ADmtVs. Our findings highlight the pathological roles of mtVs in AD and highlight mtVs and Ggt1 as potential therapeutic targets.},
}

@article {pmid43009667,
year = {2026},
author = {Chang, J and Dimter, E},
title = {Different Pipelines, Different EEG Microstate Results: Evidence from Dementia Samples.},
journal = {Brain topography},
volume = {40},
number = {1},
pages = {},
pmid = {43009667},
issn = {1573-6792},
mesh = {Humans ; *Electroencephalography/methods ; Female ; Male ; *Alzheimer Disease/physiopathology ; *Brain/physiopathology ; Aged ; *Frontotemporal Dementia/physiopathology ; Middle Aged ; Reproducibility of Results ; Bayes Theorem ; *Dementia/physiopathology ; Signal Processing, Computer-Assisted ; Clustering Algorithms ; Cluster Analysis ; },
abstract = {Electroencephalography (EEG) microstate analysis has been proposed as a potential biomarker for neurological disorders, yet the influence of analytic pipeline choices on clinical findings remains unclear. Resting-state EEG from patients with Alzheimer's disease (n = 36), frontotemporal dementia (n = 23), and healthy controls (n = 29) was analyzed using multiple microstate pipelines combining k-means or atomize-agglomerate hierarchical clustering with different temporal-smoothing conditions. Bayesian ANCOVA showed that evidence for group differences varied substantially across pipelines, particularly as a function of temporal smoothing. Rank-correlation analyses further demonstrated reduced agreement between smoothed and unsmoothed pipelines, indicating that smoothing altered the relative ordering of microstate temporal parameters across participants. To assess methodological stability, intra-subject split-half analyses were performed. Microstate topographies showed > 92% shared variance between independent data halves, whereas the reliability of duration, occurrence, and coverage varied across pipelines. Unsmoothed pipelines generally showed equal or greater split-half reliability for selected microstate B measures, and the reproducibility of clinical effect sizes differed by clustering algorithm and diagnostic contrast. These findings demonstrate that temporal smoothing and clustering choices can substantially influence the reliability and clinical interpretation of EEG microstate measures, underscoring the need for explicit pipeline validation in biomarker studies.},
}

Humans
*Electroencephalography/methods
Female
Male
*Alzheimer Disease/physiopathology
*Brain/physiopathology
Aged
*Frontotemporal Dementia/physiopathology
Middle Aged
Reproducibility of Results
Bayes Theorem
*Dementia/physiopathology
Signal Processing, Computer-Assisted
Clustering Algorithms
Cluster Analysis

@article {pmid43010096,
year = {2026},
author = {Ghazanfarpour, S and Das, RK and Ihnatovych, I and Sule, N and Sharikova, A and Aalinkeel, R and Khmaladze, A and Szigeti, K and Mahajan, SD},
title = {Raman spectroscopic identification of biochemical alterations in Alzheimer's disease brain tissue.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {43010096},
issn = {2051-5960},
mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; *Spectrum Analysis, Raman/methods ; *Brain/metabolism/pathology ; Female ; Aged, 80 and over ; Male ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by chronic inflammation, neuronal loss, and continuous decline in memory and cognitive function. Raman Spectroscopy (RS) offers a powerful, label‑free approach for detecting early biochemical alterations in AD by generating highly sensitive molecular fingerprints, which is valuable for identifying subtle changes associated with protein misfolding, lipid dysregulation, and oxidative stress, key processes underlying AD onset and progression. In our study, full‑spectrum RS revealed clear biochemical distinctions between control and AD brain tissues, as well as between Braak IV and Braak VI AD stages. Multivariate analytical methods, including Singular Value Decomposition (SVD) and Linear Discriminant Analysis (LDA), were applied to manage spectral complexity and highlight the principal biochemical contributors to AD pathology. Multiple Raman bands in the 1200-1800 cm[-1] region showed increased intensity in AD tissue, including 1296 cm[-1] (lipid CH2 deformation), 1440 cm[-1] (lipid/cholesterol deformation), 1554 cm[-1] (Amide II), 1585 cm[-1] (protein‑folding-related vibrations), and 1640-1680 cm[-1] (Amide I). These changes indicate enhanced protein aggregation, loss of ordered secondary structure, and extensive lipid membrane disorganization. Complementary gene‑expression analysis further demonstrated dysregulation of lipid homeostasis in AD, with altered expression of ABCA1, LIPE, CPT1A, PPARA, and SREBP‑1, indicating broad metabolic reprogramming. Together, the coordinated spectral and transcriptional shifts underscore lipid‑metabolic dysfunction as a central feature of AD. By capturing these molecular signatures, RS provides a promising tool for early detection and monitoring of AD progression.},
}

*Alzheimer Disease/pathology/metabolism
Humans
*Spectrum Analysis, Raman/methods
*Brain/metabolism/pathology
Female
Aged, 80 and over
Male

@article {pmid43010103,
year = {2026},
author = {Kano, M and Kimura, T and Yanagisawa, H and Yamashita, K and Tatsumi, L and Sakai, A and Li, X and Saido, TC and Saito, T and Takatori, S and Kikkawa, M and Tomita, T},
title = {Cryo-EM structure of pro-aggregant P301L/S320F double-mutant tau filaments formed in mouse brains following peripheral AAV delivery.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {43010103},
issn = {2051-5960},
support = {JP25KJ1009//Japan Society for the Promotion of Science/ ; JP23K06112//Japan Society for the Promotion of Science/ ; JP23H00394//Japan Society for the Promotion of Science/ ; GCL/IIW//University of Tokyo/ ; JP23dm0207073, JP24wm0625303//Japan Agency for Medical Research and Development/ ; JPMJMS2024-1//Moonshot Research and Development Program/ ; },
mesh = {Animals ; *tau Proteins/genetics/ultrastructure/metabolism ; *Brain/metabolism/pathology/ultrastructure ; Dependovirus/genetics ; Humans ; Cryoelectron Microscopy ; Mice ; Mutation ; Mice, Transgenic ; *Tauopathies/pathology/genetics/metabolism ; },
abstract = {Tauopathies are characterized by the accumulation of abnormally phosphorylated tau filaments, with disease-specific folds revealed by cryo-electron microscopy (cryo-EM). Here, we delivered a recombinant human tau carrying the P301L/S320F double mutation into App[NL-G-F]/MAPT double knock-in mice using a blood-brain-barrier-permeable AAV (AAV-PHP.eB), enabling rapid induction of tau aggregation in vivo. The mutant tau was systemically administered via retro-orbital injection, providing a minimally invasive approach for widespread neuronal transduction. Phosphorylated tau aggregation, as well as seeding activity, were observed without the need for exogenous seeds. Our cryo-EM analysis resolved a novel filament fold incorporating residues 279-329, in which the P301L and S320F mutations introduced stabilizing interactions that reinforced filament assembly. This conformation was distinct from previously reported folds, including Alzheimer and Pick tau filaments. Moreover, the filaments adopted a more compact architecture than those observed in patient-derived samples or other model mice. This finding demonstrates that P301L/S320F double-mutant tau adopts a structurally unique, highly aggregation-prone fold, and that this system provides a rapid platform for modeling tau filament formation.},
}

Animals
*tau Proteins/genetics/ultrastructure/metabolism
*Brain/metabolism/pathology/ultrastructure
Dependovirus/genetics
Humans
Cryoelectron Microscopy
Mice
Mutation
Mice, Transgenic
*Tauopathies/pathology/genetics/metabolism

@article {pmid43010123,
year = {2026},
author = {Kim, JS and Han, SS and Yoo, SH and Lee, DH and Jang, J and Lee, HJ and Song, JH and Hoe, HS},
title = {AI-Integrated multimodal neuroimaging in Alzheimer's disease: toward biologically informed precision diagnostics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {43010123},
issn = {1552-5279},
support = {//the KBRI basic research program through KBRI funded by the Ministry of Science/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Artificial Intelligence ; *Neuroimaging/methods ; *Multimodal Imaging/methods ; Brain/diagnostic imaging/pathology ; *Precision Medicine/methods ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD), which is characterized by the progressive accumulation of amyloid beta plaques and neurofibrillary tangles (NFTs), metabolic dysfunction, and neuroinflammation, is the most prevalent neurodegenerative disorder. The distinct pathological features of AD can be characterized in vivo via neuroimaging: Structural magnetic resonance imaging captures brain atrophy, while positron emission tomography detects Aβ/NFT deposition. The application of artificial intelligence (AI) can enhance the interpretation of neuroimaging data, but single-modality AI provides only limited biological information. This limitation has motivated the development of multimodal approaches that integrate complementary imaging, molecular, and clinical data for diagnosis and prognosis. However, there has been no comprehensive examination of how modality-specific neuroimaging information is incorporated into single-modality AI and subsequently integrated within multimodal frameworks. This review addresses this gap by evaluating conventional neuroimaging, single-modality AI, and multimodal AI as part of a unified framework, with particular emphasis on the added diagnostic and prognostic value of multimodal integration. We further identify key methodological and translational bottlenecks in developing clinically robust multimodal AI, including cross-modal and cross-cohort heterogeneity, model complexity, missing modalities, interpretability, and generalizability. Finally, we propose a translational roadmap emphasizing data harmonization, independent external validation, clinically meaningful explainability, and prospective evaluation. Ultimately, the clinical value of multimodal AI will depend on whether its added predictive value is reproducible across independent populations and translates into meaningful improvements in clinical decision-making and patient outcomes.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Artificial Intelligence
*Neuroimaging/methods
*Multimodal Imaging/methods
Brain/diagnostic imaging/pathology
*Precision Medicine/methods
Magnetic Resonance Imaging
Positron-Emission Tomography

@article {pmid43010124,
year = {2026},
author = {Bey, GS and Emrani, S and Kulick, ER and Román, CAF and De Anda-Duran, I and Ashford, MT and Boyle, R and Bubu, OM and Dixon, J and Franzen, S and Gao, PY and George, K and Guest, MA and Heston, MB and Heyn, P and Jackson, D and Krishnamurthy, S and Phillips, JS and Rirash, AF and Viswanathan, J and Zanwar, PP and Zuelsdorff, M and Stites, SD},
title = {Lifestyle interventions on Alzheimer's disease and related dementias: Social and structural determinants of implementation effectiveness and sustainability.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {43010124},
issn = {1552-5279},
support = {24PRE1200264//American Heart Association/ ; 3OT2OD032581-0151-184//Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity/ ; RF00280-SUB00278-FE//Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity/ ; R13AT012585-01A1/AT/NCCIH NIH HHS/United States ; //California Department of Public Health/ ; 10510032120004 NDPI/ZONMW_/ZonMw/Netherlands ; ADR A202033S//BrightFocus Foundation/ ; AARG-22-926144/ALZ/Alzheimer's Association/United States ; AARG-D-21-848397/ALZ/Alzheimer's Association/United States ; AARG-D-1244595/ALZ/Alzheimer's Association/United States ; 45127/PCORI/Patient-Centered Outcomes Research Institute/United States ; L32MD019916/MD/NIMHD NIH HHS/United States ; K23MD019232/MD/NIMHD NIH HHS/United States ; 23AG065442/AG/NIA NIH HHS/United States ; R00AG075327/AG/NIA NIH HHS/United States ; F32 AG072730-02/AG/NIA NIH HHS/United States ; U19AG024904/AG/NIA NIH HHS/United States ; K08AG086588/AG/NIA NIH HHS/United States ; P30AG073105/AG/NIA NIH HHS/United States ; RF1AG083975/AG/NIA NIH HHS/United States ; R01AG082278/AG/NIA NIH HHS/United States ; K23AG0868534A/AG/NIA NIH HHS/United States ; K01AG081499/AG/NIA NIH HHS/United States ; K00AG097172/AG/NIA NIH HHS/United States ; R13AG072884/AG/NIA NIH HHS/United States ; F30AG085932/AG/NIA NIH HHS/United States ; R01AG054519/AG/NIA NIH HHS/United States ; U54AG090792/AG/NIA NIH HHS/United States ; K23AG065442/AG/NIA NIH HHS/United States ; P30AG06619/AG/NIA NIH HHS/United States ; AARFD-23-1150584//Alzheimer's Association Research Fellowship/ ; SCN-25-1474727//Alzheimer's Association/Michael J. Fox Foundation/Cure PSP/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy ; *Life Style ; *Dementia/therapy ; *Social Determinants of Health ; },
abstract = {Alzheimer's disease and related dementias (ADRD) pose a global public health challenge, and epidemiological evidence underscores profound disparities in ADRD risk and outcomes that are rooted in social/structural determinants of health (S/SDOH). Yet, these determinants are seldom integrated into intervention design or implementation strategies. In this review, we identify S/SDOH that influence the equitable implementation of evidence-based ADRD lifestyle interventions across diverse groups and explore implications. Guided by Bronfenbrenner's ecological model, we: (1) examined theoretical foundations, focusing on how macrosystem and microsystem factors modulate implementation effectiveness across multiple intervention modalities; (2) synthesized empirical literature, highlighting successful and suboptimal intervention outcomes in marginalized populations; (3) identified critical gaps, especially where evidence on implementation across socially defined groups is lacking; and (4) discussed implications for enhancing design and policy for equitable ADRD intervention delivery. Our goal is to produce a conceptual and empirical synthesis that offers actionable guidance for clinicians, researchers, and policy makers.},
}

Humans
*Alzheimer Disease/therapy
*Life Style
*Dementia/therapy
*Social Determinants of Health

@article {pmid43010136,
year = {2026},
author = {Wu, M and Luan, Y and Xu, X and Mao, X and Lin, H and He, K and Huang, Q and Zhang, J and Kuang, S and Guan, Y and , and , and O'Bryant, S and Li, B and Guo, Q and Xie, F and Luo, B},
title = {Diabetes mellitus is associated with altered Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {43010136},
issn = {1552-5279},
support = {2022ZD0213800//STI2030-Major Projects/ ; 82171473//National Natural Science Foundation of China/ ; 82201583//National Natural Science Foundation of China/ ; 2025ZHYL035//Shanghai Municipal Health Commission/ ; LGL-3142-ADB510100//Lingang Laboratory Grant/ ; 2017QD081//Huashan Hospital/ ; 2022C03064//Key Research and Development Program of Zhejiang Province/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Female ; tau Proteins/metabolism/blood ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Male ; Aged ; *Brain/pathology/diagnostic imaging/metabolism ; *Diabetes Mellitus/pathology ; Cognitive Dysfunction/pathology ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Diabetes mellitus (DM) is a major risk factor for dementia, yet it remains unclear whether DM accelerates cognitive decline through amyloid beta (Aβ) or tau accumulation in Alzheimer's disease (AD).

METHODS: In this study, we included 2784 participants from three independent observational cohorts: the Chinese Preclinical Alzheimer's Disease Study (CPAS), the Alzheimer's Disease Neuroimaging Initiative (ADNI), and Health and Aging Brain Study-Health Disparities (HABS-HD). We examined the associations of DM with Aβ positron emission tomography (PET), tau PET, plasma phosphorylated tau (p-tau)217, and longitudinal cognitive change. We also tested whether DM modified the associations of Aβ and plasma p-tau217 with subsequent tau accumulation and explored the association of metformin use with tau accumulation.

RESULTS: We found that DM was associated with lower global Aβ burden and lower tau accumulation in CPAS and ADNI, in which cognitive impairment was more common than in HABS-HD. The associations of Aβ and plasma p-tau217 with tau accumulation were weaker among individuals with DM. In addition, DM was associated with reduced propagation of tau from early to later stage Braak regions. Longitudinal analyses in ADNI indicated that individuals with DM exhibited slower tau-related cognitive decline. In exploratory analyses, metformin use among individuals with DM was associated with lower tau accumulation compared to individuals without DM.

DISCUSSION: These findings suggest that DM is associated with an attenuation of amyloid- and tau-related processes, particularly in participants with cognitive impairment, and further suggest that diabetes-related mechanisms and its management may modulate the progression of AD pathology.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Female
tau Proteins/metabolism/blood
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
Male
Aged
*Brain/pathology/diagnostic imaging/metabolism
*Diabetes Mellitus/pathology
Cognitive Dysfunction/pathology
Aged, 80 and over
Longitudinal Studies

@article {pmid43010295,
year = {2024},
author = {Konis, G and Koenig, E and Takahashi, K and Iredale, P and Tugnait, M and Waksman, J and Chang, I and Blackmon, S and Perry, P and Leoni, M and Sanchez, R},
title = {EMPOWERing the Next-Generation: A Phase 2 Program to Evaluate Emraclidine, a Selective M4 Positive Allosteric Modulator (PAM), for the Treatment of Schizophrenia.},
journal = {CNS spectrums},
volume = {29},
number = {5},
pages = {495},
doi = {10.1017/S1092852924001548},
pmid = {43010295},
issn = {2165-6509},
abstract = {BACKGROUND: Emraclidine is a novel, highly selective positive allosteric modulator of M4 muscarinic acetylcholine receptors currently in development for the treatment of schizophrenia and Alzheimer's disease psychosis. By selectively activating M4 receptors, emraclidine may reduce excess dopamine signaling in the striatum, potentially leading to a reduction in psychotic symptoms. Unlike current antipsychotics, emraclidine does not interfere with signaling at dopamine, serotonin, or histamine receptors, which can lead to adverse events. A previous phase 1b study supports further investigation of emraclidine. The phase 2 EMPOWER program will fully evaluate the efficacy, safety, tolerability, and dose-range of once-daily (QD) emraclidine in schizophrenia.

METHODS: EMPOWER-1 and EMPOWER-2 are two adequately powered, multicenter, randomized, double-blind, placebo-controlled, parallel group, 6-week inpatient studies of emraclidine monotherapy (10 mg QD, 15 mg QD, 30 mg QD). The trials are enrolling adult participants with schizophrenia who are experiencing an acute exacerbation of psychosis. Eligible participants will have a Positive and Negative Syndrome Scale (PANSS) Total Score between ≥85 and ≤120 and a Clinical Global Impression - Severity (CGI-S) score ≥4 at baseline. Both de novo participants and those who complete EMPOWER-1 or EMPOWER-2 will be eligible to participate in EMPOWER-3, a 52-week open label extension trial to evaluate the long-term safety and tolerability of emraclidine in adult participants with stable schizophrenia.

RESULTS: Detailed study designs for the EMPOWER program will be presented. Primary outcome measure for EMPOWER 1 and 2 is change from baseline in PANSS total score at week 6. Other outcome measures include change from baseline in CGI-S score at week 6. Data from EMPOWER-3 will contribute to the overall evaluation of safety and tolerability of emraclidine in adult participants with schizophrenia.

CONCLUSIONS: The development of emraclidine is promising, as it selectively activates M4, a novel target that has been implicated in reducing psychotic symptoms while potentially avoiding many of the side effects currently associated with antipsychotics. The EMPOWER program aims to establish the efficacy, safety, tolerability, and appropriate dose-range of emraclidine in the treatment of schizophrenia.

FUNDING: Cerevel Therapeutics.},
}

@article {pmid43010306,
year = {2024},
author = {Brannan, SK and Cutler, AJ and Sawchak, S and Kando, J and Miller, AC and Claxton, A and Paul, SM and Kaul, I},
title = {Safety and Tolerability of KarXT (Xanomeline Trospium): Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials.},
journal = {CNS spectrums},
volume = {29},
number = {5},
pages = {515},
doi = {10.1017/S1092852924001901},
pmid = {43010306},
issn = {2165-6509},
abstract = {INTRODUCTION: In prior studies, the dual M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic activity in people with schizophrenia and Alzheimer's disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline's beneficial central nervous system effects while mitigating adverse events (AEs) due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia was demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

METHODS: The EMERGENT trials enrolled people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale total score ≥80, and Clinical Global Impression-Severity score ≥4. Eligible participants were randomized 1:1 to KarXT or placebo. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. Safety was assessed by monitoring for spontaneous AEs after administration of the first dose of trial drug until the time of discharge on day 35. Data from the EMERGENT trials were pooled, and all safety analyses were conducted in the safety population, defined as all participants who received ≥1 dose of trial drug.

RESULTS: A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the pooled safety analyses. Across the EMERGENT trials, 51.8% of people in the KarXT group compared with 29.4% in the placebo group reported ≥1 treatment-related AE. The most common treatment-relatedAEs occurring in ≥5% of participants receiving KarXT and at a rate at least twice that observed in the placebo group were nausea (17.1% vs 3.2%), constipation (15.0% vs 5.2%), dyspepsia (11.5% vs 2.3%), vomiting (10.9% vs 0.9%), and dry mouth (5.0% vs 1.5%). The most common treatment-related AEs in the KarXT group were all mild or moderate in severity.

CONCLUSIONS: In pooled analyses from the EMERGENT trials, KarXT was generally well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the efficacy results showing a clinically meaningful reduction in the symptoms of schizophrenia, support the potential of KarXT to be the first in a new class of antipsychotic medications based on muscarinic receptor agonism and a well-tolerated alternative to currently available antipsychotics.

FUNDING: Karuna Therapeutics.},
}

@article {pmid43010364,
year = {2024},
author = {Kaul, I and Citrome, L and Sawchak, S and Kando, J and Miller, AC and Paul, SM and Brannan, SK},
title = {Efficacy of KarXT (Xanomeline Trospium) in Schizophrenia: Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials.},
journal = {CNS spectrums},
volume = {29},
number = {5},
pages = {489-490},
doi = {10.1017/S1092852924001445},
pmid = {43010364},
issn = {2165-6509},
abstract = {INTRODUCTION: Prior studies demonstrated the antipsychotic activity of the dual M1/M4 preferring muscarinic receptor agonist xanomeline in people with schizophrenia and Alzheimer's disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline's beneficial central nervous system effects while mitigating side effects due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia were demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

METHODS: The EMERGENT trials randomized people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale (PANSS) total score ≥80, and Clinical Global Impression-Severity (CGI-S) score ≥4. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. In each trial, the primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Other efficacy measures included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and CGI-S scores. Data from the EMERGENT trials were pooled, and efficacy analyses were conducted in the modified intent-to-treat population, defined as all randomized participants who received ≥1 trial drug dose and had a baseline and ≥1 postbaseline PANSS assessment.

RESULTS: The pooled analyses included 640 participants (KarXT, n=314; placebo, n=326). Across trials, KarXT was associated with a significantly greater reduction in PANSS total score at week 5 compared with placebo (KarXT, -19.4; placebo, -9.6 [least squares mean (LSM) difference, -9.9; 95% CI, -12.4 to -7.3; P<0.0001; Cohen's d, 0.65]). At week 5, KarXT was also associated with a significantly greater reduction than placebo in PANSS positive subscale (KarXT, -6.3; placebo, -3.1 [LSM difference, -3.2; 95% CI, -4.1 to -2.4; P<0.0001; Cohen's d, 0.67]), PANSS negative subscale (KarXT, -3.0; placebo, -1.3 [LSM difference, -1.7; 95% CI, -2.4 to -1.0; P<0.0001; Cohen's d, 0.40]), PANSS Marder negative factor (KarXT, -3.8; placebo, -1.8 [LSM difference, -2.0; 95% CI, -2.8 to -1.2; P<0.0001; Cohen's d, 0.42]), and CGI-S scores (KarXT, -1.1; placebo, -0.5 [LSM difference, -0.6; 95% CI, -0.8 to -0.4; P<0.0001; Cohen's d, 0.63]).

CONCLUSIONS: In pooled analyses from the EMERGENT trials, KarXT demonstrated statistically significant improvements across efficacy measures with consistent and robust effect sizes. These findings support the potential of KarXT to be first in a new class of medications to treat schizophrenia based on muscarinic receptor agonism and without any direct dopamine D2 receptor blocking activity.

FUNDING: Karuna Therapeutics.},
}

@article {pmid43010397,
year = {2026},
author = {Zhang, Z and Ning, Y and Wu, Z and Sun, J and Gao, F},
title = {A pKa-Guided BBB-Permeable NIR Fluorescent Probe for Tracking Lipid Droplets in Microglia with Neuroinflammation and Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {98},
number = {44},
pages = {30825-30836},
doi = {10.1021/acs.analchem.6c04279},
pmid = {43010397},
issn = {1520-6882},
support = {22274003, 21874001, 21575004//National Natural Science Foundation of China (NSFC)/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; *Microglia/metabolism/chemistry ; Animals ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Blood-Brain Barrier/metabolism ; Mice ; *Lipid Droplets/metabolism/chemistry ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Optical Imaging ; Humans ; Infrared Rays ; Fluorescent Chemosensor Compounds ; Thiadiazoles/chemistry/chemical synthesis ; },
abstract = {Abnormal accumulation of lipid droplets (LDs), accompanied by altered microenvironmental polarity within the microglia, is closely associated with neuroinflammation and also has been increasingly recognized as an early and dynamic indicator of Alzheimer's disease (AD). Herein, a LD-targeting polarity-sensitive blood-brain barrier (BBB)-permeable near-infrared (NIR) probe, BTDN, was screened by tuning the electron-donating substituents to modulate the pKa values of benzothiadiazole-based derivatives. Endowed with the donor-acceptor-donor (D1-A-D2) architecture and strong intramolecular charge-transfer (ICT) characteristics, the BTDN probe exhibited high sensitivity to polarity change. The BTDN probe displayed suitable physicochemical properties such as a pKa of 7.47 and lipophilicity with a log P of 3.72 for favorable BBB-penetrating efficiency with a permeability percentage of 24.23%. In addition, the BTDN probe showed advantages for fluorescence imaging including NIR emission from 643 to 770 nm with the increased polarity, Stokes shift larger than 308 nm, comparable two-photon absorption capacity with an absorption cross-section of 10 GM at 870 nm, good biocompatibility, and robust photostability. Using this multifunctional BTDN probe, the dynamic fluorescence imaging of accumulation behaviors of LDs in BV2 microglia with neuroinflammation was performed, demonstrating that LD formation may serve as a potential biomarker for neuroinflammation. Furthermore, overproduced LDs within microglia were directly observed in vivo and in tissue sections from the brains of AD mice. This work not only provides an imaging tool for dynamically characterizing LD accumulation in microglia but also provides insights into the relationship between LD accumulation in microglia and AD pathogenesis.},
}

*Alzheimer Disease/diagnostic imaging/metabolism
*Microglia/metabolism/chemistry
Animals
*Fluorescent Dyes/chemistry/chemical synthesis
*Blood-Brain Barrier/metabolism
Mice
*Lipid Droplets/metabolism/chemistry
*Neuroinflammatory Diseases/diagnostic imaging/metabolism
Optical Imaging
Humans
Infrared Rays
Fluorescent Chemosensor Compounds
Thiadiazoles/chemistry/chemical synthesis

@article {pmid43010452,
year = {2026},
author = {Yin, G and Tan, W and Wang, D and He, Z and Dou, C and Wang, H and Lu, Q and Zhong, G and Du, F and Yin, P},
title = {Simultaneous Visualization of Labile Ferrous Iron Pool and Biothiols Reveals Divergent Pathological Trajectories in Ferroptosis and Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {98},
number = {44},
pages = {31348-31359},
doi = {10.1021/acs.analchem.6c05055},
pmid = {43010452},
issn = {1520-6882},
support = {2024JJ6088//Natural Science Foundation of Hunan Province/ ; 22277026//National Natural Science Foundation of China (NSFC)/ ; 22407018//National Natural Science Foundation of China (NSFC)/ ; 32303040//National Natural Science Foundation of China (NSFC)/ ; 23B0786//Research Foundation of Education Bureau of Hunan Province/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *Ferroptosis ; Animals ; *Ferrous Compounds/analysis/metabolism ; Humans ; Mice ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Sulfhydryl Compounds/metabolism/analysis ; Fluorescent Chemosensor Compounds ; Glutathione/analysis/metabolism ; *Iron/analysis/metabolism ; Cysteine/analysis/metabolism ; },
abstract = {Alzheimer's disease (AD) and ferroptosis share certain pathobiochemical features, yet the spatiotemporal evolution patterns and metabolic trajectories of their core hallmarks, labile ferrous iron pool and biothiols, and their pathophysiological relationship remain elusive. Herein, we developed a single-molecule dual-site fluorescent probe, FCG, for simultaneous discrimination of Fe2+, Cys/Hcy, and GSH via analyte-specific cascade reaction mechanisms. The probe exhibits rapid kinetics (k = 0.16-1.23 min-1), nanomolar sensitivity (detection limits: 38.8-509.2 nM), and well-separated emission signatures (Δλem ≥ 60 nm), facilitating concurrent visualization of these endogenous species dynamics in living systems. Importantly, application to cellular and mouse models revealed divergent metabolic pathways: ferroptosis displays synchronized labile ferrous iron pool accumulation, catastrophic lipid peroxidation, and global biothiols depletion, whereas AD exhibits modest iron elevation, a unique biothiols profile (elevated total Cys and Hcy but depleted GSH), and protein aggregation that is absent in ferroptosis. Comparative proteomic analysis further elucidated the molecular landscape of these dynamically regulated networks, as well as their distinct pathological metabolic trajectories. This study not only clarifies the mechanistic basis for the fundamentally different pathological trajectories underlying ferroptosis and AD but also provides critical evidence and analytical tools for targeted interventions in neurodegenerative diseases.},
}

*Alzheimer Disease/metabolism/pathology
*Ferroptosis
Animals
*Ferrous Compounds/analysis/metabolism
Humans
Mice
*Fluorescent Dyes/chemistry/chemical synthesis
*Sulfhydryl Compounds/metabolism/analysis
Fluorescent Chemosensor Compounds
Glutathione/analysis/metabolism
*Iron/analysis/metabolism
Cysteine/analysis/metabolism

@article {pmid43010991,
year = {2026},
author = {Lee, H and Ha, SY and An, H and Lee, SE and Oh, M and Kim, JS and Lee, JH and Lim, JS and Jang, H},
title = {CSF Biomarker-Supported Alzheimer's Disease Presenting as Primary Progressive Aphasia With a Negative Amyloid PET: A Case Report.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {4},
pages = {268-272},
pmid = {43010991},
issn = {2384-0757},
}

@article {pmid43010999,
year = {2026},
author = {Park, SH},
title = {Fetal Alcohol Spectrum Disorder as a Potential Early-Life Risk Factor for Dementia: A Life-Course Perspective.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {4},
pages = {195-209},
pmid = {43010999},
issn = {2384-0757},
abstract = {Current models of modifiable dementia risk span the life course but begin with formal education, leaving the prenatal period unexamined. Prenatal alcohol exposure (PAE) is the leading preventable cause of neurodevelopmental disability; its clinical expression is fetal alcohol spectrum disorder (FASD), of which fetal alcohol syndrome is the most severe form. FASD affects about 0.8% of children worldwide and considerably more in residential and foster care, yet its late-life trajectory is unstudied: the first diagnosed cohort is only now in its sixth decade. This review examines whether PAE may be an early-life dementia risk factor. In rodent models, developmental alcohol exposure produces hippocampal, cholinergic, and epigenetic changes demonstrable in adult animals; the report of Alzheimer-type markers in middle-aged exposed animals rests on a single unreplicated study. In humans, FASD is associated with low cognitive reserve, social adversity, and a high prevalence of adult alcohol use disorder, each an established dementia risk factor. Two hypotheses are distinguished: a pathology hypothesis, in which PAE promotes neurodegenerative change, and a reserve hypothesis, in which lower premorbid reserve brings forward clinical expression at comparable pathological burden. The expected phenotype is more likely mixed than purely Alzheimer-type. No human evidence yet links PAE to incident dementia; the proposition remains a hypothesis, not an established association. Given the mechanistic plausibility, examination is warranted through midlife biomarker studies and record linkage in cohorts with documented exposure; recording PAE in memory clinic history taking and at entry into residential and foster care would supply the data required.},
}

@article {pmid43011117,
year = {2026},
author = {Wang, Y and Lin, L and Xu, C and Zheng, Y and Zhu, Q},
title = {Association of systemic inflammation indices with severe cognitive impairment in Chinese Han patients with Alzheimer's disease: a cross-sectional study of NLR, PLR, SII, and SIRI.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1877189},
pmid = {43011117},
issn = {1663-4365},
abstract = {OBJECTIVE: The relationship between systemic inflammatory markers and cognitive impairment severity in Alzheimer's disease (AD) remains unclear. This study aimed to investigate the association of the neutrophil-to-lymphocyte ratio (NLR) and additional composite inflammatory indices-platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI)-with severe cognitive impairment (SCI) in Chinese Han patients with AD.

METHODS: This cross-sectional study included 282 Chinese Han patients with AD. Sociodemographic characteristics and biochemical indicators were collected, and NLR, PLR, SII, and SIRI were calculated. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), and SCI was defined as a MoCA score ≤9. Multivariable logistic regression was used to analyze the associations of the four inflammatory indicators with SCI risk. Smooth curve fitting and piecewise linear regression models were applied, with threshold effect analysis performed. Subgroup analyses were conducted according to sex, age, years of education, disease duration, diabetes, hemoglobin, triglycerides, and free triiodothyronine.

RESULTS: After adjustment for covariates, NLR was linearly and positively associated with SCI risk (OR = 1.17, 95% CI: 1.00-1.37, p = 0.048). Neither PLR nor SIRI showed a significant association with SCI after multivariable adjustment (p > 0.05). In contrast, SII exhibited a non-linear association with SCI risk, with an inflection point at approximately 861.9. Above this threshold, each unit increase in SII was associated with a higher risk of SCI (OR = 1.02, 95% CI: 1.01-1.04, p = 0.01), whereas no significant association was observed below the threshold (p = 0.06).

CONCLUSION: In Chinese Han patients with AD, NLR was independently and linearly associated with a higher risk of SCI, while SII showed a threshold effect; PLR and SIRI exhibited no independent associations after multivariable adjustment. Among the four composite inflammatory indices, NLR and SII may hold potential value for assessing cognitive impairment severity in AD, whereas the negative findings for PLR and SIRI suggest that not all composite inflammatory indices are independently associated with SCI.},
}

@article {pmid43011190,
year = {2026},
author = {Parlak, MM and Bozdağ, Ö and Bizpınar Munis, Ö},
title = {Applicability of the Turkish Version of the Quick Aphasia Battery in Individuals With Alzheimer's Disease.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {4},
pages = {228-242},
pmid = {43011190},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: Language impairment is a core clinical feature of Alzheimer's disease, emerging early and worsening progressively with disease stage. Although multidimensional language assessment tools are needed in Turkish clinical practice, validated rapid multidimensional batteries for this population remain limited. The Turkish version of the Quick Aphasia Battery (QAB-TR) covers eight language subdomains and can be administered in approximately 15 minutes. This study examined the applicability of QAB-TR in individuals with Alzheimer's disease (IwAD), its correlations with cognitive measures, and its sensitivity to disease stage.

METHODS: This cross-sectional study enrolled 55 IwAD (mild: n=19, moderate: n=18, severe: n=18). Participants underwent the Standardized Mini-Mental State Examination (SMMSE), Addenbrooke's Cognitive Examination III-Turkish Version (ACE-3-TR), and QAB-TR, with language assessments performed by a speech-language pathologist blinded to cognitive results and disease stage.

RESULTS: QAB-TR total scores differed significantly across all stage pairs (p<0.05). Grammatical construction distinguished all three stage pairs, while word comprehension, sentence comprehension, word finding, motor speech programming, and repetition distinguished mild-severe and moderate-severe pairs but not mild-moderate. The reading subtest distinguished only the mild-severe pair. QAB-TR total score correlated strongly with SMMSE (r=0.851, p<0.001) and ACE-3-TR (r=0.852, p<0.001), while motor speech programming showed notably lower correlations (r=0.281-0.338).

CONCLUSIONS: QAB-TR appears to be a clinically sensitive, multidimensional tool for assessing language impairment in IwAD. Its brevity, comprehensive subdomain coverage, and stage sensitivity provide preliminary evidence supporting its applicability in Turkish-speaking clinical settings.},
}

@article {pmid43011204,
year = {2026},
author = {Ashley, CC and Macauley, SL},
title = {The role of lactate in Alzheimer's disease: from controversies to therapeutic opportunities.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {50},
pmid = {43011204},
issn = {3059-4944},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder of disrupted brain metabolism, yet the role of specific metabolic intermediates in disease pathogenesis remains incompletely defined. Lactate, long considered a byproduct of glycolysis, is now understood to function as both an energy substrate and signaling molecule that links neuronal activity, glial biology, and network function. In this review, we synthesize clinical, preclinical, and multi-omic evidence to reframe lactate as a dynamic regulator of AD pathophysiology. Emerging data demonstrate that lactate is differentially regulated across disease stages and cellular compartments, with early increases associated with amyloid pathology, reactive glia, and neuronal hyperexcitability. We highlight evidence that disease reactive microglia undergo glycolytic reprogramming and represent a major and spatially enriched source of lactate in the AD brain, challenging the traditional astrocyte-centric view of lactate metabolism. We further discuss how lactate participates in feed-forward mechanisms linking metabolism to inflammation, neuronal excitability, and protein aggregation, but also through epigenetic modifications such as lactylation. Importantly, we propose a context-dependent framework in which lactate exerts both beneficial and maladaptive effects on disease progression. While transient or well-regulated lactate supports synaptic function and cognitive processes, sustained or dysregulated elevations may contribute to neuroinflammation, network dysfunction, sleep loss, and disease progression. Finally, we evaluate the potential of lactate as both a biomarker and therapeutic target. Together, this perspective integrates metabolism, neuroinflammation, and systems-level dysfunction, positioning lactate as a key therapeutic target in AD.},
}

@article {pmid43011205,
year = {2026},
author = {Lee, S and Heo, M and Kim, Y and Kim, S and Lee, SY and Jang, JW and , },
title = {Mediation of the Association Between APOE Genotype and Cognitive Change Through Alzheimer's Disease Biomarkers in Patients With Mild Cognitive Impairment.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {4},
pages = {243-252},
pmid = {43011205},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: Apolipoprotein E (APOE) ε4 is associated with Alzheimer's disease risk and amyloid pathology, but whether cerebrospinal fluid (CSF) Alzheimer's disease biomarkers show statistical indirect effects in its association with longitudinal clinical worsening in mild cognitive impairment (MCI) remains unclear.

METHODS: We analyzed 397 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative. The primary analysis used 36-month change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) in the full cohort. APOE ε4 carrier status was the predictor, baseline CSF amyloid beta 1-42 (Aβ42) and phosphorylated tau 181 (p-tau181) were serial mediators, and age, sex, and education were covariates. Secondary analyses were stratified by amyloid status, and 12- and 24-month analyses and APOE ε4 allele-count models were exploratory and sensitivity analyses, respectively. Indirect effects were evaluated using 5,000 percentile bootstrap resamples.

RESULTS: In the full cohort, the total effect of APOE ε4 on 36-month CDR-SB change was significant (estimate, 1.047; 95% bootstrap confidence interval [CI], 0.552 to 1.540), whereas the residual direct effect was not (0.097; 95% CI, -0.447 to 0.636). The Aβ42-specific indirect effect was significant (0.751; 95% CI, 0.474 to 1.035), while the p-tau181-specific (0.068; 95% CI, -0.007 to 0.167) and sequential Aβ42-to-p-tau181 indirect effects (0.131; 95% CI, -0.002 to 0.309) were not. Secondary and allele-count sensitivity analyses were directionally consistent.

CONCLUSIONS: Lower CSF Aβ42 showed a significant statistical indirect association between APOE ε4 carrier status and 36-month clinical worsening in MCI. These observational findings do not establish a causal mediating mechanism.},
}

@article {pmid43011218,
year = {2026},
author = {Gonzalez-Ortiz, F and Kirsebom, BE and Santos, C and Arslan, B and Gundersen, JK and Kvartsberg, H and Sävman, K and Turton, M and Harrison, P and Coley Gleerup, HS and Frederiksen, KS and Hasselbalch, SG and Simonsen, AH and Fladby, T and Barreto Henriksson, H and Frandberg, S and Hellström, A and Groenendaal, F and Nafash, MN and Klaus, EN and Zeng, X and Karikari, TK and Zetterberg, H and Sjöbom, U},
title = {The antagonistic pleiotropy of tau phosphorylation: plasma tau species in newborns and Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {6},
pages = {fcag413},
pmid = {43011218},
issn = {2632-1297},
abstract = {Tau phosphorylation is essential for early brain development but is also central to Alzheimer's disease pathogenesis, suggesting an antagonistic pleiotropy model in which the same biology is beneficial early in life and harmful in ageing. Here, we investigate whether healthy term newborns exhibit higher concentrations of multiple phosphorylated tau species in plasma and compare their profiles against older adults and Alzheimer's disease patients. In this multicentre study, we used the Simoa HD-X platform to measure plasma phospho-tau (p-tau) species (p-tau217 and p-tau205), Glial fibrillary acidic protein (GFAP), Neurofilament light (NfL) and amyloid-β species (Aβ1-40 and Aβ1-42) in healthy term newborns (n = 42), aged controls (n = 41) and patients with Alzheimer's disease (n = 73). Perinatal associations were examined using multivariable regression adjusted for gestational age and birth weight. In an exploratory subset analysis comprising 12 aged controls and 27 term newborns, 220 analytes were measured using the Central Nervous System panel on the NULISA proteomics platform. Group comparisons were performed using either linear regression or Welch t-tests with Benjamini-Hochberg correction for multiple testing. In the Simoa analysis, plasma p-tau217 and p-tau205 showed a stepwise increase from controls to Alzheimer's disease and from Alzheimer's disease to newborns. Mean p-tau217 concentrations were 2.6 pg/mL in controls, 8.6 pg/mL in Alzheimer's disease and 17 pg/mL in newborns; corresponding p-tau205 concentrations were 0.5, 0.7 and 3.3 pg/mL. All pairwise differences for both tau species were significant. Correlations between p-tau markers differed across groups. Newborns showed a strong correlation (r = 0.81, P < 0.001), whereas correlations were weaker in Alzheimer's disease (r = 0.44, P < 0.001). Newborns also had the highest GFAP concentrations, whereas NfL was highest in Alzheimer's disease and lowest in newborns. Mode of delivery affected GFAP and NfL levels, but not p-tau217 or p-tau205, arguing against birth stress as the main driver of neonatal tau phosphorylation. The NULISA analysis independently supported broad neonatal enrichment of tau. Phosphorylated tau species were markedly higher in newborns than controls, and multiple epitopes, including the brain-derived forms of p-tau181, p-tau205, p-tau212, p-tau217 and p-tau231, clustered among proteins with positive newborn-control differences and strong statistical significance. Our findings identify a high early-life phospho-tau state across multiple epitopes that exceeds Alzheimer's disease levels but occurs outside of the amyloid/neurodegenerative biomarker profile. The results support the hypothesis that tau phosphorylation has divergent biological meanings across the lifespan and motivate mechanistic studies of how the developing brain tolerates high phospho-tau without an amyloid/neurodegenerative biomarker profile.},
}

@article {pmid43011223,
year = {2026},
author = {Duran, T and Barcus, RA and Gaussoin, SA and Bacci, JR and Bateman, JR and Hughes, TM and Whitlow, CT and Craft, S and Lockhart, SN},
title = {Diffusion MRI metrics of white matter association tracts are associated with cognitive migration in older adults without dementia.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70520},
pmid = {43011223},
issn = {2352-8729},
abstract = {INTRODUCTION: We analyzed baseline diffusion magnetic resonance imaging (MRI) data including diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to predict cognitive transitions over a 1-year follow-up in older adults without dementia.

METHODS: A total of 366 participants from the Wake Forest Alzheimer's Disease Research Center (ADRC) Healthy Brain Study (HBS) were included. The outcome was cognitive migration (CM), defined based on Clinical Dementia Rating (CDR) global score transitions: CDR 0 to 0 (CDR-0 Stable), CDR 0 to 0.5 (Migrant[-]), CDR 0.5 to 0.5 (CDR-0.5 Stable), and CDR 0.5 to 0 (Reverter[+]). NODDI free water (FW) and DTI metrics (fractional anisotropy [FA] and mean diffusivity [MD]) from whole brain and white matter (WM) association tracts were examined for their association with 1-year CM status.

RESULTS: CM transition rates were: 46% CDR-0 Stable, 29% CDR-0.5 Stable, 16% Reverter[+], and 9% Migrant[-]. In WM association tracts, the Reverter[+] group had higher DTI FA and lower MD than the CDR-0.5 Stable group.

DISCUSSION: FA and MD (not FW) may be sensitive markers for reversion during early transitions in WM association tracts.},
}

@article {pmid43011234,
year = {2026},
author = {Zhang, S and Hu, H and Wang, X and Xiong, C and Kanekiyo, T and Asmann, YW and Ren, Y},
title = {scMINA: an interpretable workflow for paired scRNA-scATAC multiome integration and regulatory prioritization.},
journal = {NAR genomics and bioinformatics},
volume = {8},
number = {4},
pages = {lqag140},
pmid = {43011234},
issn = {2631-9268},
mesh = {Humans ; Multiomics ; *Single-Cell Analysis/methods ; Single-Cell Gene Expression Analysis ; Workflow ; Alzheimer Disease/genetics/pathology/metabolism ; *Software ; *RNA-Seq/methods ; Gene Regulatory Networks ; Chromatin/genetics/metabolism ; *RNA, Small Cytoplasmic/genetics ; },
abstract = {Single-cell multiomic technologies that jointly profile transcriptomic and epigenomic states provide unprecedented opportunities to investigate cellular heterogeneity and gene regulatory mechanisms in complex diseases. However, analysis of paired single-cell RNA-seq (scRNA-seq) and chromatin accessibility (scATAC-seq) data remains computationally challenging due to modality-specific technical variation, integration complexity, and limited interpretability of downstream regulatory inference. Here, we present scMINA (single-cell Multimodal Integration and Network Attribution), a modular and interpretable analytical workflow for the analysis of paired single-cell multiome datasets. scMINA comprises coordinated modules for multimodal integration, technical covariate correction, and regulatory feature prioritization, enabling systematic characterization of cellular states across transcriptomic and epigenomic modalities. In addition, scMINA incorporates explainable artificial intelligence-based attribution strategies to prioritize candidate genes and transcription factors associated with cell-state heterogeneity and disease-related regulatory alterations. We applied scMINA to the single-cell multiome data from the Seattle Alzheimer's Disease Brain Cell Atlas, where the workflow robustly resolved major glial cell populations and identified regulatory features associated with Alzheimer's disease pathology. By coupling multimodal integration with interpretable regulatory prioritization, scMINA provides a practical workflow for systematic analysis and biological interpretation of paired scRNA-seq and scATAC-seq datasets.},
}

Humans
Multiomics
*Single-Cell Analysis/methods
Single-Cell Gene Expression Analysis
Workflow
Alzheimer Disease/genetics/pathology/metabolism
*Software
*RNA-Seq/methods
Gene Regulatory Networks
Chromatin/genetics/metabolism
*RNA, Small Cytoplasmic/genetics

@article {pmid43011405,
year = {2026},
author = {Lamola, II and Veliotes, DGA and Mochan, A},
title = {The profile of patients diagnosed with Parkinson's disease at the Charlotte Maxeke Johannesburg Academic Hospital.},
journal = {Journal of the colleges of medicine of South Africa},
volume = {4},
number = {1},
pages = {425},
pmid = {43011405},
issn = {2960-110X},
abstract = {BACKGROUND: Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disorder after Alzheimer's disease, but data from Sub-Saharan Africa are scarce. This study describes the demographic and clinical characteristics of IPD patients at the Charlotte Maxeke Johannesburg Academic Hospital movement disorder clinic and evaluates disease severity with the Unified Parkinson's Disease Rating Scale (UPDRS-III) and the Hoehn and Yahr staging scales.

METHODS: A prospective cohort study was conducted from May 2024 to May 2025, enrolling adult patients (≥ 18 years) with a diagnosis of IPD.

RESULTS: Eighty-two patients were included (mean age 68.2 years, s.d. 10.9; 59.8% male; 52.4% Black African). Median disease duration was 3 years (interquartile range [IQR] 1-6). Levodopa monotherapy was the most common treatment (42.7%), followed by combinations with amantadine or pramipexole. The median UPDRS-III score was 60 (IQR 48-76), with 73.2% classified as having severe disease. The Hoehn and Yahr staging revealed that 39% of patients were at Stage 4 and 11% at Stage 5.

CONCLUSION: Most patients in this cohort had advanced disease at presentation, underscoring the need for earlier diagnosis and timely referral to specialist clinics.

CONTRIBUTION: These findings highlight the importance of strengthening movement disorder services in South Africa and suggest that delayed presentation may contribute to the high burden of severe disease in this population.},
}

@article {pmid43011462,
year = {2026},
author = {Ashish, RM and Turner, JA},
title = {Evaluating the Accuracy of Remote Questionnaire and Speech Measures in Detecting Cognitive Impairment in the ADNI4 Remote Digital Cohort: Cross-Sectional Study.},
journal = {JMIR neurotechnology},
volume = {5},
number = {},
pages = {e108372},
pmid = {43011462},
issn = {2817-092X},
abstract = {BACKGROUND: Scalable remote approaches are increasingly needed to identify cognitive impairment in clinical research. The Everyday Cognition (ECog) scale and its short form (12-item Everyday Cognition [ECog12]) capture subjective cognitive and functional decline, whereas automated speech-based story recall provides an objective measure of cognitive performance. Whether speech recall contributes information beyond remote questionnaire assessment remains unclear.

OBJECTIVE: This study aimed to determine whether automated speech-based story recall measures provide incremental discrimination of cognitive impairment diagnoses beyond the self-reported ECog12 (Self-ECog12) scale and demographics, both without and with 2 additional subjective memory measures that assess current memory/thinking concerns and perceived recent decline.

METHODS: This cross-sectional study included 7268 individuals from the Alzheimer's Disease Neuroimaging Initiative 4 (ADNI4) Remote Digital cohort with complete baseline questionnaire, demographic, and Storyteller speech-recall data. The outcome was defined as a participant report of a prior diagnosis of mild cognitive impairment or memory problem, Alzheimer disease, or dementia (n=574, 7.9%). Participants completed a smartphone-based Storyteller assessment involving immediate and delayed spoken recall of standardized stories; recordings were automatically analyzed to derive 5 prespecified recall and language measures. Participants were stratified into training and independent natural-prevalence test cohorts. Logistic regression models evaluated Self-ECog12 alone; Self-ECog12 plus demographics; Storyteller added to that model; the 2 additional subjective memory measures; and the full model incorporating Storyteller. Model development and threshold selection were confined to training data. Discrimination, calibration, and threshold-dependent performance were evaluated in the held-out test cohort. Area under the receiver operating characteristic curve (AUC) comparisons used paired DeLong tests.

RESULTS: The test cohort included 1817 participants, of whom 143 (7.9%) reported a prior diagnosis. Self-ECog12 alone achieved an AUC of 0.792 (95% CI 0.755-0.828), increasing to 0.827 (95% CI 0.792-0.859) with demographics. Adding Storyteller increased AUC to 0.853 (95% CI 0.821-0.883; ΔAUC 0.026, 95% CI 0.009-0.043; paired DeLong P=.002). With the 2 subjective memory measures included, AUC was 0.857 (95% CI 0.830-0.882) and increased to 0.875 (95% CI 0.851-0.899) after adding Storyteller (ΔAUC 0.019, 95% CI 0.008-0.030; P<.001). At the frozen threshold, the full model achieved sensitivity of 0.874 (95% CI 0.818-0.930), specificity of 0.746 (95% CI 0.725-0.767), positive predictive value of 0.227 (95% CI 0.210-0.246), and negative predictive value of 0.986 (95% CI 0.980-0.992). The Brier score was 0.060, with a calibration intercept of 0.023 and a slope of 0.870, suggesting acceptable calibration with overfitting.

CONCLUSIONS: Speech measures provided incremental information beyond Self-ECog12 and demographics, with and without additional subjective memory measures. These findings support further evaluation of multimodal remote assessment as a scalable screening or enrichment approach for identifying individuals who may benefit from clinical evaluation. Because the outcome was a participant-reported prior diagnosis rather than an independently adjudicated current diagnosis, validation against clinically adjudicated outcomes is necessary before diagnostic use.},
}

@article {pmid43011480,
year = {2026},
author = {Vesque, C and Segobin, S and Coppalle, R and Colas, A and Naveau, M and Mauger, C and Hommet, M and de la Sayette, V and Eustache, F and Platel, H and Groussard, M},
title = {Newly learned items form long-term memory in severe Alzheimer's disease despite hippocampal atrophy.},
journal = {Brain communications},
volume = {8},
number = {6},
pages = {fcag399},
pmid = {43011480},
issn = {2632-1297},
abstract = {Alzheimer's disease is a neurodegenerative disorder marked by a progressive decline in episodic memory and impaired encoding of new information. While hippocampal atrophy is a hallmark of the disease, several observations suggest that some mechanisms may remain preserved, including familiarity-based recognition. Artistic items, such as music and paintings, are particularly suitable to elicit these spared processes, as they engage reward, emotional, and implicit learning networks that remain intact in this condition. However, the extent to which patients with moderate to severe Alzheimer's disease can learn new information in these domains remains unclear. Thirty-three patients with Alzheimer's disease (79.30 ± 5.82 years; mean Mini-Mental State Examination [MMSE] score = 14.76 ± 5.42) and 24 healthy control participants (77.17 ± 4.62 years; mean MMSE score = 28.83 ± 0.92) were included in the protocol. A data-driven stratification based on neuropsychological scores identified two subgroups of patients, classified as moderate and severe cognitive impairments. Participants first completed repeated exposure sessions to unknown musical and pictorial items until they reported a sense of familiarity, assessed by a six-point scale designed for this population. One to two days later, a recognition session during which target items and distractor items were presented was conducted; participants' performance was also evaluated using the familiarity scale. Structural MRI was acquired to quantify hippocampal atrophy and examine the relationship between grey matter volume and recognition performance. Despite significantly different learning rates across clinical groups (cumulative link mixed model, all pairwise comparisons P < 0.001), 31 patients out of 33 reached the learning criterion for at least one of the two artistic materials. In the recognition session, pairwise comparisons confirmed that all clinical groups significantly discriminated target from distractor items (cumulative link mixed model, all pairwise comparisons P < 0.001), with a gradient of discrimination consistent with disease severity, indicating preserved but modulated familiarity-based recognition. Structural imaging confirmed substantial hippocampal atrophy in both patient subgroups relative to healthy controls (P < 0.001). Multiple regression revealed that higher familiarity scores in recognition session were associated with greater grey matter volume in the right caudate nucleus (cluster-level, P FWE < 0.05). These findings demonstrate that patients with moderate to severe Alzheimer's disease retain the ability to encode new musical and pictorial information despite pronounced hippocampal atrophy. Familiarity-based mechanisms, supported by subcortical regions, appear to underpin this preserved learning and may offer promising perspectives for care in patients with Alzheimer's disease.},
}

@article {pmid43011630,
year = {2026},
author = {Vahid, A and Faghihzadeh, S and Hubert, J and Hosseini, SMH},
title = {Choroid plexus biomarkers capture neuroinflammatory processes associated with amyloid and neurodegeneration in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70491},
pmid = {43011630},
issn = {2352-8729},
abstract = {INTRODUCTION: The amyloid/tau/neurodegeneration (ATN) framework characterizes Alzheimer's disease (AD) biomarkers but does not fully capture neuroinflammation. The choroid plexus (CP), a critical blood-cerebrospinal fluid (CSF) barrier component, has emerged as a neuroinflammatory imaging marker whose relationship to established AD biomarkers remains unclear.

METHODS: We analyzed multimodal data from 641 Alzheimer's Disease Neuroimaging Initiative participants using magnetic resonance imaging, amyloid/tau positron emission tomography, CSF/plasma biomarkers, and cognitive measures. Associations were examined via correlations, amyloid-stratified analyses, and structural equation modeling (SEM).

RESULTS: CP volume was consistently associated with hippocampal atrophy but did not differentiate amyloid-positive from amyloid-negative individuals. Plasma glial fibrillary acidic protein showed the strongest association with CP volume, particularly in amyloid-positive participants. SEM linked CP volume and entorhinal tau to hippocampal atrophy, with amyloid contributing indirectly through tau.

DISCUSSION: CP volume reflects neuroinflammatory processes more closely tied to neurodegeneration than to amyloid or tau pathology, supporting its role as a complementary biomarker within the ATN framework.},
}

@article {pmid43011645,
year = {2026},
author = {Luo, Y and Yu, H and Zhang, J and Wu, Z and Zhang, H},
title = {Deciphering the effects of aging on Alzheimer's disease based on mitochondrial dysfunction and neuroinflammation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1991837},
pmid = {43011645},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), a neurological disorder characterized by progressive deterioration of cognitive function, has complex pathogenic mechanisms and lacks curative therapies with proven efficacy. Aging and inflammatory responses, which play indispensable roles in the onset and progression of AD, are closely intertwined with mitochondrial dysfunction. During aging, a series of degenerative alterations, including accumulated mitochondrial DNA (mtDNA) mutations, excessive mitochondrial reactive oxygen species (ROS) accumulation, disrupted mitochondrial quality control (MQC) and disturbed energy metabolism, further induce structural mitochondrial damage. This damage causes the leakage of damage-associated molecular patterns (DAMPs) and activates numerous downstream inflammatory signaling pathways. In brain tissue, inflammatory cytokines, which continuously facilitate blood-brain barrier (BBB) disruption, aberrant activation of microglial cells, tau protein hyperphosphorylation, as well as Aβ accumulation, drive an endlessly amplified neuroinflammatory cascade that leads to irreversible neuronal damage and fuels the initiation and progression of AD. In this review, we clarify the regulatory effects of aging on AD pathogenesis through the mitochondrial dysfunction-chronic inflammation axis and ultimately focus on mitochondrial-targeted therapies, with future outlooks for AD treatment provided.},
}

@article {pmid43011657,
year = {2026},
author = {Wang, J and Wu, J and Liang, F and Huang, S and Liu, L and Huang, Y and Wang, Y},
title = {Gastrodin combined with donepezil alleviates cognitive dysfunction in Alzheimer's disease mice by improving mitochondrial function through AMPK/PGC-1α/SIRT3 axis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1978729},
pmid = {43011657},
issn = {1663-4365},
abstract = {OBJECTIVE: This study aims to explore whether gastrodin (Gas) combined with donepezil (Don) has a neuroprotective effect on Alzheimer's disease (AD) mice by regulating the AMPK/PGC-1α/SIRT3 signaling axis.

METHODS: HT22 cells were transfected with SIRT3 siRNA or control siRNA. Cells were then treated with the AMPK inhibitor, Don, Gas, or their combination. Subsequently, HT22 cells were treated with Amyloid beta 1-42 (Aβ 1-42) to induce an in vitro AD model. Cell viability was detected by CCK8 assay. DCFH-DA fluorescent probe was used to evaluate cell reactive oxygen species (ROS). Adenosine triphosphate (ATP) content was detected by luciferase chemiluminescence method. Cell membrane potential was measured by flow cytometry. For in vivo experiments, WT mice and APP/PS1 mice were treated with Don, Gas or a combination of drugs. Morris water maze test, Y-maze test and novel object recognition test were used to evaluate the cognitive impairment of mice. The pathological changes of hippocampus were detected by HE staining, and the expression of Aβ protein in hippocampus and cortex was detected by IHC. In addition, the protein and mRNA expressions of APP, Tau, and AMPK/PGC-1α/SIRT3 signaling axis were determined by Western blot and RT-QPCR.

RESULTS: Gas combined with Don significantly improved cognitive dysfunction, reduced Aβ plaque deposition in the cortex and hippocampus, up-regulated AMPK/PGC-1α/SIRT3 axis, and inhibited the abnormal phosphorylation of Tau and APP in APP/PS1 mice compared with the model group and the Don group (p < 0.05). In vitro cell experiments confirmed that the combination of the two drugs could improve cell viability, inhibit cell apoptosis, restore ATP level, reduce ROS accumulation, stabilize mitochondrial membrane potential, and improve mitochondrial function (p < 0.05). Molecular experiments and complementary experiments showed that Gas combined with Don activated AMPK/PGC-1α/SIRT3 signaling axis (p < 0.05). Silencing SIRT3 or inhibiting AMPK could reverse the protective effect of the combined regimen (p < 0.05).

CONCLUSION: Gas combined with Don can maintain mitochondrial homeostasis through AMPK/PGC-1α/SIRT3 pathway, alleviate AD-relaated pathological damage, and exert neuroprotection.},
}

@article {pmid43011830,
year = {2026},
author = {Lin, J and Zou, X},
title = {From intestinal barrier sensing to glial immune programming: a barrier-immune-glia relay in microbiota-associated neurodegeneration.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1956619},
pmid = {43011830},
issn = {1664-3224},
mesh = {Humans ; Intestinal Barrier Function ; Animals ; *Neurodegenerative Diseases/immunology/metabolism/microbiology/etiology ; *Neuroglia/immunology/metabolism ; *Gastrointestinal Microbiome/immunology ; Blood-Brain Barrier/immunology/metabolism ; *Intestinal Mucosa/immunology/metabolism/microbiology ; },
abstract = {The gut microbiota contributes to host homeostasis through metabolic, immunological, neural, and barrier-related pathways, and its role in the onset and progression of neurodegenerative diseases has received increasing attention. Patients with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis often exhibit alterations in gut microbial composition, microbial metabolic function, and peripheral inflammatory phenotypes. However, existing clinical evidence is derived predominantly from cross-sectional studies, and the direction of causality between microbiota alterations and disease pathology remains to be established. This review uses a "barrier-immune-glial relay" framework to systematically summarize the potential mechanisms through which gut microbiota-associated signals influence immune homeostasis in the central nervous system. First, alterations in microbial composition, short-chain fatty acids, bile acids, tryptophan derivatives, and lipopolysaccharide may act on the intestinal epithelial barrier, enteric nervous system, and intestinal mucosal immune cells, thereby affecting local immune tolerance and inflammatory responses. Second, intestinal macrophages, dendritic cells, innate lymphoid cells, T cells, and B cells may translate local microbial signals into circulating metabolites, inflammatory mediators, and immune cell-associated signals, which may in turn influence blood-brain barrier function and the central immune microenvironment. Furthermore, microglia and astrocytes, as key integrators within the central nervous system, can respond to gut-derived metabolites and peripheral immune signals. Their interaction network may determine whether neuroinflammation, synaptic injury, and neurodegenerative pathology are amplified or constrained. This review also evaluates the levels of evidence supporting these mechanisms in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Although these disorders may share mechanistic nodes, including barrier impairment, immunometabolic dysregulation, and glial responses, their core pathologies, immune contexts, and temporal disease trajectories differ substantially. Finally, we propose that establishing a verifiable causal chain linking "microbial functional genes-metabolites-barrier and immune remodeling-glial cell states-neuropathology-clinical phenotypes" will provide a basis for biomarker development and precision interventions in neurodegenerative diseases.},
}

Humans
Intestinal Barrier Function
Animals
*Neurodegenerative Diseases/immunology/metabolism/microbiology/etiology
*Neuroglia/immunology/metabolism
*Gastrointestinal Microbiome/immunology
Blood-Brain Barrier/immunology/metabolism
*Intestinal Mucosa/immunology/metabolism/microbiology

@article {pmid43011839,
year = {2026},
author = {Ramineni, V and Khan, FF and Kim, JH and Kwon, GR},
title = {Speech and sMRI as multimodal biomarkers for early detection of Alzheimer's disease using machine learning, deep learning, and transformer-based models.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1975870},
pmid = {43011839},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) and its prodromal stage, MCI are typically diagnosed using cerebrospinal fluid analysis and amyloid positron emission tomography procedures that are invasive, costly, and poorly suited to population-scale screening. Speech and structural magnetic resonance imaging (sMRI) have emerged as complementary non-invasive alternatives: speech captures the real-time functional consequences of neurodegeneration on lexical retrieval, semantic organization, and prosody, while structural MRI reveals the anatomical substrate of cortical and subcortical atrophy that underlies these impairments. This Mini Review examines how machine learning, deep learning, graph based and transformer based models have been applied to these two modalities, individually and in combination, for classifying cognitively normal individuals and those with MCI or AD. We trace the progression from classical machine learning on hand-engineered acoustic and lexical features, through convolutional and recurrent neural networks that learn volumetric atrophy patterns and discourse-level speech representations, to vision transformers and graph neural networks that capture long-range spatial and connectomic dependencies in brain structure. We then examine multimodal fusion strategies early, late, intermediate and the cross-modal attention architectures that link speech and MRI within a single, interpretable framework. While intermediate fusion shows the strongest diagnostic performance in early evidence, this advantage narrows in the three-way classification task most relevant to clinical screening. We close by identifying dataset diversity, language dependency, and the lack of longitudinal multimodal studies as the principal barriers to clinical translation.},
}

@article {pmid43011928,
year = {2026},
author = {Blanton, C and Hines, J and Ginsburg, J and Parnell, S},
title = {Acute Neurologic Decline in the ED: A Case Report on Recognizing ARIA in the Age of Anti-Amyloid Therapy.},
journal = {Journal of education & teaching in emergency medicine},
volume = {11},
number = {4},
pages = {V37-V43},
pmid = {43011928},
issn = {2474-1949},
abstract = {UNLABELLED: Anti-amyloid beta (Aβ) immunotherapies are an emerging treatment for Alzheimer's disease (AD) with a rare but significant risk of amyloid-related imaging abnormalities (ARIA). This visual case report describes a patient with lecanemab-induced ARIA to familiarize emergency providers with this critical adverse effect of novel anti-amyloid therapies. An 85-year-old female receiving lecanemab infusions presented to the emergency department (ED) with abruptly worsening confusion, an unsteady gait, and new left-sided deficits, including homonymous hemianopia and hemineglect. A non-contrast head computed tomography (CT) revealed extensive right parieto-occipital vasogenic edema, prompting magnetic resonance imaging (MRI), which confirmed extensive ARIA with edema (ARIA-E) on fluid-attenuated inversion recovery (FLAIR) sequences and microhemorrhages (ARIA-H) on T2-weighted sequences. Lecanemab was discontinued, and the patient experienced partial neurologic recovery after a four-day admission. However, she was discharged with persistent functional limitations, including an inability to drive and a need for caregiver assistance. This case underscores the need for emergency physicians to maintain a high index of suspicion for ARIA in patients on anti-Aβ immunotherapies who present with new neurologic symptoms. Definitive diagnosis requires MRI, and management warrants prompt neurologic consultation.

TOPICS: Alzheimer's, dementia, neurology, medication adverse effects, ARIA.},
}

@article {pmid43012281,
year = {2026},
author = {Mohammed, SI and Taha, MA and Allami, AJ and Mohammed, EA and Ibrahim, RO},
title = {Artificial Intelligence for Brain MRI Diagnosis: A Scoping Review and Evidence-Gap Map Across Neurological Diseases.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056523075261026051524},
pmid = {43012281},
issn = {1573-4056},
abstract = {INTRODUCTION/OBJECTIVE: Artificial Intelligence (AI), including machine learning and deep learning, is increasingly applied to brain Magnetic Resonance Imaging (MRI) for disease detection, classification, segmentation, and clinically relevant prediction. This review aimed to map the evidence on AI-assisted brain MRI diagnosis, identify methodological and clinical translation gaps, and propose priorities for future research.

METHODS: This scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. PubMed/MEDLINE, Scopus, IEEE Xplore, and Web of Science were searched for peer-reviewed English-language publications from January 2018 to April 2026. Data were charted according to disease domain, study design, AI method, dataset, validation strategy, performance metrics, explainability, and key limitations.

RESULTS: The search identified 1,020 records. After duplicate removal and screening, 61 publications were included, comprising 24 original studies used for the primary evidence map and 37 reviews or commentaries used for contextual synthesis. Evidence was strongest for brain tumor imaging and Alzheimer's disease, whereas stroke, multiple sclerosis, pediatric neuroimaging, and rare neurological conditions were underrepresented. Most studies relied on public benchmark datasets and retrospective validation, whereas external validation, prospective clinical evaluation, subgroup analysis, explainability, and workflow integration were inconsistently reported.

DISCUSSION: The findings indicate that AI-assisted brain MRI research remains unevenly developed and is constrained by dataset dependence, limited external validation, limited prospective clinical evaluation, and inconsistent reporting of explainability, subgroup performance, and workflow integration.

CONCLUSION: AI shows promising research-stage potential for brain MRI-based diagnosis, particularly in brain tumor analysis and Alzheimer's disease classification. Future research should prioritize multicenter validation, diverse and disease-specific datasets, explainable and equitable AI design, transparent reporting, and prospective evaluation within real clinical workflows.},
}

@article {pmid43012292,
year = {2026},
author = {Eng, JH and Chong, AEY and Koh, RY and Ling, APK},
title = {Ferroptosis as a Therapeutic Target in Neurological Disorders: Pharmacological Advances and Translational Challenges.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010520055261019113815},
pmid = {43012292},
issn = {1873-4316},
abstract = {Ferroptosis is an iron-mediated form of programmed cell death characterised by distinct features, including excessive iron accumulation, lipid peroxidation, and impaired antioxidant mechanisms. The susceptibility of the Central Nervous System (CNS) to ferroptosis has been reported, along with evidence that ferroptosis is associated with neurological disorders such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), stroke, and Multiple Sclerosis (MS). To date, major ferroptosis inhibitors encompass iron chelators, lipid-trapping antioxidants, and antioxidant modulators. Translational challenges in drug toxicity, selectivity, and delivery promote drug development in terms of improving pharmacokinetics through structural modification, alternative routes of administration, and nanoparticle encapsulation. In addition, research on identifying novel and promising ferroptosis inhibitors from natural products and known drug compounds is continuous, accompanied by ongoing drug optimisation and modification. Biomarkers of ferroptosis have been discussed given the emerging clinical interest in them for disease diagnosis or prognosis and patient stratification. Standalone anti-ferroptotic treatments for CNS disorders have been found to be difficult to achieve favourable clinical outcomes, thereby suggesting combination therapies that not only harness ferroptosis but also address diverse pathological pathways in the respective diseases as a prospect for managing CNS disorders. Thus, this article aims to review recent updates on clinically approved ferroptosis inhibitors as well as summarise the current drug development landscape and outline future directions to provide a better understanding of the contemporary development of ferroptosis inhibitors for neurological disorders.},
}

@article {pmid43012625,
year = {2026},
author = {Chen, L and Wei, M and Zhang, Q and Jia, L and Zheng, Z and Tan, R},
title = {Natural Glycosides in Neurodegenerative Diseases: Multi-Target Mechanisms via the Gut-Brain Axis.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70521},
pmid = {43012625},
issn = {1099-1573},
support = {2024zd021//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 25ZDAZX012//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 2024zd033//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; },
abstract = {The multifactorial complexity of neurodegenerative diseases (NDs), including Alzheimer's and Parkinson's disease, limits the efficacy of single-target therapies. Natural glycosides exhibit promising neuroprotective potential, but their clinical translation is hindered by poor oral bioavailability and limited blood-brain barrier (BBB) penetration. The gut-brain axis offers a framework for understanding their potential biological effects beyond direct central exposure. This review explores the multi-target mechanisms of natural glycosides in NDs, focusing on their interactions with the gut-brain axis. A narrative literature search was conducted in PubMed, Web of Science, and ScienceDirect for studies published up to June 2026. Relevant literature on glycosides, NDs, gut microbiota, microbial biotransformation, pharmacokinetics, and neuroprotective mechanisms was critically reviewed. Natural glycosides may affect ND-related processes through gut-mediated and systemic/central mechanisms. Poorly absorbed glycosides can interact with intestinal microbiota, potentially modulating microbial composition, intestinal barrier integrity, and short-chain fatty acids (SCFAs) production. Microbial biotransformation may generate metabolites with altered physicochemical properties and systemic exposure, potentially enhancing central nervous system accessibility in a compound-specific manner. Experimental evidence also suggests effects on neuroinflammation, mitochondrial homeostasis, autophagy, and synaptic function. However, most findings remain preclinical, with limited direct human evidence. The gut-brain axis provides a valuable perspective for understanding the biological activities of natural glycosides despite their limited oral bioavailability and BBB penetration. Further pharmacokinetic studies, causal investigations of microbiota-mediated effects, and controlled clinical trials are needed to establish their therapeutic potential in NDs.},
}

@article {pmid43012695,
year = {2026},
author = {Hao, M and Wu, D and Sun, L and Lai, X and Chen, R and Zhang, Z and Li, Q and Zhang, S and Zheng, X and Li, D and Sun, S},
title = {Isovitexin Attenuates Aβ-Induced Neurotoxicity by Activating SKN-1/Nrf2 Signaling and Suppressing Ferroptosis in Caenorhabditis elegans Models of Alzheimer's Disease.},
journal = {Journal of agricultural and food chemistry},
volume = {74},
number = {44},
pages = {34867-34884},
doi = {10.1021/acs.jafc.6c10083},
pmid = {43012695},
issn = {1520-5118},
support = {R2026PY-TJ027//Guangdong Academy of Agricultural Sciences/ ; XT202506//Guangdong Academy of Agricultural Sciences/ ; 2022A1515110190//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010264//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2024A1515010696//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2021ZDZX002//Guangdong Provincial Science and Technology Achievements Reach Townships Special Project/ ; R2021YJ-YB3014//Guangdong Academy of Agricultural Sciences Special Fund Project to Introduce Science and Technology Talent/ ; R2024YJ-YB3005//Guangdong Academy of Agricultural Sciences Special Fund Project to Introduce Science and Technology Talent/ ; SKXRC2025483//Guangdong Provincial Association for Science and Technology/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics/drug effects ; *Amyloid beta-Peptides/metabolism/toxicity/genetics ; *Alzheimer Disease/metabolism/drug therapy/genetics/physiopathology ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Signal Transduction/drug effects ; *Ferroptosis/drug effects ; *Transcription Factors/metabolism/genetics ; *NF-E2-Related Factor 2/metabolism/genetics ; *Apigenin/administration & dosage ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; Disease Models, Animal ; Mitochondria/metabolism/drug effects ; Neuroprotective Agents/administration & dosage ; Oxidative Stress/drug effects ; Tea/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, oxidative stress, ferroptosis, and mitochondrial dysfunction, while effective therapeutic interventions remain limited. Epidemiological evidence indicates that tea and flavonoids with antiaging properties lower AD risk. In this study, untargeted metabolomic profiling identified isovitexin as a differentially abundant flavonoid in postfermented dark tea (DT), and Caenorhabditis elegans (C. elegans) AD models were employed to evaluate its anti-AD potential and elucidate the underlying molecular mechanisms. The results showed that isovitexin significantly extended lifespan, reduced Aβ accumulation, and improved neuromuscular function, demonstrating marked neuroprotective effects. Mechanistically, isovitexin mitigated Aβ-triggered toxicity through SKN-1 signaling, accompanied by the attenuation of Aβ-evoked ferroptosis and mitochondrial dysfunction. Collectively, these results broaden the therapeutic potential of dark tea flavonoids and support further investigation of isovitexin as a candidate for mitigating Aβ-induced neurodegeneration.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics/drug effects
*Amyloid beta-Peptides/metabolism/toxicity/genetics
*Alzheimer Disease/metabolism/drug therapy/genetics/physiopathology
*Caenorhabditis elegans Proteins/metabolism/genetics
Signal Transduction/drug effects
*Ferroptosis/drug effects
*Transcription Factors/metabolism/genetics
*NF-E2-Related Factor 2/metabolism/genetics
*Apigenin/administration & dosage
*DNA-Binding Proteins/metabolism/genetics
Humans
Disease Models, Animal
Mitochondria/metabolism/drug effects
Neuroprotective Agents/administration & dosage
Oxidative Stress/drug effects
Tea/chemistry

@article {pmid43012735,
year = {2026},
author = {Tuncgovde, E and Kemiklioglu, E and Kocabiyik, M and Erac, Y and Ozsarlak-Sozer, G},
title = {A unique liquid crystal-based biosensor for label-free detection of amyloid beta-42 peptide using gelsolin protein.},
journal = {Analytical methods : advancing methods and applications},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ay01961g},
pmid = {43012735},
issn = {1759-9679},
abstract = {In this study, we report the development of a liquid crystal (LC)-based biosensor functionalized with gelsolin protein for the detection of Alzheimer's disease (AD)-related amyloid beta-42 (Aβ42). The gelsolin-modified glass substrate induced a robust homeotropic alignment of the LC molecules. Binding between gelsolin and Aβ42 disrupted this ordered orientation and produced a shift from a dark to a bright optical response under polarized optical microscopy (POM), enabling straightforward visual detection. The biosensor demonstrated a wide detection range of 1-1000 pg mL[-1] and an exceptionally low detection limit of 1 pg mL[-1] for Aβ42. In addition, apolipoprotein E4 (ApoE4), a major genetic risk factor for AD, was detected in the range of 0.1-30 nM. The interaction between Aβ42 and ApoE4 induced measurable changes in LC orientation, confirming the sensor's capability to transduce biomolecular interactions. Moreover, this LC-based biosensor was used for the detection of the Aβ42 peptide in cell culture samples. The obtained results demonstrate that with further optimization, the developed biosensor could pave the way for practical applications in real clinical samples.},
}

@article {pmid43012927,
year = {2026},
author = {Gupta, PR and Shahapure, P and Sarkar, N and Venu, G and Krishnan, D and Ramasamy, S and Justin, A},
title = {Death-Associated Protein Kinase 1 (DAPK1) Signalling at the Crossroads of Apoptosis, Autophagy, and Post-transcriptional Cascades in Neurodegenerative Diseases.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {43012927},
issn = {1573-6830},
mesh = {Humans ; *Death-Associated Protein Kinases/metabolism/genetics ; *Neurodegenerative Diseases/genetics/pathology/metabolism/enzymology ; *Signal Transduction/physiology ; Animals ; *Autophagy/physiology ; *Apoptosis/physiology ; *RNA Processing, Post-Transcriptional ; },
abstract = {Death-associated Protein Kinase-1 is a Ca2+/calmodulin- dependent serine/threonine protein kinase which controls various cellular processes and functions, including apoptosis, autophagy, and post-transcriptional processes, through multiple microRNAs. Increasing evidence suggests that, aberrant increase in the level of DAPK1 may result in neuronal injury and neurodegeneration by integration of multiple pathological processes such as excitotoxicity, neuroinflammation, and protein aggregation. DAPK1 contributes to disease progression through mechanisms such as NMDA receptor-mediated excitotoxicity, tau and α-synuclein hyperphosphorylation, apoptotic signaling, autophagic dysregulation, and synaptic loss. This review overviews the structural organization, regulatory mechanisms and role of DAPK1 in various cellular processes involved in neurodegeneration. This review discusses the complex transcriptional, post-transcriptional, and post-translational mechanisms governing DAPK1 activity, including regulation by transcription factors, microRNAs, phosphorylation events, and protein degradation pathways. Particular highlighting is given to the involvement of DAPK1 in both chronic and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, diabetic encephalopathy, traumatic brain injury, and cerebral ischemic stroke. Finally, current therapeutic approaches based on the modulation of DAPK1 activity, including kinase inhibitors, competitive peptides, and gene-regulatory approaches, are reviewed, along with the challenges associated with target selectivity, blood-brain barrier penetration, and clinical translation. Collectively, this review emphasizes the therapeutic potential and discusses future directions for the development of disease-modifying interventions targeting DAPK1 in neurodegenerative diseases.},
}

Humans
*Death-Associated Protein Kinases/metabolism/genetics
*Neurodegenerative Diseases/genetics/pathology/metabolism/enzymology
*Signal Transduction/physiology
Animals
*Autophagy/physiology
*Apoptosis/physiology
*RNA Processing, Post-Transcriptional

@article {pmid43013102,
year = {2026},
author = {Rapant, S and Beňová, N and Cvečková, V and Stehlíková, B and Hunarova, N and Ižarik-Verešpejová, A and Kolísek, M},
title = {Drinking water hardness and nervous system mortality: a 15 year ecological study of calcium and magnesium content in the Slovak Republic.},
journal = {Environmental geochemistry and health},
volume = {48},
number = {17},
pages = {},
pmid = {43013102},
issn = {1573-2983},
support = {LIFE17 ENV/SK/000036//LifeScan/ ; },
mesh = {*Magnesium/analysis ; Slovakia/epidemiology ; Humans ; *Calcium/analysis ; *Drinking Water/chemistry/analysis ; *Nervous System Diseases/mortality/epidemiology ; },
abstract = {The chemical composition of the natural physical environment significantly impacts human health, yet the specific influence of drinking water minerals on nervous system disorders remains largely unexamined. This study investigated the relationship between drinking water hardness, specifically calcium and magnesium concentrations, and nervous system disease mortality across populations in the Slovak Republic. Two size wise comparable groups of rural municipalities supplied exclusively by public water systems were monitored over a 15 year period (1994-2008), totaling 1.58 million person-years. The soft water cohort comprised 34 municipalities (Ca ≤ 25 mg L[-1]; Mg ≤ 10 mg L[-1]), and the hard water cohort comprised 21 municipalities (Ca ≥ 50 mg L[-1]; Mg ≥ 20 mg L[-1]). Relative mortality rates and indirectly age-standardized mortality ratios were calculated using national registry data for 99 specific nervous system diagnoses (ICD-10 codes G00-G99). Total nervous system mortality was approximately 2.5 times higher in the soft water regions than in the hard water regions. Highly significant statistical associations were discovered for epilepsy and cerebral palsy, with relative mortality rates expanding 4.25 and 16.41 times higher in the soft water group, respectively. No statistically significant differences were observed for neurodegenerative conditions like Alzheimer's or Parkinson's diseases. Low levels of calcium and magnesium in public drinking water are associated with increased population-level mortality from epilepsy and cerebral palsy. However, due to the ecological design of this study, these findings represent geographical correlations and cannot establish a direct causal relationship. Controlled individual-level epidemiological studies or clinical trials are required to determine whether targeted mineral interventions would successfully reduce mortality in high-risk demographics.},
}

*Magnesium/analysis
Slovakia/epidemiology
Humans
*Calcium/analysis
*Drinking Water/chemistry/analysis
*Nervous System Diseases/mortality/epidemiology

@article {pmid43013131,
year = {2026},
author = {Vorberg, IM and Priola, SA},
title = {The evolution of prion cell biology: from viruses to prions to prion-like proteins.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {43013131},
issn = {1432-0533},
mesh = {Humans ; Animals ; *Prions/metabolism ; *Prion Diseases/metabolism/pathology ; },
abstract = {Prion diseases are inevitably fatal, rare, and infectious neurodegenerative diseases of humans and animals. Initially, they were thought to be caused by unconventional slow viruses, and early research therefore relied heavily on experimental approaches used in virology. This view changed with the discovery that the causative agent of these diseases is not a virus but a conformational variant of a host-encoded protein. The conversion of the normally soluble host prion protein into an insoluble, infectious form enables the spread of pathology between cells and throughout the host. Over the past two decades, it has become clear that similar prion-like mechanisms of protein misfolding and templated self-propagation also underlie more common, non-infectious neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Thus, just as the cell biology of viruses provided important insights into the first studies of prion cell biology, discoveries in prion research have profoundly influenced our understanding of the cell biology of other amyloid-forming proteins. In this review, we discuss common principles and differences in the cell biology of prions and prion-like particles. We also highlight the seminal contributions of the late Dr. Byron Caughey and his laboratory, whose pioneering work has helped to shape our current understanding of how pathogenic protein aggregates form, propagate, and ultimately cause devastating neurological diseases.},
}

Humans
Animals
*Prions/metabolism
*Prion Diseases/metabolism/pathology

@article {pmid43013143,
year = {2026},
author = {Vu, NH and Esper, GW and Pettit, C and Ganta, A and Egol, KA and Konda, SR},
title = {Association between Alzheimer's disease and related dementias and postoperative outcomes after geriatric hip fracture surgery.},
journal = {European journal of orthopaedic surgery & traumatology : orthopedie traumatologie},
volume = {37},
number = {1},
pages = {},
pmid = {43013143},
issn = {1432-1068},
mesh = {Humans ; Female ; Retrospective Studies ; Male ; *Postoperative Complications/epidemiology/etiology ; *Hip Fractures/surgery/complications ; Aged, 80 and over ; Aged ; *Alzheimer Disease/complications/epidemiology ; *Dementia/complications/epidemiology ; Patient Readmission/statistics & numerical data ; Comorbidity ; Treatment Outcome ; Proximal Femoral Fractures ; Length of Stay/statistics & numerical data ; },
abstract = {BACKGROUND: Patients with Alzheimer's Disease and Related Dementias (ADRD) represent a vulnerable subset of geriatric hip fracture patients, yet the extent to which ADRD influences postoperative outcomes remains incompletely characterized. The purpose of this study was to examine the association between Alzheimer's Disease and Related Dementias (ADRD) and outcomes.

METHODS: A retrospective cohort analysis was conducted of patients 65 years or older undergoing operative management for hip fractures at a multi-site urban academic medical center. Patients were stratified by ADRD status as documented in the electronic medical record. Univariate analyses compared demographic characteristics, injury and surgical variables, hospital quality metrics, and mortality using chi-square and Student's t-tests, as appropriate. Multivariable regression models controlling for age, sex, BMI, ASA class, Charlson Comorbidity Index, baseline functional status, and fracture classification evaluated the association between ADRD and study outcomes.

RESULTS: A total of 3,312 patients were included: 829 (25.0%) ADRD vs. 2483 (75.0%) control. ADRD patients were older, had greater comorbidity burden, and had worse baseline functional status. ADRD patients had increased minor and major complications, ICU admissions, readmissions, 1-year mortality, and longer hospitalization (all p < 0.001). Variance inflation factor analysis confirmed no meaningful multicollinearity among covariates (VIF range 1.04-1.34). On multivariable analysis, ADRD was independently associated with major complications (OR 1.372, 95% CI 1.066-1.760), ICU admission (OR 1.581, 95% CI 1.231-2.025), length of stay (β 0.958, 95% CI 0.624-1.292), 30-day (OR 1.994, 95% CI 1.521-2.608) and 31- to 90-day readmission (OR 1.956, 95% CI 1.453-2.625), and mortality between 31 days and 1 year (HR 1.54, 95% CI 1.18-2.01).

CONCLUSION: ADRD is independently associated with worse postoperative outcomes after geriatric hip fracture. These associations persisted after adjustment for baseline comorbidity, functional status, and fracture classification, though residual confounding by unmeasured frailty domains cannot be excluded. Orthogeriatric co-management should be directed toward this vulnerable population to optimize outcomes.},
}

Humans
Female
Retrospective Studies
Male
*Postoperative Complications/epidemiology/etiology
*Hip Fractures/surgery/complications
Aged, 80 and over
Aged
*Alzheimer Disease/complications/epidemiology
*Dementia/complications/epidemiology
Patient Readmission/statistics & numerical data
Comorbidity
Treatment Outcome
Proximal Femoral Fractures
Length of Stay/statistics & numerical data

@article {pmid43013230,
year = {2026},
author = {Kan, CN and Chew, J and Lim, WS and Tan, CH},
title = {Neural correlates of frailty and the development of a cerebral frailty risk score for dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {43013230},
issn = {2509-2723},
support = {RG58/23//Ministry of Education - Singapore/ ; SSRC2023-SSHR-003//Ministry of Education - Singapore/ ; },
abstract = {Frailty is a multisystem clinical syndrome closely linked to cognitive aging, yet its relationship with brain pathology and contribution to neurological outcomes remain unclear. We examined neuroimaging correlates of frailty and evaluated their integrative impact on incident dementia within a cerebral frailty risk score (CFRS) framework. In a population-based UK Biobank cohort, we analyzed neuroimaging-derived phenotypes, including cerebral volumetrics and thickness, white matter hyperintensities (WMH), cerebral blood flow (CBF), and diffusion metrics. Associations between global neuroimaging markers and frailty index (FI), and their joint effects on incident dementia over 10 years were analyzed using regression models. Long-term dementia risk was modelled using extreme gradient boosting with accelerated failure time, integrating FI and multimodal neuroimaging features. A total of 63,509 dementia-free participants (mean age = 65.02 years, 52.3% female) were included. Higher FI values were associated with greater WMH volume, lower CBF, reduced hippocampal volume, greater cortical thinning, and impaired diffusion metrics. Higher FI and neuroimaging markers independently increased dementia and mortality risks. The cerebral frailty model outperformed FI-only model (nested C-index = 0.825, iAUC = 0.759), driven by higher FI, WMH burden, and key Alzheimer's disease-related brain regions and circuits. Integrating the top 10 predictors into an integer-based CFRS achieved strong discriminatory performance (C-index = 0.843, iAUC = 0.808) and was robust to competing mortality risk. Our findings suggest that systemic frailty is associated with mixed cerebral pathologies. Both frailty and cerebral pathological burden may represent parallel but distinct pathways contributing to dementia. With external validation and recalibration, the CFRS framework integrating these vulnerabilities demonstrates potential for dementia risk profiling.},
}

@article {pmid43013232,
year = {2026},
author = {Cai, Y and Miao, J and Gogniat, MA and Snitz, BE and Cohen, AD},
title = {Multidimensional 24-h activity patterns in relation to cognition and Alzheimer's disease plasma biomarkers: a cross-sectional study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {43013232},
issn = {2509-2723},
support = {R03AG088612/AG/NIA NIH HHS/United States ; UF1AG051197/AG/NIA NIH HHS/United States ; },
abstract = {Beyond total volume, how physical activity is distributed, timed, and structured across the 24-h cycle may reflect aspects of brain aging missed by conventional measures. We examined how these activity dimensions relate to cognitive status, cognitive performance, and Alzheimer's disease (AD)-related plasma biomarkers. In this cross-sectional analysis of 164 adults aged 50-89 from the Human Connectome Project-Connectomics in Brain Aging and Dementia study, 7-day wrist actigraphy measured activity volume, fragmentation, complexity, and rest-activity rhythms. Outcomes were adjudicated: mild cognitive impairment (MCI)/AD diagnosis, cognitive performance, and plasma amyloid-β 42/40 ratio, phosphorylated tau217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). Logistic and linear regression models were adjusted for age, sex, race, education, and comorbidities; cognitive and biomarker models were additionally adjusted for MCI/AD diagnosis. Benjamini-Hochberg false discovery rate (FDR) correction was applied. Forty-four participants had MCI/AD. In fully adjusted models, higher interdaily stability (IS) and most-active-10-h activity (M10) were associated with lower odds of MCI/AD (IS: odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.44-0.95, FDR-p = 0.212; M10: OR = 0.57, 95% CI 0.38-0.82, FDR-p = 0.053). Higher IS, M10, and relative amplitude (RA) were associated with better verbal memory, language, and executive function, respectively. Higher RA was associated with lower GFAP and NfL, whereas higher IS and M10 were associated with higher p-tau217. These associations did not remain significant after FDR correction. Multiple 24-h activity dimensions, particularly rest-activity rhythm stability and amplitude, were associated with cognition and AD-related plasma biomarkers, supporting further study of these measures as accessible indicators of brain aging and AD-related biology.},
}

@article {pmid43013309,
year = {2026},
author = {Bokor, L and Yu, MKL and Carter, B and Chauhan, U and Sheehan, R and Strydom, A},
title = {Avoidable Mortality in Adults With Down Syndrome or With Other Intellectual Disabilities.},
journal = {JAMA network open},
volume = {9},
number = {11},
pages = {e2643229},
doi = {10.1001/jamanetworkopen.2026.43229},
pmid = {43013309},
issn = {2574-3805},
mesh = {Humans ; *Down Syndrome/mortality ; *Intellectual Disability/mortality ; Male ; Female ; England/epidemiology ; Adult ; Retrospective Studies ; Middle Aged ; Cause of Death ; Aged ; },
abstract = {IMPORTANCE: Down syndrome is the most common genetic cause of Alzheimer disease. Adults with Down syndrome experience higher mortality than the general population. However, the avoidable causes and their associated factors remain unclear.

OBJECTIVE: To compare the proportion and causes of avoidable mortality in adults with Down syndrome, adults with other intellectual disabilities, and the general population, and to identify factors associated with avoidable death.

This population-based retrospective cohort study used data from the Learning From Lives and Deaths mortality review and the Office for National Statistics in England from 2016 to 2023. It included adults with Down syndrome (n = 3381), other adults with intellectual disabilities (n = 15 347), and the general population (n = 4 163 160).

EXPOSURES: Down syndrome status, ethnicity, socioeconomic deprivation, co-occurring health conditions, COVID-19 pandemic period.

MAIN OUTCOMES AND MEASURES: Proportion and causes of avoidable, treatable, and preventable deaths according to Organisation for Economic Co-operation and Development/Eurostat criteria; odds of avoidable death estimated using logistic regression; and age at avoidable death using Cox regression. Factors associated with avoidable death and age at death were also evaluated.

RESULTS: Among 3381 adults with Down syndrome (1892 male [56.0%]; median [IQR] age at death, 59.5 [54.3-64.2] years), 1589 (47.0%) died from avoidable causes. Among 15 347 adults with other intellectual disabilities (8675 male [56.5%]; median [IQR] age at death, 63.8 [51.7-73.4] years), 6885 (44.9%) died from avoidable causes. Both proportions were substantially higher than in the general population (22.0%) (both P < .001). Treatable deaths were more common (972 [28.7%] vs 3847 [25.1%] vs 317 968 [7.6%]), with epilepsy and pneumonia as the leading treatable causes. Down syndrome was independently associated with higher odds of avoidable death (aOR, 1.15; 95% CI, 1.06-1.25) and earlier age at avoidable death (aHR, 1.49; 95% CI, 1.40-1.58). Minoritized ethnic background, asthma, diabetes, and osteoporosis were each independently associated with higher odds of avoidable death, and minoritized ethnic background and greater socioeconomic deprivation with earlier age at avoidable death.

CONCLUSIONS AND RELEVANCE: In this cohort study of adults with Down syndrome and other adults with intellectual disabilities in England, avoidable mortality exceeded that of the general population. For the adults with Down syndrome, epilepsy and pneumonia were the dominant treatable causes. These findings support proactive integrated neurological care, including epilepsy review with dementia monitoring, pneumonia prevention, and respiratory vaccination, alongside targeted interventions for minoritized ethnic groups and socioeconomically deprived groups.},
}

Humans
*Down Syndrome/mortality
*Intellectual Disability/mortality
Male
Female
England/epidemiology
Adult
Retrospective Studies
Middle Aged
Cause of Death
Aged

@article {pmid43013411,
year = {2026},
author = {Gedankien, T and Kriegel, J and Zabeh, E and McDonagh, D and Lega, BC and Jacobs, J},
title = {Cholinergic blockade reveals a role for human hippocampal theta in memory encoding but not retrieval.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
pmid = {43013411},
issn = {2050-084X},
support = {R01-MH104606/NH/NIH HHS/United States ; R01-NS125250/NH/NIH HHS/United States ; R01-NS107357/NH/NIH HHS/United States ; },
mesh = {Humans ; *Hippocampus/physiology/drug effects ; Scopolamine/administration & dosage/pharmacology ; *Theta Rhythm/drug effects ; Male ; Female ; *Memory/drug effects/physiology ; *Mental Recall/drug effects ; Middle Aged ; Muscarinic Antagonists/administration & dosage/pharmacology ; Adult ; },
abstract = {Cholinergic dysfunction is a hallmark of Alzheimer's disease and other memory disorders. Yet, the neurophysiological mechanisms linking cholinergic signaling to memory remain poorly understood. In this study, we administered scopolamine, a muscarinic cholinergic antagonist, to neurosurgical patients with intracranial electrodes as they performed an associative recognition memory task. When scopolamine was present at encoding, we observed disruptions to hippocampal slow theta oscillations (2-4 Hz), with selective impairments to recollection-based memory. However, when scopolamine was present during retrieval alone, we observed disruptions to slow theta without impaired memory performance. These disruptions included dose-dependent reductions in theta power, theta phase reset, and encoding-retrieval pattern reinstatement. Together, our results challenge the notion that theta oscillations are necessary for memory retrieval, and instead suggest that theta universally reflects an encoding-related neural state. These findings motivate updates to current models of acetylcholine's role in memory and may inform future therapies targeting rhythmic biomarkers of memory dysfunction.},
}

Humans
*Hippocampus/physiology/drug effects
Scopolamine/administration & dosage/pharmacology
*Theta Rhythm/drug effects
Male
Female
*Memory/drug effects/physiology
*Mental Recall/drug effects
Middle Aged
Muscarinic Antagonists/administration & dosage/pharmacology
Adult