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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

TRIAL REGISTRATION NUMBERS: NCT05995418; ChiCTR2300074723.},
}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid42751194,
year = {2026},
author = {Lukyova, L and Zatkova, A and Minarik, J and Holesova, Z and Budis, J and Kucharik, M and Benes, V and Gazdarica, J and Szemes, T},
title = {Alzheimer's disease: genetic background in the era of next-generation sequencing technologies.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag332},
pmid = {42751194},
issn = {2632-1297},
abstract = {While rare, highly penetrant variants in APP, PSEN1 and PSEN2 are associated with early-onset Alzheimer's disease, especially its familial form, the disease in general is shaped by a complex interplay of various genetic factors. Both common and rare variants across numerous loci, which were identified mainly during large genome-wide association studies, contribute to disease risk, phenotypic heterogeneity and progression in both early- and late-onset forms. This review synthesizes current understanding of the genetic architecture of Alzheimer's disease in the era of next-generation sequencing, with particular emphasis on variant classes beyond single nucleotide polymorphisms. Structural variants, including copy number variations, tandem repeat expansions and transposable element insertions, are considered as potential contributors to the 'missing heritability' in Alzheimer's disease. In addition, we discuss somatic mosaicism that represents another layer of its complexity. We highlight how whole-genome sequencing, combined with advanced bioinformatic pipelines and reference resources, enables systematic detection of different variant types. We also outline the translational potential of genetic discoveries, including polygenic risk and hazard score models for patient stratification, and underscore the importance of integrative genomic and multi-omic approaches in advancing precision medicine in Alzheimer's disease.},
}

@article {pmid42751391,
year = {2026},
author = {Akomaning, E and Joseph, C and Ovbiagele, I and Tagge, R},
title = {Con-sequins 2026: From mission to momentum.},
journal = {Equity neuroscience},
volume = {2},
number = {3},
pages = {100066},
pmid = {42751391},
issn = {3050-8401},
abstract = {A foundational challenge of equity neuroscience is understanding how to move from describing inequitable neurological disparities to identifying the mechanisms, systems, and infrastructures needed to reduce them. The Society for Equity Neuroscience (SEQUINS) was founded in 2024 to advance brain health equity and reduce neurological disparities through science [1]. CON-Sequins '26, held on May 14, 2026, in Charleston, South Carolina, was the society's second annual meeting and reflected its expanding role as a scientific, educational, disseminative, and workforce-development platform. It convened investigators, clinicians, trainees, public health leaders, and community-engaged scholars from across the United States and beyond. Major scientific themes included social drivers of Alzheimer's disease and related dementias, upstream contributors to racial disparities in stroke, global neurology, cerebral malaria, global health security, translational science infrastructure, artificial intelligence, clinical trial representation, community-engaged research, and workforce development. Early career scholars presented their work in three distinct poster sessions. This proceedings report summarizes the conference program, emerging scholarship, workforce-development activities, dissemination efforts, participation metrics, and future priorities for the field. Con-Sequins '26 suggests that recurring convenings may provide a key mechanism for translating equity neuroscience from a conceptual framework into research, implementation, mentorship, and policy objectives.},
}

@article {pmid42751437,
year = {2026},
author = {Zhao, G and Zhou, X and Yin, S and Xu, F and Xu, L and Wang, Q and Zhou, J and Liu, S},
title = {Seven-year follow-up demonstrating sustained survival following [125]I seed brachytherapy in an elderly patient with lip squamous cell carcinoma and Alzheimer's disease: A case report.},
journal = {Oncology letters},
volume = {32},
number = {5},
pages = {490},
pmid = {42751437},
issn = {1792-1082},
abstract = {Lip squamous cell carcinoma is a distinct subtype of oral malignancy. Surgical resection provides satisfactory local tumor control; however, it frequently compromises oral function, diminishes local sensation and disfigures facial contour-sequelae are disproportionately debilitating in elderly patients with multimorbidity. This study reported the case of an 80-year-old woman with Alzheimer's disease who presented with locally advanced lip squamous cell carcinoma (cT3N2bM0, stage IVA) and cervical lymph node metastases. Following multidisciplinary team evaluation, the patient was deemed unsuitable for curative surgical resection or definitive external-beam radiotherapy. Therefore, computed tomography (CT)-guided radioactive [125]I seed implantation, assisted by a three-dimensional (3D) printed template, was performed for both the primary lip tumor and the metastatic cervical nodes, with a prescribed dose of 140 Gy. Postprocedural dosimetric verification confirmed adequate target volume coverage. The patient achieved a durable clinical complete response, with remarkable tumor regression, preserved speech and swallowing function, and remains alive with overall survival exceeding 7 years. This case demonstrates the long-term efficacy and safety of the aforementioned minimally invasive approach in an elderly patient with severe cognitive impairment-a population routinely excluded from prospective trials. No radiation-related toxicities, including xerostomia or osteoradionecrosis, were documented during follow-up. These findings indicate that CT-guided [125]I seed brachytherapy with 3D-printed templates is a feasible, function-preserving and potentially curative treatment option for carefully selected elderly patients with advanced lip squamous cell carcinoma who are unable to tolerate conventional definitive therapy. These results further challenge the common view that interventional brachytherapy serves only as a palliative measure.},
}

@article {pmid42751568,
year = {2025},
author = {Miller, E and Bambakidis, P and Templin, P and Paul, BD and Pieper, AA},
title = {Emerging roles of the ciliary-mitochondrial axis in cellular homeostasis and neuroprotection.},
journal = {Molecular neurodegeneration advances},
volume = {1},
number = {1},
pages = {5},
pmid = {42751568},
issn = {3059-4944},
abstract = {Primary cilia and mitochondria, long studied as separate cellular players, are now recognized as a tightly coupled signaling and metabolic hub whose interplay powerfully shapes cell fate. The bidirectional ciliary-mitochondrial axis integrates extracellular sensing, calcium dynamics, bioenergetics, and organelle quality control to drive adaptive responses to stress and sustain neuronal resilience. Recent studies reveal compelling associations that merit further investigation, such as the impact of primary cilium-initiated signaling cascades on mitochondrial dynamics and mitophagy, and the effects on cilia of shifting mitochondrial metabolic states. Dysfunction at any node in this axis has potential to trigger neurodegeneration. Framing primary cilia and mitochondria as a coordinated physiologic axis enables reconsideration of neurodegeneration and reveals novel, tractable entry points for therapeutic restoration of brain homeostasis. This review traces the field's evolution, synthesizes key molecular mechanisms, and highlights exciting translational opportunities to harness the ciliary-mitochondrial axis for neuroprotection.},
}

@article {pmid42751573,
year = {2026},
author = {Ikanga, J and Obenauf, C and Patel, SS and Schwinne, M and Gikelekele, G and Epenge, E and Potshi, JM and Tomadia, T and Kazadi, J and Kavugho, I and Santolini, GL and Nkosi, A and Sabowa, FM and Musewu, BM and Mawisa, E and Tsangu, JP and Beya, FMK and Mampunza, S and Mananga, L and Bukabau, J and Teunissen, CE and Karikari, T and Gross, AL and Rojas, JC and Alonso, A},
title = {Cohort profile: a community-based prospective cohort study of Alzheimer's disease and related dementias in the Democratic Republic of Congo.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {2},
number = {2},
pages = {e70085},
pmid = {42751573},
issn = {2997-3805},
abstract = {INTRODUCTION: The Étude du Vieillissement Cognitif et de Démence en République Démocratique du Congo (EVCD-RDC) launched in 2024 to investigate socioenvironmental and biological determinants of dementia in Kinshasa.

METHODS: The study recruited 1000 adults aged ≥65 years across four diagnostic groups - cognitively unimpaired (CU), mild cognitive impairment (MCI), Alzheimer's disease (AD), and other dementias (OD) - through community and clinical settings. Participants complete neuropsychological, neurological, social, and environmental assessments with biennial follow-up.

RESULTS: To date, 506 individuals have enrolled (mean age 73.4; 59.3% women), including 70 CU, 136 MCI, 120 AD, and 180 with OD. Dementia cases show higher rates of hypertension, comorbidities, neuropsychiatric symptoms, smoking, and alcohol use, along with lower body weight, education, and resilience, and greater exposure to pollution, conflict, trauma, and poverty.

DISCUSSION: EVCD-RDC is the first large-scale dementia cohort in French-speaking sub-Saharan Africa and will provide critical longitudinal insights into modifiable risks, infectious diseases, and multi-omics in the region.},
}

@article {pmid42742528,
year = {2026},
author = {Su, Z and Liu, M and Su, L and Kuai, J and Xu, B and Wang, C and Su, M and Zheng, Y and Peng, J and Bao, X and Zuo, M and Guo, X},
title = {Associations of plasma lipid burden with cognitive performance and decline across dementia with Lewy bodies, Alzheimer's disease, and Parkinson's disease dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487127},
doi = {10.1177/13872877261487127},
pmid = {42742528},
issn = {1875-8908},
abstract = {BackgroundPeripheral lipid dysregulation has been implicated in neurodegeneration, but most studies have focused on single lipid measures within one dementia subtype.ObjectiveTo determine whether a composite plasma lipid burden score (PLBS), derived from routine fasting lipid indices, differs across dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and Parkinson's disease dementia (PDD) and whether it relates to baseline cognition and subsequent cognitive decline.MethodsWe conducted a longitudinal observational study including 227 patients with probable DLB (n = 65), AD (n = 79), or PDD (n = 83). PLBS was defined as the unweighted mean of z-standardized non-HDL cholesterol, remnant cholesterol, apolipoprotein B, apolipoprotein B/apolipoprotein A1, LDL-C/HDL-C, triglyceride/HDL-C, and triglyceride-glucose index. Multivariable linear regression and linear mixed-effects models were used to examine associations with baseline cognition and annualized cognitive decline.ResultsPLBS differed significantly across diagnoses and showed the clearest separation among lipid-related measures, with higher values in DLB and PDD than in AD. Higher PLBS was associated with poorer baseline global cognition and faster longitudinal decline. These associations appeared to be numerically more pronounced in DLB, with intermediate estimates in PDD and weaker estimates in AD in this exploratory analysis. Higher PLBS was linked to poorer attention and visuospatial/executive performance and greater rapid cognitive decline.ConclusionsAn adverse plasma lipid burden profile is associated with worse cognition and faster decline across degenerative dementias, with the strongest effects in DLB. Routinely lipid-derived indices may complement existing approaches to longitudinal risk assessment. These findings require independent external validation and formal evaluation of predictive performance before clinical application.},
}

@article {pmid42742529,
year = {2026},
author = {Nikumaa, H and Näkki, K and Niinimäki, J and Issakainen, M and Ppali, E and Kalapudas, J and Suhonen, N and Ervasti, K and Mäki-Petäjä-Leinonen, A and Solje, E},
title = {Empowered by participation: Patients' and caregivers' experiences in the law clinic. Multidisciplinary dementia research at the intersection of law and medicine.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487378},
doi = {10.1177/13872877261487378},
pmid = {42742529},
issn = {1875-8908},
abstract = {BackgroundA pilot study, the Law Clinic, implemented extensive cognitive, neuropsychiatric, and legal assessments within an interdisciplinary framework. A study design of this kind has not been previously applied. The study was necessary to generate knowledge on the relationship between symptoms of dementia and patients' legal status.ObjectiveThe pilot aimed to determine, through participants' experiences, whether expanding such multi-component research is ethically sustainable, and whether clinical studies that combine medical and legal perspectives of this nature can feasibly be conducted.Methods20 people with Alzheimer's disease and related disorders and 20 caregivers (spouses) participated in the study, which included several assessments and interviews for both parties. In the final interview, participants reflected on their experiences participating in the study. The transcribed material was analyzed using inductive content analysis to identify key themes related to participation and perceived burden.ResultsParticipants reported positive experiences, with 90% indicating no burden. Most described the study as meaningful, empowering, and even enjoyable. Separate interviews for patients and caregivers were considered essential for open communication and comprehensive perspectives. The findings support scaling up the Law Clinic Study.ConclusionsThe novel Law Clinic Study protocol proved sustainable and feasible. Thoughtful design, and multidisciplinary expertise can ensure respectful and meaningful engagement in research for people with Alzheimer's disease and related disorders and their caregivers. Our findings suggest that research addressing complex and sensitive issues through broad interdisciplinary methods can be ethically sound, generate unique knowledge that would otherwise remain inaccessible, and may even prove empowering for participants.},
}

@article {pmid42742530,
year = {2026},
author = {Takahashi, R and Kashibayashi, T and Fujita, J and Yoshida, K and Hashiramoto, A and Kowa, H and Mizuta, E},
title = {Lower baseline cerebrospinal fluid amyloid-β 42 is associated with amyloid-related imaging abnormalities during real-world lecanemab treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488874},
doi = {10.1177/13872877261488874},
pmid = {42742530},
issn = {1875-8908},
abstract = {Amyloid-related imaging abnormalities (ARIA) are a safety concern during lecanemab treatment for early Alzheimer's disease. We examined baseline cerebrospinal fluid amyloid-β 42 (Aβ42) in 97 lecanemab-treated patients; 11 developed ARIA. Aβ42 was lower in ARIA cases than in non-ARIA cases (483.2 ± 108.6 versus 667.4 ± 185.4 pg/mL; p < 0.001). ROC analysis yielded an AUC of 0.806 (95% CI, 0.670-0.919). Aβ40 was also lower, whereas the Aβ42/Aβ40 ratio was not significantly different and tau biomarkers were not higher. Lower Aβ42 was associated with subsequent ARIA, but the internally derived cutoff requires external validation.},
}

@article {pmid42742534,
year = {2026},
author = {Wang, M and Jing, C and Wu, T and Wang, D},
title = {A parsimonious three-gene mitochondrial classifier from frontal cortex for Alzheimer's disease: Nested cross-validation and multicenter external validation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487424},
doi = {10.1177/13872877261487424},
pmid = {42742534},
issn = {1875-8908},
abstract = {BackgroundMitochondrial dysfunction is a hallmark of Alzheimer's disease (AD). The frontal cortex is among the earliest and most severely affected regions, yet no AD diagnostic classifier based on frontal cortical mitochondrial genes exists.ObjectiveWe aimed to construct a parsimonious diagnostic classifier from frontal cortex mitochondrial gene expression and rigorously validate it across independent cohorts.MethodsFour public brain transcriptomic datasets were downloaded from the NCBI Gene Expression Omnibus (GEO) database: GSE48350, GSE5281, GSE44770, and GSE33000. The training set (n = 103) was restricted to superior frontal gyrus samples. After ComBat correction, differentially expressed genes (adj. p < 0.2, |log2FC|>0.3) were intersected with MitoCarta 3.0. A 10-fold nested cross-validation (CV) was applied to eliminate pre-selection bias: mitochondrial DEGs were re-selected in each fold, followed by LASSO regression. The final model was externally validated on GSE44770 (n = 230) and GSE33000 (n = 467).ResultsFrom 25 candidate genes, LASSO retained three: PRKACA, ACSM3, and BIK. Nested CV AUC was 0.635 (95% CI 0.527-0.744); external AUCs reached 0.714 (GSE44770) and 0.753 (GSE33000). The 25 genes were enriched in oxidative phosphorylation. Calibration was acceptable, and decision curve analysis indicated net benefit for guiding confirmatory testing. In external cohorts, BIK was upregulated and PRKACA downregulated, while ACSM3 showed a non-significant downward trend. With an optimized threshold, the model achieved a sensitivity of 0.726 and a specificity of 0.682 on the largest cohort.ConclusionsA three-gene mitochondrial signature derived from the frontal cortex provides a highly parsimonious, externally reproducible diagnostic tool for AD, with biological plausibility and clinical potential.},
}

@article {pmid42742624,
year = {2026},
author = {Wang, Y and Zhu, S and Ma, Y and Chen, X and Zhou, M},
title = {Correlation between MMP-3-1171 5A/6A polymorphism and the risk of Alzheimer's disease: A meta-analysis.},
journal = {Medicine},
volume = {105},
number = {37},
pages = {e50560},
pmid = {42742624},
issn = {1536-5964},
support = {2420001003520//Foshan 14th Five-Year-Plan High Level Medical Discipline Priority Construction Project, 2024 Foshan City Self-funded Science and Technology Innovation Project/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Asian People/genetics ; Case-Control Studies ; *Genetic Predisposition to Disease ; *Matrix Metalloproteinase 3/genetics ; Odds Ratio ; *Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Risk Factors ; White People/genetics ; },
abstract = {BACKGROUND: Previous studies of matrix metalloproteinase-3 (MMP-3) -1171 5A/6A polymorphism in Alzheimer's disease (AD) have been extensively investigated; however, the results from different studies are inconsistent. This meta-analysis was performed to clarify the link between this variant and AD.

METHODS: We searched PubMed, Embase, Chinese National Knowledge Infrastructure and Wanfang Database. The associations were calculated as odds ratios with the corresponding 95% confidence intervals (CIs).

RESULTS: 7 case-control studies with a total of 1457 cases and 1959 controls were included. Overall, there was no significant association between matrix metalloproteinase-3-1171 5A/6A polymorphism and AD risk in all genetic models (the allele model 5A vs. 6A: odds ratio (OR) = 1.06, 95% CI 0.82-1.36, P = .65; the heterozygote model 5A/6A vs. 6A/6A: OR = 0.98, 95%CI 0.75-1.28, P = .89; the homozygous model 5A/5A vs. 6A/6A: OR = 1.20, 95%CI 0.70-2.07, P = .51; the dominant model 5A/6A + 5A/5A vs. 6A/6A: OR = 1.03, 95%CI 0.76-1.40, P = .85; the recessive model 5A/5A vs. 5A/6A + 6A/6A: OR = 1.24, 95%CI 0.80-1.93, P = .34). In subgroup analysis by ethnicity, no significant difference was detected in both Caucasians and Asians between matrix metalloproteinase-3-1171 5A/6A polymorphism and AD risk. Similar results were obtained in sensitivity analysis.

CONCLUSION: In summary, the present meta-analysis suggests that MMP-3-1171 5A/6A polymorphism may not be associated with genetic susceptibility to AD in the general population. Given the limited sample size and study heterogeneity, findings warrant cautious interpretation and require verification through larger, well-designed trials.},
}

Humans
*Alzheimer Disease/genetics
Asian People/genetics
Case-Control Studies
*Genetic Predisposition to Disease
*Matrix Metalloproteinase 3/genetics
Odds Ratio
*Polymorphism, Genetic
Polymorphism, Single Nucleotide
Risk Factors
White People/genetics

@article {pmid42742642,
year = {2026},
author = {Laureyssen, C and Thal, DR and Sleegers, K},
title = {A new era of genome-wide association studies in the field of Alzheimer's disease and overlapping co-pathologies: lessons learned from a neuropathology-centered approach.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42742642},
issn = {1432-0533},
support = {G065721N, G024925N//FWO/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Genome-Wide Association Study/methods ; Animals ; Genetic Predisposition to Disease ; *Neuropathology ; *Brain/pathology ; },
abstract = {Alzheimer's disease (AD) and overlapping pathologies represent a growing worldwide health concern. With the first disease-modifying treatments on the rise, it becomes increasingly important to move research in this area forward. Genetic research is excellent at discovering novel contributors to disease mechanisms, which has been demonstrated by the discovery of over 75 disease loci associated with AD. However, classical large-scale genome-wide association studies (GWAS) use cohorts of individuals that have been assigned a case or a control status based on a clinical diagnosis. For AD, this can result in bias due to the complex nature of the disease profile. More specifically, on the neuropathological level, AD is multifaceted with co-morbid pathological lesions being the norm rather than the exception. Together with the substantial preclinical phase, this can lead to the introduction of type I and type II errors. An alternative to using large-scale clinical cohorts is to shift toward studying individuals where the disease diagnosis has been neuropathologically confirmed, or cohorts where an endophenotype is used which can directly reflect ongoing pathological processes in vivo. Such endophenotypes could entail biofluid or imaging-based biomarkers, but the most undiluted signal is obtained when employing neuropathological data. These data typically represent the presence or absence of a lesion or reflects the semi-quantitative burden of pathological features. Here, we review what this shift toward more detailed phenotypes has already contributed to the field by investigating the genetic background of AD hallmark lesions as well as commonly observed co-pathologies.},
}

Humans
*Alzheimer Disease/genetics/pathology
*Genome-Wide Association Study/methods
Animals
Genetic Predisposition to Disease
*Neuropathology
*Brain/pathology

@article {pmid42742759,
year = {2026},
author = {Ez-Zizi, A and Seelam, K and Leggett, L and Malik, BR},
title = {A Flexible-Horizon Clinical Decision Support Model for Dementia Early Detection and Risk Prediction in Secondary Care: A Responsible AI Approach.},
journal = {Journal of medical systems},
volume = {50},
number = {1},
pages = {},
pmid = {42742759},
issn = {1573-689X},
mesh = {Humans ; *Dementia/diagnosis ; *Decision Support Systems, Clinical/organization & administration ; Predictive Learning Models ; Female ; *Machine Learning ; *Secondary Health Care/organization & administration ; Male ; Sensitivity and Specificity ; Early Diagnosis ; Prediction Algorithms ; United Kingdom ; Aged ; Aged, 80 and over ; Risk Assessment ; },
abstract = {Existing machine learning (ML) models for dementia detection typically use fixed prediction windows and often lack clinically informed variable selection and responsible AI principles, thereby limiting performance, generalisability and clinical trust. We aimed to develop a single clinically informed model capable of both diagnosing dementia and predicting its onset over flexible time horizons up to 10 years. We trained our ML model on the NACC Uniform Data Set using 20 inputs compatible with UK National Healthcare Service secondary-care workflows, including a HORIZON feature encoding months from baseline. We also integrated explainability and fairness analyses. Same-visit classification achieved sensitivity of 0.951 (95% confidence interval 0.947-0.954), specificity of 0.810 (0.805-0.814), a geometric mean (G-mean) of 0.877 (0.874-0.880) and an area under the receiver operating characteristic curve (AUC) of 0.959 (0.957-0.960). Across future horizons from 24 to 120 months, sensitivity/specificity ranged between 0.808/0.856 at 24 months and 0.833/0.706 at 120 months, while AUCs were 0.906 and 0.851. Compared with a Cox proportional hazards model, our flexible-horizon ML model achieved a higher G-mean at four of the five evaluated horizons and higher specificity from 48 months onwards, whereas Cox achieved greater sensitivity from 48 months onwards. Shapley additive explanations highlighted functional independence, prediction horizon and cognitive measures as influential. Exploratory subgroup analyses showed broadly similar balanced discrimination across sex, race and age groups, although sensitivity-specificity trade-offs varied. An interactive web application was also developed for demonstration and clinical feedback. These findings support the feasibility of flexible-horizon, clinically-informed and responsible ML-based decision support for dementia early detection; however, external validation, recalibration and prospective clinical evaluation are required before deployment.},
}

Humans
*Dementia/diagnosis
*Decision Support Systems, Clinical/organization & administration
Predictive Learning Models
Female
*Machine Learning
*Secondary Health Care/organization & administration
Male
Sensitivity and Specificity
Early Diagnosis
Prediction Algorithms
United Kingdom
Aged
Aged, 80 and over
Risk Assessment

@article {pmid42742907,
year = {2026},
author = {Abdel-Rasol, MA},
title = {Pharmacological modulation of cGAS-STING-NLRP3 signaling by nano-immunomodulators in Alzheimer and Parkinson disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42742907},
issn = {1568-5608},
abstract = {Neuroinflammation is a central driver of neurodegeneration in Alzheimer's disease (AD) and Parkinson's disease (PD), driven by interconnected pathways involving microglial state dysregulation, inflammasome activation, cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, impaired mitophagy, CD33-TREM2 imbalance, gut-brain axis disruption, and peripheral immune infiltration across a compromised blood-brain barrier (BBB). Conventional anti-inflammatory therapies remain limited by poor CNS delivery, inadequate cell specificity, and the inability to simultaneously modulate multiple inflammatory pathways. Nano-immunomodulators (NIMs) have emerged as a promising strategy to modulate CNS immunity in preclinical models. This review critically evaluates recent advances in NIM-based strategies for AD and PD, including intrinsically therapeutic nanomaterials, targeted delivery systems, and precision gene-regulatory platforms. Intrinsically therapeutic materials, such as polydopamine nanoparticles and biomimetic nanozymes, provide antioxidant and mitochondrial protective functions, whereas BBB-targeted systems, including nanobody-based platforms and engineered exosomes, enhance targeted CNS delivery. Nanotheranostics approaches integrate imaging capabilities with stimuli-responsive release, while precision interceptors aim to simultaneous regulate pathological processes such as amyloid-beta (Aβ)-associated inflammation and cGAS-STING activation. Emerging gene-delivery strategies, including TREM2 mRNA and CD33-targeting lipid nanoparticles, offer opportunities for microglial reprogramming but remain largely restricted to proof-of-concept and early preclinical stages. The review further discusses AI-driven nanomedicine optimization and advanced human-relevant models, including brain-on-a-chip systems and three-dimensional (3D) bioprinting, as tools to improve translational prediction. Currently, AI approaches primarily support candidate selection, formulation optimization, and mechanistic prediction rather than clinical validation. Major challenges for clinical advancement include achieving precise modulation of microglial states beyond the simplified M1/M2 framework, developing context-dependent regulation of NLRP3 and cGAS-STING pathways, establishing gut-CNS therapeutic strategies, improving pluripotent stem cell (iPSC)-based validation platforms, and defining long-term CNS safety frameworks. By integrating molecular mechanisms, AI-assisted nanomedicine, nanoparticle-enabled immune and gene modulation, and advanced preclinical models, this review provides a mechanistic and translational framework for advancing next-generation NIM strategies in AD and PD. This integrated perspective addresses the limitations of previous single-domain analyses focused either on neuroinflammation or nanotechnology and outlines key considerations for translating NIMs from experimental platforms toward clinical applications.},
}

@article {pmid42742914,
year = {2026},
author = {Perneczky, R and Jessen, F and Grimmer, T and Levin, J and Hufnagel, A and Flöel, A and Peters, O and Froelich, L and Hofmann, A and , },
title = {From Proof of Principle to Therapeutic Discipline: Strategies to Improve the Benefit/Risk Profile of Amyloid-Targeting Treatments for Alzheimer's Disease.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {42742914},
issn = {1179-1934},
abstract = {The first generation of clinically approved amyloid-targeting treatments has changed the terms of debate in Alzheimer's disease. It is no longer persuasive to argue that amyloid removal is biologically irrelevant or clinically inert in early symptomatic Alzheimer's disease. Lecanemab and donanemab have both demonstrated statistically robust and clinically meaningful, albeit still modest, slowing of disease progression, thereby establishing disease modification as a realistic therapeutic objective rather than a speculative aspiration. At the same time, these agents have exposed the defining limitation of the current therapeutic concept: although clearly beneficial for some patients, the margin for benefit versus risk remains narrow, and its realization in routine care is operationally demanding and heavily dependent on careful patient selection and surveillance rather than on drug effect alone. The central task for the field is therefore no longer to prove that amyloid-targeting treatments can work, but to make them work more effectively, more safely, more targeted, and less burdensome. In current practice, most plausible gains in net clinical value will come from earlier and more precise patient selection, structured risk stratification using the APOE genotype and baseline magnetic resonance imaging status, strict management of vascular risk factors, intensified monitoring during the early hazard period, more personalized treatment exposure, and amyloid antibodies engineered for lower vascular toxicity, for example, using brain shuttle technology. Further, alternative routes of administration have the potential to reduce burden on patients, caregivers, and providers likewise. Real-world registries will be essential to define long-term safety, effectiveness, and treatment patterns outside clinical trial populations. Therefore, future improvement of amyloid-targeting treatments is likely to come from widening the therapeutic margin by drug engineering as well as precision implementation in real-world settings.},
}

@article {pmid42743096,
year = {2026},
author = {Lozano, J and Lim Oliva, C and Hernandez, E and Yosick, S and Grovner, J and Graves, LV},
title = {Cohabitation status influences subjective informant reports of daily functioning in aging Asian American adults.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/23279095.2026.2731482},
pmid = {42743096},
issn = {2327-9109},
abstract = {OBJECTIVE: Informant reports of daily functioning, and their associations with neuropsychological performance, have been shown to vary based on informant characteristics. However, associations among informant characteristics, reported functioning, and neuropsychological performance have not been examined with Asian American (AA) samples.

METHOD: We examined associations of informant characteristics with subjective informant reports of participants' functioning (assessed via the Functional Activities Questionnaire [FAQ]), and potential moderating effects of these characteristics on associations between reported functioning and objective neuropsychological performance among aging AA adults in the National Alzheimer's Coordinating Center cohort (n = 259).

RESULTS: Cohabiting informants reported significantly higher FAQ scores (worse participant daily functioning) compared to non-cohabiting informants (p=.007). However, cohabitation status was not shown to be significantly associated with neuropsychological performance, nor was it shown to moderate associations between FAQ scores and neuropsychological performance, in any domain (ps>.05). Cohabitating participants did have higher rates of dementia diagnoses nonetheless (p=.008).

CONCLUSIONS: Although neuropsychological performance, as well as the degree to which subjective informant reports correspond with neuropsychological performance, does not vary as a function of cohabitation status among aging AA adults, differences in subjective reports of daily functioning based on cohabitation status may nonetheless influence diagnostic outcomes.},
}

@article {pmid42743276,
year = {2026},
author = {Liu, X and Gu, J and Chen, Z and Chu, B and Liu, L and Morrison, T and Butler, RR and Edelson, J and Li, J and Longo, FM and Tang, H and Ionita-Laza, I and Sabatti, C and Candès, E and He, Z},
title = {Uncovering heterogeneous effects via localized feature selection.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {38},
pages = {e2527033123},
doi = {10.1073/pnas.2527033123},
pmid = {42743276},
issn = {1091-6490},
support = {814641//Simons Foundation (SF)/ ; R56HG010812//HHS | NIH | National Human Genome Research Institute (NHGRI)/ ; DMS2210392//NSF | MPS | Division of Mathematical Sciences (DMS)/ ; N00014-20-1-2157//DOW | USN | Office of Naval Research (ONR)/ ; AG089509//HHS | NIH | National Institute on Aging (NIA)/ ; AG066206//HHS | NIH | National Institute on Aging (NIA)/ ; AG066515//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {*Alzheimer Disease/genetics ; Humans ; *Precision Medicine/methods ; Single-Cell Analysis ; Algorithms ; Sequence Analysis, RNA ; },
abstract = {Identifying features that interact to trigger disease, while accounting for heterogeneity across diverse populations, is essential for the development of precision and targeted medicine. Despite the availability of vast and complex health-related datasets, most existing works focus on identifying disease-associated features at the population level or within a few subpopulations, often overlooking individual-level heterogeneity within these groups. To address this limitation, we propose a framework that utilizes localized test statistics to identify disease-associated features tailored to individual profiles. Our method leverages the recently developed knockoffs methodology to control the noise level of the selection set so that the results are replicable. Moreover, it allows for the discovery of hidden heterogeneous effects within the data, as demonstrated in an application to single-cell RNA sequencing data for Alzheimer's disease. By aggregating localized feature selection results, our framework also enables powerful population-level feature selection. Our framework provides a powerful tool for exploratory studies of precision medicine, offering the potential to generate novel hypotheses for confirmatory biological experiments.},
}

*Alzheimer Disease/genetics
Humans
*Precision Medicine/methods
Single-Cell Analysis
Algorithms
Sequence Analysis, RNA

@article {pmid42743693,
year = {2026},
author = {Noguchi-Shinohara, M and Muramatsu, D and Shima, A and Sakashita, Y and Tada, Y and Yamaguchi, H and Komatsu, J and Ikeda, T and Ono, K},
title = {Corrigendum to "Real-world long-term continuation of lecanemab therapy and the clinical utility of phosphorylated tau 181" [The Journal of Prevention of Alzheimer's Disease (2026) 100664].},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100668},
doi = {10.1016/j.tjpad.2026.100668},
pmid = {42743693},
issn = {2426-0266},
}

@article {pmid42743802,
year = {2026},
author = {Chen, Z and Liu, T and Wang, J and Li, P and Yuan, H and Liu, Z and Guo, J},
title = {Unraveling shared immunotoxicological mechanisms linking exposure to PPCPs with Alzheimer's disease and atherosclerosis: integrative multi-omics, network toxicology, and experimental validation.},
journal = {Environment international},
volume = {216},
number = {},
pages = {110518},
doi = {10.1016/j.envint.2026.110518},
pmid = {42743802},
issn = {1873-6750},
abstract = {BACKGROUND: Pharmaceuticals and personal care products (PPCPs) are pseudo-persistent contaminants with potential exposure risks. Atherosclerosis (AS) and Alzheimer's disease (AD) share neurovascular and myeloid-immune remodeling, but whether chemical-target networks associated with exposure to PPCPs converge on shared mechanisms linking AD and AS remains unclear.

PURPOSE: To explore how exposure to PPCPs may contribute to AD-AS comorbidity through shared immune-toxicology mechanisms, and to identify natural compounds as candidate interventions against prioritized disease-relevant targets.

METHODS: We integrated AD and AS bulk transcriptomic cohorts with single-cell datasets to define shared disease targets and locate them within relevant immune-cell states. Chemical-gene interactions associated with exposure to PPCPs were then overlaid onto this AD-AS target network, and candidate natural compounds were prioritized by reverse network pharmacology, structure-based virtual screening, molecular docking, molecular dynamics and genetic evidence analyses. The prioritized targets and intervention hypotheses were further examined in APP/PS1 AD mice, ApoE-knockout high-fat-diet AS mice, RAW264.7 macrophage-like cells and HMC3 microglial cells.

RESULTS: The integrated analyses identified TREM2, SPP1, TGFBI and MRGPRF as four AD-AS signature genes, with diagnostic discrimination in independent AD (AUC 0.783-0.996) and AS (AUC 0.892-0.924) cohorts. Among them, TREM2 and SPP1 emerged as the key signature genes, were highly expressed in disease-associated microglial and macrophage states, and formed an SPP1-linked myeloid communication axis with neighboring disease niches. Metabolic scoring and in silico TREM2 perturbation pointed to lipid-metabolic remodeling in AD microglia and macrophage metabolic, adhesive and inflammatory-migration programs in AS lesions. Bisphenol A, bisphenol F, estradiol and acetaminophen were identified as PPCPs related to signature-gene regulation. Salvianolic acid B, β-sitosterol, quercetin and tanshinone IIA were identified as potential phytochemical modulators of TREM2, SPP1, TGFBI and MRGPRF, respectively, with favorable structural-stability evidence. MR analyses supported genetic causal associations between the signature genes and AD/AS outcomes, while TREM2-centered SMR and GTEx v10 eQTL colocalization for TREM2, SPP1 and TGFBI provided locus-level support. In vivo, TREM2, OPN/SPP1, and TGFBI were upregulated in both AD and AS tissues, whereas MRGPRF showed disease-context-dependent regulation, with increased expression in AD tissues but decreased expression in AS tissues. In vitro, BPA decreased TREM2 and increased OPN/SPP1, accompanied by enhanced lipid deposition, CD86 activation, and inflammatory transcription, whereas salvianolic acid B increased TREM2, suppressed OPN/SPP1, and attenuated lipid deposition and inflammatory responses.

CONCLUSIONS: TREM2, SPP1, TGFBI, and MRGPRF constitute a recurrent but directionally heterogeneous molecular signature across AD and AS, with MRGPRF showing disease-context-dependent regulation. Within this signature, TREM2 and SPP1 showed the strongest mechanistic convergence in disease-associated myeloid states. BPA disrupted the TREM2/OPN-SPP1 axis in microglia and macrophages, whereas salvianolic acid B partially counter-regulated these changes and attenuated associated inflammatory and lipid-metabolic disturbances.},
}

@article {pmid42743871,
year = {2026},
author = {Guin, S and Jangli, A and Dandekar, MP},
title = {Dimethyl fumarate ameliorates amyloid-beta generated cognitive deficits by inhibiting RIPK1/RIPK3/MLKL necroptosis signalling in rats.},
journal = {International immunopharmacology},
volume = {189},
number = {},
pages = {117407},
doi = {10.1016/j.intimp.2026.117407},
pmid = {42743871},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive dysfunction. Necroptosis plays a pertinent role in the neurobiology of AD, which is governed by receptor-interacting protein kinases (RIPK) and mixed lineage kinase domain-like protein (MLKL). Dimethyl fumarate (DMF), a disease-modifying drug used to treat multiple sclerosis, is also known to inhibit necroptosis pathway. Herein, we examined the effect of DMF in C6 cell line and Aβ1-42-induced AD model. DMF treatment reversed the C6 cell viability and expression of RIPK1, RIPK3, and MLKL in lipopolysaccharide model. Intracerebroventricular injection of Aβ1-42 in rats developed the cognitive deficits. Administration of DMF, at 25 and 50 mg/kg doses via peroral route for 14 days, showed a decrease in escape latency and increased exploration of target quadrant Morris water maze test. DMF-recipient rats also displayed exploration of novel object in novel object recognition test, while locomotor activity remained unchanged in open field test. DMF reduced oxidative processes by decreasing lipid peroxidation and increasing catalase and glutathione. Moreover, DMF treatment decreased the levels of IL-6, TNF-α, and CRP cytokines in frontal cortex. A significant downregulation of RIPK1, RIPK3, and MLKL gene expression and protein expression of p-MLKL were observed in the hippocampus following DMF treatment. DMF was also able to improve synaptic plasticity by increasing the expression of synaptophysin, BDNF, MBP, and PSD95, which were determined by using immunoblot. Our results indicate the cognitive improvement and neuroprotective effects of DMF in Aβ1-42 CE model by modulating the necroptosis signalling. We suggest that the selective targeting of necroptosis process may open new treatment avenues for AD.},
}

@article {pmid42743907,
year = {2026},
author = {Coskun, EP and Barber, J and Bojarski, L and McLouth, CJ and Abner, EL and Van Eldik, LJ and Nelson, PT and Jicha, GA},
title = {Autopsy findings in Alzheimer's disease clinical trial participants demonstrate a high frequency of off-target coexisting pathologic features.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100669},
doi = {10.1016/j.tjpad.2026.100669},
pmid = {42743907},
issn = {2426-0266},
abstract = {BACKGROUND: Having multiple comorbid neuropathologic features may confound the results of interventional trials that were designed to target a specific pathophysiologic mechanism in Alzheimer's disease (AD) and or related dementias (ADRD). However, it is unknown what percentage of individuals undergoing AD/ADRD interventional studies have mixed pathologies.

OBJECTIVE: To characterize the spectrum of coexisting neuropathologies in brains of AD/ADRD clinical trial participants to inform trial design and therapeutic strategies METHODS: Autopsied participants from the University of Kentucky Alzheimer Disease Research Center (UK-ADRC) community-based cohort who died between January 2005, and February 2024 were included and queried retrospectively for participation in therapeutic interventional trials. Of a total of 614 autopsied cases, 67had been enrolled in one of the following types of clinical trials: cognitively normal participants in prevention trials for AD/ADRD (designated group P; n = 21); interventions for mild cognitive impairment or early dementia (MCI/D; n = 26); and, interventions for vascular cognitive impairment (V; n = 20). The trial-engaged groups were compared to the trial-naïve group in terms of their demographic, clinical, and genetic characteristics. Pathological features (amyloid-β, tau, α-synuclein, TDP-43, and cerebrovascular disease) were assessed using consensus-based neuropathologic methods.

RESULTS: All interventions were designed to target only a single pathologic feature. The trial-engaged group did not differ significantly from those who were trial-naïve with respect to demographic, genetic (APOE), or clinical characteristics, except for a marginally higher level of education among trial participants (p=0.04). Pure on-target pathology (i.e., only one isolated pathology was found at autopsy that was the signature pathology targeted by the intervention) was only seen in 10, 23, and 29 % of the engaged participants of V, MCI/D and P trials respectively. Comorbid pathologies were common in all three groups. On average, the trial-engaged groups altogether had a mean of 2.54 pathologic features/person, whereas the MCI/D trial-engaged group had a mean of 3.2 pathologic features/person.

CONCLUSION: Multi-etiology dementia was the norm rather than the exception for AD/ADRD trial participants. Recognizing the heterogeneity of multiple pathologies in clinical trial participants may enable the development of improved inclusion/exclusion criteria, as well as the rational use of antemortem biomarkers to stratify the likelihood of mixed comorbid pathologies that may be undesirable for single-target interventional studies. Further, multitargeted treatment strategies may be required in future trials of disease-modifying agents.},
}

@article {pmid42743996,
year = {2026},
author = {Li, Z and Pan, L and Yu, Y and Qin, G and Fu, B},
title = {Deconfounded-Debiased Estimation and Inference for High-Dimensional Mediation Analysis With Pervasive Hidden Confounders.},
journal = {Statistics in medicine},
volume = {45},
number = {20-22},
pages = {e70741},
pmid = {42743996},
issn = {1097-0258},
support = {ZD2021CY001//Shanghai Municipal Science and Technology Major Project/ ; 82473724//National Natural Science Foundation of China/ ; 82273730//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Mediation Analysis ; Alzheimer Disease/diagnostic imaging/blood ; Computer Simulation ; Confounding Factors, Epidemiologic ; Bias ; Models, Statistical ; DNA Methylation ; Causality ; Neuroimaging ; Data Interpretation, Statistical ; },
abstract = {Mediation analysis is a powerful tool for elucidating the causal mechanisms by which exposures influence outcomes through mediators. However, conventional approaches often yield biased estimates of mediation effects in scenarios involving high-dimensional exposures and high-dimensional mediators, alongside a small number of pervasive hidden confounders that simultaneously affect the exposures, mediators, and outcome or the exposures and outcome. To address these challenges, we propose a deconfounded-debiased method for estimation and inference in high-dimensional mediation analysis based on the difference-in-coefficients strategy. This approach effectively corrects biases arising from both pervasive hidden confounders and high-dimensionality without requiring prior knowledge of hidden confounders or a sparse precision matrix assumption. We establish the asymptotic normality of the proposed estimators for both direct and indirect effects, and develop hypothesis testing procedures that asymptotically achieve validity and power lower bounds. Simulation experiments demonstrate our method's superior finite-sample performance in both estimation and inference, especially in the presence of pervasive hidden confounding. We also apply the proposed method to real data from the Alzheimer's Disease Neuroimaging Initiative to identify serum metabolites that influence Alzheimer's disease progression through DNA methylation pathways.},
}

Humans
*Mediation Analysis
Alzheimer Disease/diagnostic imaging/blood
Computer Simulation
Confounding Factors, Epidemiologic
Bias
Models, Statistical
DNA Methylation
Causality
Neuroimaging
Data Interpretation, Statistical

@article {pmid42744009,
year = {2026},
author = {Chen, X and Fu, P and Kang, C and Wu, Y and Wu, Y and Luo, X and Chen, L and Liu, H and Ouyang, J and Zhang, M and Yin, X and Chen, Z},
title = {The mechanism of cerebellar involvement in cognitive disorders and therapeutic prospects.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113324},
doi = {10.1016/j.exger.2026.113324},
pmid = {42744009},
issn = {1873-6815},
abstract = {The cerebellum has traditionally been regarded as a brain region primarily involved in motor coordination and balance. However, increasing evidence suggests that the cerebellum plays a significant role in multiple higher-order cognitive functions. This review explores the mechanisms underlying cerebellar involvement in cognitive impairment, focusing on four prevalent cognitive disorders: Alzheimer's disease, vascular cognitive impairment, Parkinson's disease dementia, and frontotemporal dementia. Analysis of existing neuroimaging, neuropathological, and clinical studies indicates that cerebellar structural and functional abnormalities constitute a common pathological feature of cognitive dysfunction in these conditions. Deepening our understanding of cerebellar-cerebral interactions offers new perspectives for early diagnosis, disease monitoring, and therapeutic interventions in cognitive disorders. This review also summarizes research on the cerebellum as a potential target for non-invasive brain stimulation therapy, which holds promise for opening up new avenues for intervention in cognitive disorders and ultimately leading to better treatment outcomes and quality of life for patients.},
}

@article {pmid42744151,
year = {2026},
author = {Yoshikawa, H and Matsumoto, T and Yoshida, E and Ohta, T and Yoshida, T and Noda, Y and Shimohama, S and Takata, K},
title = {Amyloid-β aggregation inhibitory activity and neuroprotective effects of metabolites of Trichoderma pluripenicillatum.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130778},
doi = {10.1016/j.bmcl.2026.130778},
pmid = {42744151},
issn = {1464-3405},
abstract = {Three new compounds, pluripenicillatumols І-ІІІ (1-3), and five known compounds (4-8) were isolated from the fungus, Trichoderma pluripenicillatum JKYM-KI28. The planar chemical structures and relative configurations of 1 and 2 and the geometry of 3 were elucidated using high-resolution mass spectrometry, one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy, and DP4+ analysis using the calculated [13]C NMR chemical shifts. The absolute configurations of 1 and 2 were determined using electronic circular dichroism calculations. Further bioassays for the isolated compounds, 3-6, indicated inhibitory effects against amyloid-(Aβ) aggregation and neuroprotective effects against Aβ-induced cytotoxicity in human induced pluripotent stem cell-derived basal forebrain cholinergic neurons. These results suggest that the new compounds in this study may have potency as Alzheimer's disease treatments and as preventive agents via Aβ aggregation inhibition and neuroprotection.},
}

@article {pmid42744164,
year = {2026},
author = {Li, J and Yue, D and Xie, W and Xiong, Z and Wang, X},
title = {Alternative splicing in Alzheimer's disease: event-level evidence, risk-locus biology, and RNA-based therapeutic perspectives.},
journal = {Gene},
volume = {},
number = {},
pages = {150397},
doi = {10.1016/j.gene.2026.150397},
pmid = {42744164},
issn = {1879-0038},
abstract = {Genetic and transcriptomic studies have identified many Alzheimer's disease (AD) risk loci, but many remain difficult to interpret at the level of gene expression alone. Alternative splicing (AS) provides an event-level framework for linking genetic variation, transcript architecture, RNA surveillance, and protein-domain remodeling to AD biology. This Review evaluates AD-associated splice and isoform events according to event definition, human recurrence, genetic proximity, molecular consequence, perturbation evidence, and translational tractability. Current evidence is concentrated in several mechanistic areas, including amyloid processing and endolysosomal trafficking, tau biology and spliceosome dysfunction, TDP-43-associated cryptic splicing, immune and lipid-risk loci, and transport or endocytic risk loci. ApoER2 exon 19 correction provides AD-specific preclinical evidence for splice-event modulation, whereas BIIB080/MAPTRx illustrates the feasibility of CNS antisense oligonucleotide delivery and target-engagement monitoring in patients. By contrast, evidence for CD33, PSEN2, MAPT intron retention, TREM2, APOE/CLU, and MS4A-associated post-transcriptional regulation currently supports risk-locus interpretation, molecular stratification, or assay development rather than intervention-ready splice targets. CircRNAs, age-related loss of splicing fidelity, and sex-biased intron retention broaden the field, but their AD-specific functional relevance remains incompletely defined. Overall, AS should not be viewed as a single pathogenic mechanism in AD. Selected splice events may improve AD risk-locus interpretation, molecular stratification, biomarker development, and the design of RNA-based therapeutic strategies.},
}

@article {pmid42744302,
year = {2026},
author = {Reskiawan A Kadir, R and Bons, J and Vega Hormazabal, G and Vadhana Ashok Kumaar, P and Gerónimo-Olvera, C and Tshilenge, KT and Pihán, P and Galicia Aguirre, C and Schneider, K and Roberts, A and Ambrose, BD and Lerner, C and Devanney, NA and Sandholm, AM and Hady, M and Alderfer, S and Hetz, C and Furman, D and Gerencser, AA and Verdin, E and Schilling, B and Ellerby, LM},
title = {The longevity gene APOE2 enhances pericyte function and reduces lipid droplets.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag311},
pmid = {42744302},
issn = {1460-2156},
abstract = {Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer's disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity. To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation. Using unbiased proteomic profiling to understand these cellular phenotypes, we found significant alterations in lipid metabolism-related proteins. Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet (LD) accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated LD accumulation in APOE3 and APOE4 pericytes. Collectively, these findings demonstrate that APOE2 expression supports pericyte functionality through increased lipid processing, providing mechanistic insight into the cerebrovascular protective effects of APOE2 in pericytes. These findings could be translated into novel therapies aimed at enhancing pericyte function and lipid metabolism, particularly in individuals at risk for neurodegenerative diseases.},
}

@article {pmid42744633,
year = {2026},
author = {Lv, Z and Xie, D and Li, H and Chen, C and Chen, R},
title = {[Effect of moxibustion-induced deqi on hippocampal autophagy function in APPswe/PSEN1dE9 transgenic Alzheimer's disease mice].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {9},
pages = {1465-1472},
doi = {10.13703/j.0255-2930.20250408-k0003},
pmid = {42744633},
issn = {0255-2930},
mesh = {Animals ; *Moxibustion ; *Alzheimer Disease/therapy/physiopathology/genetics/metabolism/psychology ; *Autophagy ; Male ; *Hippocampus/metabolism/physiopathology/cytology ; Mice ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic ; Disease Models, Animal ; Presenilin-1/genetics/metabolism ; },
abstract = {OBJECTIVE: To investigate the effect of moxibustion on autophagy regulation under deqi (arrival of qi) versus non-deqi moxibustion, using APPswe/PSEN1dE9 transgenic Alzheimer's disease (AD) model mice.

METHODS: Forty SPF-grade male APPswe/PSEN1dE9 transgenic mice were randomly divided into a model group (n=10) and a moxibustion group (n=30) at a ratio of 1∶3. Ten SPF-grade male C57BL/6 mice served as the control group. In the moxibustion group,gentle moxibustion was operated at the site around 3 cm far from "Dazhui" (GV14), 40 min each intervention, once daily and for 28 consecutive days. The deqi group (the mean tail temperature increase [TTI]>1 ℃ within 7 days, n=20) and non-deqi group (the mean TTI≤1 ℃, n=10) were subdivided according to the change of tail temperature within 7 days after intervention with moxibustion. After intervention completion, Morris water maze was performed to determine cognitive behavior of mice, HE staining was to observe hippocampal morphology, transmission electron microscopy (TEM) was to observe hippocampal autophagy-related ultrastructure; Western blot analysis was to detect the expression of hippocampal β-amyloid protein (Aβ) and autophagy-related proteins (microtubule-associated protein light chain 3 [LC3]Ⅱ、LC3Ⅰ,benzochlorine 1 [Beclin-1], ubiquitin-binding protein [p62], lysosome-associated membrane protein 1 [LAMP1]).

RESULTS: Compared with the control group, in the model group, the escape latency was prolonged in the hidden platform test for 5 consecutive days (P<0.001), and the number of platform crossings was reduced in spatial probe test (P<0.000 1). The hippocampal neuronal arrangement was disorganized, cell morphology was abnormal, and the number of autophagolysosome complexes reduced, and a large number of insoluble cellular components were visible within them. The ratio of LC3Ⅱ/LC3Ⅰand the protein expression of Aβ, p62 and LAMP1 increased (P<0.001, P<0.000 1, P<0.05), while the protein expression of Beclin-1 decreased (P<0.000 1). When compared with the model group, the escape latency was shortened during the last 2 days of hidden platform test in the non-deqi group (P<0.05), and it was shortened for 5 consecutive days in the deqi group (P<0.05, P<0.01); in the deqi group and the non-deqi group, the hippocampal neuronal morphology was improved, a large number of autophagosomes increased in size, and the number of lysosomes rose. Besides, the hippocampal protein expression of A β was reduced in both the deqi group and the non-deqi group (P<0.01, P<0.001), the hippocampal protein expression of Beclin-1 was elevated (P<0.01) and that of p62 was reduced (P<0.01) in the deqi group. When compared with the non-deqi group, in the deqi group, the escape latency was shortened during the last 3 days of the hidden platform test(P<0.05), the number of autophagolysosome complexes increased markedly, the amount of insoluble cellular components inside was significantly reduced; the protein expression of hippocampal Beclin-1 increased (P<0.05) and that of p62 decreased (P<0.05). The differences in the other indexes were not significant statistically between the two groups (P>0.05).

CONCLUSION: Moxibustion with deqi obviously improves autophagic function and cognitive behavioral performance in AD model, versus moxibustion without deqi.},
}

Animals
*Moxibustion
*Alzheimer Disease/therapy/physiopathology/genetics/metabolism/psychology
*Autophagy
Male
*Hippocampus/metabolism/physiopathology/cytology
Mice
Humans
Mice, Inbred C57BL
Mice, Transgenic
Disease Models, Animal
Presenilin-1/genetics/metabolism

@article {pmid42744757,
year = {2026},
author = {Aghababaei, A and Etemadifar, M and Atapour-Abarghouei, A and Innes, W and Fard, MA and Paul, F and Rabbani, H and Kafieh, R},
title = {Machine Learning for Noninvasive Diagnosis of Neurodegenerative Diseases Using Retinal and Optic Nerve Imaging: A Comprehensive Review.},
journal = {Annual review of vision science},
volume = {12},
number = {1},
pages = {155-186},
doi = {10.1146/annurev-vision-110423-025837},
pmid = {42744757},
issn = {2374-4650},
mesh = {Humans ; *Machine Learning ; *Neurodegenerative Diseases/diagnosis/diagnostic imaging ; *Optic Nerve/diagnostic imaging ; Tomography, Optical Coherence/methods ; *Retina/diagnostic imaging ; Multiple Sclerosis ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, encompass a wide range of chronic conditions with irreversible damage to the central nervous system. Current diagnostic workups of these disorders rely on invasive, time-consuming, and costly tests, such as magnetic resonance imaging and cerebrospinal fluid analysis, preventing accurate decision-making and timely therapeutic interventions. The retina is an extension of the central nervous system; thus, retinal imaging, which is a noninvasive and easily accessible tool, provides a unique window to study brain pathologies. There is a great body of evidence suggesting that neurodegenerative disorders are associated with various structural and vascular problems within the retina. Notably, training machine learning models with retinal images has yielded high levels of accuracy in classifying neurodegenerative diseases, encouraging a new era for early and automated diagnosis of these disorders. This article reviews studies that use such models for classifying these disorders.},
}

Humans
*Machine Learning
*Neurodegenerative Diseases/diagnosis/diagnostic imaging
*Optic Nerve/diagnostic imaging
Tomography, Optical Coherence/methods
*Retina/diagnostic imaging
Multiple Sclerosis

@article {pmid42744775,
year = {2026},
author = {Zhang, J and Sun, L and Yang, X and Kang, L and Zheng, Y and Huang, Q and Xu, W and Guan, Y and Liu, J and Deng, Y and Xie, F and Xu, X and Li, B and , },
title = {Regional juxtacortical microstructural changes and gene expression provide insights into neurodegeneration in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {16},
number = {1},
pages = {},
pmid = {42744775},
issn = {2158-3188},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism ; Female ; Male ; Aged ; *White Matter/diagnostic imaging/pathology ; Diffusion Magnetic Resonance Imaging ; *Gene Expression ; Aged, 80 and over ; Positron-Emission Tomography ; Transcriptome ; },
abstract = {White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer's disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism
Female
Male
Aged
*White Matter/diagnostic imaging/pathology
Diffusion Magnetic Resonance Imaging
*Gene Expression
Aged, 80 and over
Positron-Emission Tomography
Transcriptome

@article {pmid42744782,
year = {2026},
author = {Dichter, A and Lee, EJ and Park, T and Tawk, K and Ghanbarian, E and Abouzari, M},
title = {Clinical and self-reported hearing measures and dementia risk.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488509},
doi = {10.1177/13872877261488509},
pmid = {42744782},
issn = {1875-8908},
abstract = {This study evaluated hearing loss (HL) as a factor associated with dementia in a large population-based cohort. We analyzed 16,270 participants from the All of Us database, including 1224 (7.5%) with dementia, matched to controls by U.S. census demographics. Self-reported severe hearing difficulty showed the strongest association with dementia (OR 6.76), followed by sensorineural HL (SNHL) (OR 3.90), smoking (OR 1.71), parental HL (OR 1.48), and hypertension (OR 1.48), all p < 0.001. Effect sizes were largest for self-reported severe hearing difficulty (1.91) and SNHL (1.36). These findings indicate that self-reported severe hearing difficulty and SNHL are strongly associated with dementia.},
}

@article {pmid42744789,
year = {2026},
author = {Famurewa, BA and Nwaokorie, FO and Akinyemi, RO},
title = {Oral health and dementia in Africa: Current evidence, contemporary gaps and future perspectives.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488428},
doi = {10.1177/13872877261488428},
pmid = {42744789},
issn = {1875-8908},
abstract = {As Africa transitions to an aging population, she is faced with an increasing burden of dementia on one hand, and the complex oral health care needs of individuals with dementia. Deterioration of oral health in older adults is a global health issue, particularly in sub-Saharan Africa because of many years of low priority, lack of clear policy, underfunding, and shortage of manpower. There is paucity of published reports on oral health care of individuals with dementia in Africa.This review highlights the gaps in knowledge and practice regarding oral health care of dementia patients in Africa. Additionally, strategies aimed at bridging the gaps include policy formulation and implementation at national and continental levels to drive future practice; seamless integration of older adults dental care within neurology/memory clinic; capacity building for oral health personnel in dental gerontology; oral health promotion for people living with dementia and their caregivers, and geriatric focused oral health research. Lastly, leveraging on the Africa-wide collaborative partnership of the African Dementia Consortium, these strategies will be promoted through awareness creation, policymaker and stakeholder engagements, and research collaboration to improve oral health of people with dementia.},
}

@article {pmid42744796,
year = {2026},
author = {Sangam, M and Irvine, RE and Sunda, M and Grant, J and Vaou, O and Hohler, AD},
title = {Effects of an algorithmically enhanced personalized music-based intervention in patients with dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487385},
doi = {10.1177/13872877261487385},
pmid = {42744796},
issn = {1875-8908},
abstract = {BackgroundMusic-based interventions (MBIs) are gaining recognition as non-pharmacological strategies to support individuals with dementia. Rubato is an AI-driven music platform that uses machine learning and deep neural networks to deliver personalized music interventions aimed at reducing stress and anxiety through real-time heart rate variability monitoring.ObjectiveTo evaluate a personalized music-based intervention for individuals with mild dementia.MethodsIn this randomized controlled trial, twenty participants with mild dementia, including Alzheimer's disease, were enrolled, with ten randomly assigned to each of the intervention and control groups. Intervention participants used the Rubato app for 30 minutes daily over 12 weeks, while control participants received standard care. Pre- and post-intervention questionnaires assessed cognition (Mini-Mental State Examination), anxiety (State-Trait Anxiety Inventory), quality of life (Dementia Quality of Life Questionnaire), depression (Geriatric Depression Scale), and memory (Immediate Prose Memory Test).ResultsAnxiety and depression scores decreased significantly following the MBI in the intervention group compared to controls (p = 0.037 and p = 0.028, respectively). Overall, 80% of the intervention participants showed reduced anxiety compared to 30% of controls, and 70% showed reduced depression compared to 20% of controls. No statistically significant differences were found in cognition, quality of life, or memory, although trends toward improvement were noted in the intervention group.ConclusionsThese preliminary findings suggest that Rubato's MBI may reduce anxiety and depression in individuals with dementia, with clinically meaningful benefits despite limited statistical power. Larger studies with longer follow-up are needed to validate these findings and further examine effects on cognition and quality of life.},
}

@article {pmid42744995,
year = {2026},
author = {Hanotte, JL and Peralta, F and Escartin, C and Carrillo-de Sauvage, MÁ and Reggiani, PC},
title = {Sex-dependent Hippocampal Astrocytic Signaling and Synaptic Alterations Associated With Behavioral Impairments in Intracerebroventricular Streptozotocin-treated Rats.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42744995},
issn = {1559-1182},
support = {6173//Association France Alzheimer/ ; ANPCyT PICT#2018-2201 grant//Argentine Agency for Science and Technology/ ; },
mesh = {Animals ; Female ; *Streptozocin/administration & dosage ; Male ; *Hippocampus/pathology/drug effects/metabolism ; *Astrocytes/metabolism/drug effects/pathology ; Rats, Sprague-Dawley ; *Signal Transduction/drug effects ; *Synapses/metabolism/drug effects/pathology ; *Sex Characteristics ; *Behavior, Animal/drug effects ; STAT3 Transcription Factor/metabolism ; Ovariectomy ; Spatial Memory/drug effects ; Maze Learning/drug effects ; Injections, Intraventricular ; },
abstract = {Sporadic Alzheimer's disease (AD) disproportionately affects women, yet sex differences in disease mechanisms remain incompletely understood, raising the question of whether preclinical models such as the intracerebroventricular (ICV) streptozotocin (STZ) model adequately capture sex-dependent differences. We examined whether STZ-induced alterations are similarly expressed in males and females and whether ovarian hormones modulate vulnerability to STZ. Three-month-old Sprague-Dawley male, intact female, and ovariectomized (OVX) female rats received ICV artificial cerebrospinal fluid or STZ (3 mg/kg). Behavioral testing was conducted 14-24 days post-injection, followed by hippocampal analyses. STZ increased depressive-like behavior and reduced species-typical burying behavior overall (both p < 0.0001), whereas recognition memory performance did not differ significantly between groups. Spatial memory was more impaired in STZ-treated males, which showed increased Barnes maze latency (p = 0.0027) and fewer head entries into the goal sector (p = 0.0315) than male controls. STZ also reduced PSA-NCAM-positive cells across groups (p < 0.0001) and increased GFAP expression in CA3 (p = 0.0401). Nuclear STAT3 activation increased in STZ-treated males in CA3 (p = 0.004), CA1 (p = 0.0323), and dentate gyrus (p = 0.0058), while synaptic density in the CA3 stratum lucidum was reduced in STZ-treated males (p = 0.0208). Ovarian hormone depletion did not increase female susceptibility to STZ for these key sex-dependent outcomes. Overall, males showed greater vulnerability to STZ-induced spatial memory deficits, astrocytic JAK/STAT3 activation, and synaptic loss, whereas both intact and ovariectomized females displayed an attenuated early phenotype. These findings indicate that the STZ-induced AD-like phenotype is not equivalently expressed across sexes and underscore sex as a critical variable in the translational interpretation of this model.},
}

Animals
Female
*Streptozocin/administration & dosage
Male
*Hippocampus/pathology/drug effects/metabolism
*Astrocytes/metabolism/drug effects/pathology
Rats, Sprague-Dawley
*Signal Transduction/drug effects
*Synapses/metabolism/drug effects/pathology
*Sex Characteristics
*Behavior, Animal/drug effects
STAT3 Transcription Factor/metabolism
Ovariectomy
Spatial Memory/drug effects
Maze Learning/drug effects
Injections, Intraventricular

@article {pmid42745326,
year = {2026},
author = {Aye, S and Åhrberg, S and Carlsson, AC and Hasselström, J and Alshamani, I and Wallen, S and van den Hurk, W and Lund, L and Jejcic, A and Broome, ST and Duran Sidera, A and Tjernberg, L and Jönsson, L and Schedin-Weiss, S},
title = {Enhancing Alzheimer's disease diagnosis in primary care through targeted screening of people at risk of developing dementia - study design and feasibility assessment of the PREDEM primary care study.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42745326},
issn = {1758-9193},
mesh = {Humans ; Female ; *Alzheimer Disease/diagnosis/blood ; Aged ; Primary Health Care ; Male ; Feasibility Studies ; Pilot Projects ; Biomarkers/blood ; Neuropsychological Tests ; Aged, 80 and over ; Risk Factors ; Mass Screening/methods ; *Dementia/diagnosis ; },
abstract = {BACKGROUND: Timely detection of cognitive impairment due to Alzheimer's disease (AD) is increasingly important as disease modifying therapies become available. Current diagnostic pathways in primary health care (PHC) rely mainly on clinical assessment and brief cognitive screening tools, which lack sensitivity for early impairment. Blood-based biomarkers (BBMs) show promising diagnostic potential in research settings. Targeted screening of individuals with cognitive symptoms and dementia risk factors using sensitive cognitive tests and reliable biomarkers may improve early AD detection in PHC. The PREDEM primary care study evaluates a targeted screening strategy combining a multidomain digital cognitive test battery and BBMs in individuals having elevated risk of dementia. This pilot study assessed the feasibility of recruitment, digital cognitive testing, biomarker sampling, and data collection.

METHODS: This descriptive pilot study was conducted at two PHC centres in Stockholm (April-October 2024). Eligible individuals were aged ≥ 65 years with hypertension or type 2 diabetes and self-reported memory complaints. Participants completed a screening question, followed by a demographic questionnaire, a multidomain digital cognitive test battery (Mindmore), MMSE, and blood sampling for four BBMs (GFAP, NF‑L, total tau, pTau217). Feasibility metrics included recruitment yield, test completion rates, participant characteristics, cognitive performance, and biomarker distributions.

RESULTS: Of 548 identified individuals, 307 were invited and 40 were enrolled (13% participation). Among those enrolled, 37 completed all parts of the study. Digital home-based testing proved challenging: although 22 participants initially opted for home testing, only six completed it independently, and most required clinic-based support. Across cognitive tests, approximately one-third of participants scored below 1 standard deviation of normative performance, indicating detectable cognitive impairment. Non-native Swedish speakers (32%) showed significantly lower performance on verbally mediated tasks. Established cut-off values for pTau217 reflecting amyloid pathology showed pathological levels in 10-23% of participants depending on single or double cut-offs.

CONCLUSIONS: This pilot study demonstrates the feasibility of the PREDEM primary care study design and data collection procedures. Targeted recruitment of older adults with cardiometabolic risk factors was able to identify a population relevant to the study aims. Key protocol refinements include removing the requirement for subjective memory complaints, conducting all cognitive testing at PHC, and optimization of cognitive test battery.},
}

Humans
Female
*Alzheimer Disease/diagnosis/blood
Aged
Primary Health Care
Male
Feasibility Studies
Pilot Projects
Biomarkers/blood
Neuropsychological Tests
Aged, 80 and over
Risk Factors
Mass Screening/methods
*Dementia/diagnosis

@article {pmid42745402,
year = {2026},
author = {David, J and Torres, I and Smith, E and Pongpipat, E and Park, D},
title = {Evaluating the 8-Year Association Between Cognition and Beta Amyloid in the Dallas Lifespan Brain Study Cohort.},
journal = {Brain and behavior},
volume = {16},
number = {9},
pages = {e71684},
doi = {10.1002/brb3.71684},
pmid = {42745402},
issn = {2162-3279},
mesh = {Humans ; Female ; *Amyloid beta-Peptides/metabolism ; Male ; *Cognition/physiology ; Aged ; *Brain/metabolism ; Processing Speed ; *Cognitive Dysfunction/metabolism ; Memory, Short-Term/physiology ; Memory, Episodic ; Alzheimer Disease/metabolism ; Aged, 80 and over ; Neuropsychological Tests ; Cohort Studies ; },
abstract = {BACKGROUND: Mounting evidence suggests beta amyloid (Aβ) is not the sole initiating driver of cognitive decline in Alzheimer's disease (AD). This study explores whether there is an association between cognitive decline over eight years and Aβ.

METHODS: Data from 48 participants in the Dallas Lifespan Brain Study (DLBS) were analyzed in the present study. Prior to selection, participants were classified as Aβ[+] or Aβ[-] based on global Aβ deposition. All 24 Aβ[+] participants with complete data for the purposes of the present study were sex- and age-matched with an Aβ[-] participant and assorted into two respective Aβ groups. Cognitive decline across episodic memory, working memory, processing speed, and reasoning was then compared between the two groups over an 8-year observation period.

RESULTS: An association between cognitive decline over 8 years and the Aβ group was observed in reasoning but not across episodic memory, working memory, and processing speed. Still, there were differences between the two groups that reached significance on an episodic memory task (p = 0.035) and trended toward significance on an encompassing episodic memory composite (p = 0.057). Post-hoc comparisons revealed these differences were only significant at epoch 1. Broad declines in cognition were also found over the observation period, irrespective of Aβ group.

CONCLUSION: Our results contribute to the mounting evidence that suggests Aβ is not the sole initiating driver of cognitive decline in AD. However, the present study has limitations, including a relatively small sample size that must be accounted for when considering the null findings to prevent overinterpretation. Future work should validate our results in larger, similarly controlled samples and model additional AD biomarkers and risk factors to explore different mechanisms for cognitive decline in AD.},
}

Humans
Female
*Amyloid beta-Peptides/metabolism
Male
*Cognition/physiology
Aged
*Brain/metabolism
Processing Speed
*Cognitive Dysfunction/metabolism
Memory, Short-Term/physiology
Memory, Episodic
Alzheimer Disease/metabolism
Aged, 80 and over
Neuropsychological Tests
Cohort Studies

@article {pmid42745407,
year = {2026},
author = {Passarella, D and Russo, C},
title = {Rethinking γ-Secretase Dysfunction in Alzheimer's Disease: From APP Processing to Network Perturbation.},
journal = {Journal of neurochemistry},
volume = {170},
number = {9},
pages = {e70550},
doi = {10.1111/jnc.70550},
pmid = {42745407},
issn = {1471-4159},
support = {PE00000006//NextGenerationEU/ ; CN00000041//NextGenerationEU/ ; },
}

@article {pmid42745471,
year = {2026},
author = {Umezaki, U and Holladay, C and Sonia He, ZM and Chakraborty, S and Martí, AA},
title = {Molecular Binding in Supramolecular Fibrillar Biomolecules.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.09.019},
pmid = {42745471},
issn = {1542-0086},
abstract = {Amyloid-β (Aβ) fibrils are biopolymer structures associated with the onset of Alzheimer's disease. Quantitative analyses of the interactions between Aβ fibrils and ligands, including dissociation constant (Kd) and binding stoichiometry (n), are crucial. In this paper, two independent-variable binding assays were simultaneously fitted to determine the Kd and n values of ruthenium(II) dipyridophenazine complex binding to Aβ fibrils. This approach eliminates the inherent ambiguity caused by the strong correlation between Kd and n in the binding equation. We demonstrate that this method is applicable to the quantitative binding study of other biopolymers with heterogeneous binding sites, such as calf thymus DNA (ct-DNA). Our method provides a robust evaluation of binding parameters in biopolymers with periodic systems (e.g. amyloids, DNA, and collagen), yielding precise Kd and n values, particularly when the concentration of binding sites is an unknown parameter.},
}

@article {pmid42745524,
year = {2026},
author = {Chandrasekaran, A and Paget-Blanc, A and Decourt, B and Sabbagh, MN},
title = {Investigating oral blarcamesine for treatment of early Alzheimer's disease.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14656566.2026.2732056},
pmid = {42745524},
issn = {1744-7666},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative dementia affecting millions globally. Therapies primarily consist of symptomatic management and progression limitation. Further advances in treatments include disease-modifying therapies, many of which have unfavorable safety profiles and modest improvements in cognitive function. The need for novel disease-modifying therapies continues to grow as the burden of AD in the population increases.

AREAS COVERED: We outline approved disease-modifying therapies including the mechanisms of autophagy restoration through SIGMAR1 activation and its impact on neuronal homeostasis, and how oral blarcamesine, a SIGMAR1 agonist, demonstrates promise for early onset AD management. We then describe the Phase IIa and IIb/III clinical trials supporting the efficacy of blarcamesine in AD patients and other neurodegenerative diseases. Additionally, we discuss recent preclinical evidence supporting a preventive role for blarcamesine in AD. A Pubmed search was conducted for relevant literature regarding this topic using keywords including, but not limited to, 'blarcamesine,' 'disease-modifying therapy,' 'precision medicine,' 'sigma-1 receptor,' and 'SIGMAR1 agonist.'

EXPERT OPINION: Blarcamesine is a potential oral disease-modifying therapeutic candidate for early-stage AD that acts upstream of amyloid-beta pathogenesis and could prevent AD progression very early on, with emerging preclinical evidence also supporting its potential for disease prevention.},
}

@article {pmid42745714,
year = {2026},
author = {Ikeda, M},
title = {[How to Proceed with Diagnosing Memory Loss].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {9},
pages = {1003-1014},
doi = {10.11477/mf.188160960780091003},
pmid = {42745714},
issn = {1881-6096},
mesh = {Humans ; *Memory Disorders/diagnosis ; Diagnosis, Differential ; Alzheimer Disease/diagnosis ; *Dementia/diagnosis ; Cognitive Dysfunction/diagnosis ; },
abstract = {When diagnosing dementia disorders, obtaining a detailed medical history and identifying relevant findings on physical and neurological examinations are fundamental. It is essential to assess cognitive function, neurological symptoms and signs, and dementia severity; conduct additional tests; and establish a differential diagnosis. With the widespread use of anti-amyloid antibody therapies, mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and early-stage AD must not be overlooked. When evaluating patients with dementia who present with diverse symptoms, clinicians must consider neurological signs, findings from diagnostic tests, and the clinical course to establish an accurate diagnosis and guide appropriate treatment.},
}

Humans
*Memory Disorders/diagnosis
Diagnosis, Differential
Alzheimer Disease/diagnosis
*Dementia/diagnosis
Cognitive Dysfunction/diagnosis

@article {pmid42745918,
year = {2026},
author = {Ford, JN and Ferraciolli, SF and Chagui, OG and Iii, MR and Cadavid, EC and Dickson, J and Vejdani-Jahromi, M and DeSalvo, MN and Gomez, LAR and Yee, S and Griffin, HR and Kozak, B and Rohatgi, S and Huang, RY and Gomez-Isla, T and Romero, J},
title = {Imaging for anti-amyloid therapy eligibility: Comparing GRE and SWI in detecting microhemorrhages and superficial siderosis.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70477},
pmid = {42745918},
issn = {2352-8729},
abstract = {INTRODUCTION: Anti-amyloid therapies such as lecanemab require magnetic resonance imaging (MRI) screening to exclude patients with > 4 gradient-recalled echo (GRE)-detected microhemorrhages or any superficial siderosis (SS). Although GRE and susceptibility-weighted imaging (SWI) are both accepted, they differ in detection performance.

METHODS: We retrospectively analyzed 224 eligibility MRIs with paired GRE and SWI from a single academic health system. Six neuroradiologists assessed a 20-scan reliability subset; the remaining 204 scans were assigned to one rater for hemorrhagic lesion detection and MRI-based eligibility classification. Interobserver reliability was calculated using intraclass correlation coefficients (ICCs), and sequence differences were evaluated using non-parametric tests.

RESULTS: SWI detected more microhemorrhages than GRE (mean 1.24 vs. 0.67, p < 0.0001), identified eight additional SS cases, and showed higher interobserver agreement (ICC 0.951 vs. 0.764, p < 0.01). SWI classified more patients as MRI ineligible than GRE (26/204 [12.7%] vs. 11/204 [5.4%]).

DISCUSSION: SWI identifies more exclusionary hemorrhagic findings and demonstrates greater reproducibility than GRE.},
}

@article {pmid42745934,
year = {2026},
author = {Bellelli, F and González, E and Peluso, A and Angioni, D and Sourdet, S and Martin, MS},
title = {P-tau181 is longitudinally associated with a proxy measure of mild behavioral impairment among frail older adults: Insights from COGFRAIL.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70392},
pmid = {42745934},
issn = {2352-8729},
abstract = {INTRODUCTION: Cross-sectional studies link Alzheimer's disease (AD) pathogenesis to mild behavioral impairment (MBI), but longitudinal evidence remains limited. We examined whether plasma phosphorylated tau (p-tau)181 predicts progression of an MBI-proxy over 2 years in pre-frail and frail older adults with mild cognitive impairment.

METHODS: This is a secondary analysis of the Cognitive Function and Prevalence of Amyloid Marker in Frail Older Adults study, including 174 participants (mean age = 82.9 ± 5.4 years). Plasma p-tau181 was analyzed both as a continuous variable and by tertiles. MBI was approximated using a Neuropsychiatric Inventory Questionnaire (NPI-Q)-based algorithm.

RESULTS: Participants in the highest tertile showed greater progression in the number of affected NPI-Q-derived MBI domains and overall severity compared to the lowest tertile. Continuous analyses showed a similar but non-significant trend (P = 0.08).

DISCUSSION: Amyloid and tau pathology may contribute not only to cognitive but also to behavioral impairment, supporting the hypothesis that MBI reflects underlying AD pathology, and may help identify individuals at higher risk of neuropsychiatric progression.},
}

@article {pmid42745943,
year = {2026},
author = {McDonough, SR and Rao, AK and McAleer, JM and Babrowicz, BM and Sharma, M},
title = {Autophagy-lysosomal pathway in neurodegeneration.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {37},
pmid = {42745943},
issn = {3059-4944},
abstract = {Autophagy-Lysosomal Pathway (ALP) dysfunction has emerged as a prominent mechanism underlying neurodegenerative disease. Given its central role in facilitating cellular clearance of misfolded proteins, damaged organelles and other cellular debris, the ALP is vital for cellular health and survival. In mature neurons, whose post-mitotic state renders them unable to dilute such materials through cell division, this waste removal pathway takes on an even greater importance. It is therefore unsurprising that ALP dysfunction is increasingly implicated in the context of age-associated neurodegenerative disease, where impaired proteostasis and pathological protein aggregation are common hallmarks. The focus of this review is how dysregulation of ALP-associated processes, including autophagic flux, chaperone-mediated autophagy, endolysosomal trafficking, lysosomal pH and ion balance, and lysosomal metabolic signaling, is implicated in both the pathogenesis and progression of neurodegenerative diseases, with an emphasis on Alzheimer's disease and Parkinson's disease. A more detailed understanding of how these processes, both independently and cooperatively, contribute to the development and progression of neurodegenerative disease will improve our understanding of these debilitating disorders and inform the development of ALP-targeted therapeutic strategies.},
}

@article {pmid42745993,
year = {2026},
author = {Buck, SA and Madhavan, SS and Sanders, LH},
title = {Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {38},
pmid = {42745993},
issn = {3059-4944},
abstract = {Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.},
}

@article {pmid42746101,
year = {2026},
author = {Ray, WJ and Lightfoot, YL and Trinh, RT and Fawver-Kahle, J and Cooper, S and Tsai, LH and Bortz, J and Trujillo-Gonzalez, I and Zhang, T and Wu, H and Iv, GJO and Schulz, PE},
title = {Effect of choline supplementation in presymptomatic APOE ε4 carriers: a pilot study.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70323},
pmid = {42746101},
issn = {2352-8737},
abstract = {INTRODUCTION: With the advent of early detection biomarkers, it is possible to envision testing preventive strategies that delay the onset of Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (APOE ε4) is the strongest genetic risk factor for late-onset AD; approximately 50% of all patients are APOE ε4-positive.[1] APOE is the major central nervous system (CNS) lipoprotein, and studies have linked APOE4-dependent deficits in lipid metabolism to disease-relevant processes.[2-6] Choline, the precursor for phosphatidylcholine (PC), normalizes APOE ε4-mediated lipid dysfunction in human model systems,[6] and low dietary choline intake correlates with increased disease risk or progression in mouse models and humans.[7-17] We therefore tested whether biomarkers and omics provided early evidence of choline CNS target engagement in an at-risk population.

METHODS: In a 6-month open-label phase 1 study (NCT05880849), asymptomatic APOE ε4 carriers (n = 13; age 70 ± 5.5 years) received 2200 mg/day oral choline, with plasma and cerebrospinal fluid (CSF) collected before and after treatment.

RESULTS: Choline was well tolerated with no serious adverse events. Treatment increased plasma and CSF choline and betaine, indicating systemic and CNS exposure. Exploratory lipidomics identified changes in plasma PC species and, in CSF, increases in ceramides and cholesterol esters. Although this study was not powered to assess biomarker efficacy, CSF neurofilament light (NfL) was lower at the end of treatment, and CSF phosphoserine-181 tau (pTau181)/amyloid beta (Aβ)42 and plasma pTau217 showed directionally similar trends.

DISCUSSION: These findings support randomized placebo-controlled trials of choline in at-risk populations and illustrate how fluid biomarkers and omics can de-risk AD prevention studies.},
}

@article {pmid42746141,
year = {2026},
author = {Vyas, CM and Ostaszewski, BL and Anderson, AK and Cook, NR and Kang, JH and Mischoulon, D and Reynolds, CF and Chang, G and Gatchel, JR and Manson, JE and Selkoe, DJ and Okereke, OI},
title = {Effects of long-term daily supplementation with vitamin D3 and marine omega-3 fatty acids on change in ADRD biomarkers: A secondary analysis of a randomized clinical trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70312},
pmid = {42746141},
issn = {2352-8737},
abstract = {INTRODUCTION: Vitamin D3 and omega-3 supplementation may slow outcomes related to Alzheimer's disease and related dementias (ADRD), with variation by sex or race, but their effects on ADRD-associated biomarkers are unknown.

METHODS: In this secondary analysis of a randomized clinical trial (RCT), we included 929 participants from the in-clinic subcohort of the VITamin D and OmegA-3 TriaL - a completed, placebo-controlled, 2×2 factorial trial testing vitamin D3 (2000 IU/day) and omega-3s (1 g/day) for cardiovascular disease and cancer prevention. Plasma ADRD biomarkers were assayed at baseline and 2- and/or 4-year follow-up. Study outcomes were longitudinal change in four ADRD biomarkers: N-terminal tau fragment (NT1), amyloid beta (Aβ)40:42, neurofilament-light (NfL), and glial fibrillary acidic protein (GFAP). Repeated-measures models were used, with sex and race were pre-specified effect modifiers.

RESULTS: The sample mean (SD) age was 65.0 (6.6) years; 49.2% were female, and 8.2% were Black adults. Neither vitamin D3 nor omega-3s, compared to placebo, significantly reduced ADRD biomarkers over 4 years. Pre-specified subgroup analyses suggested potential interactions by sex and race. Vitamin D3 supplementation resulted in a reduction in NT1 among males (-2.7%) but not females (p-interaction = 0.08). Among Black participants, vitamin D3 supplementation resulted in a 16.2% reduction in NfL levels [95% CI: -30.5% to 1.1%; p-interaction = 0.06], while omega-3 supplementation showed a 12.4% reduction in GFAP levels [95% CI: -21.5% to -2.2%; p-interaction = 0.049].

DISCUSSION: In this secondary analysis of a RCT, neither vitamin D3 nor omega-3s significantly reduced selected plasma ADRD biomarkers over 4 years. Potential differences were observed by sex and race in reductions of ADRD biomarkers in response to these supplements; however, these analyses were uncorrected for multiple hypothesis testing and should be interpreted cautiously as hypothesis-generating signals requiring replication.

TRIAL REGISTRATION: ClinicalTrials.gov identifiers: c (VITAL); NCT01696435 (VITAL-DEP).},
}

@article {pmid42746189,
year = {2026},
author = {Deng, Z and Dunn, A and Sun, DQ and Shi, D},
title = {Breaking Biological Barriers: Engineering Nanocarriers for Efficient Drug and Gene Delivery through Nano-Bio Interfaces and Biophysical Design.},
journal = {Applied physics reviews},
volume = {13},
number = {3},
pages = {},
pmid = {42746189},
issn = {1931-9401},
abstract = {A persistent challenge in nanomedicine is achieving functional delivery of therapeutic molecules across physiological barriers. Organs impose distinct transport constraints, including the blood-brain barrier, renal filtration, hepatic sequestration, and pulmonary clearance. Although substantial effort has focused on engineering particle structure and surface chemistry, therapeutic performance also depends on dynamic interactions at the nano-bio interface. This structured critical narrative review compares how nanoparticle design variables interact with organ-specific transport mechanisms, prioritizing mechanistic primary studies and direct clinical or regulatory evidence while preserving study-specific experimental conditions. Most review papers focus on a single disease or summarize the progress of a specific nanoparticle type. In contrast, this review addresses the heterogeneity of biological filters by proposing a barrier-specific engineering framework. We evaluate diverse high-barrier environments with distinct restrictive mechanisms and describe the strategies used to overcome them in nanoparticle design. Specifically, we focus on how matching physicochemical properties to these environments can bypass physiological constraints. Using a comparative analysis methodology, we evaluate how design parameters, including size, morphology, and surface functionalization, interact with the mechanisms of major organ systems. Applying this framework across biological barriers distinguishes study-specific relationships from potentially transferable design principles. Its clinical and translational relevance is illustrated by engineered blood-brain barrier shuttles for Hunter syndrome and Alzheimer disease, lipid nanoparticle platforms for mRNA vaccination, and inhaled liposomal therapies.},
}

@article {pmid42746205,
year = {2026},
author = {Sharif, A and Mamo, JCL and Lam, V and Luna, G and Watts, GF and Nesbit, ML and Al-Salami, H and Mooranian, A and Takechi, R},
title = {Effects of HA1, a probucol analogue, and APOC3 siRNA on lipoprotein and amyloid-β metabolism and neurovascular dysfunction in type 2 diabetic mice.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1826957},
pmid = {42746205},
issn = {1663-9812},
abstract = {INTRODUCTION: Chronic vascular exposure to elevated levels of lipoprotein-amyloid-β (Aβ) contributes to blood-brain barrier (BBB) disruption and the pathogenesis of Alzheimer's disease (AD). Therapeutic agents such as probucol have been shown to reduce circulating lipoprotein-Aβ levels and mitigate neurovascular dysfunction and cognitive decline. Type 2 diabetes (T2D) impairs BBB integrity and is characterised by dyslipidaemia and metabolic disturbances that may influence the peripheral metabolism of lipoprotein-Aβ. However, the effects of diabetes on lipoprotein-Aβ homeostasis and neurovascular integrity remain poorly understood. This study investigated whether diabetes impairs lipoprotein and Aβ metabolism and whether treatment with HA1, a probucol analogue with improved bioavailability, or APOC3 siRNA can modify these metabolic changes and improve neurovascular and behavioural outcomes.

METHODS: Non-diabetic db/+ mice, untreated diabetic db/db mice, and diabetic db/db mice treated with HA1 or APOC3 siRNA were used to determine how diabetes and therapeutic modulation of lipoprotein metabolism affect circulating Aβ, neurovascular integrity, and behavioural outcomes. Total plasma Aβ and ApoB levels were measured by ELISA. Intestinal Aβ and ApoB, neurovascular integrity, neuroinflammation, and oxidative stress were assessed by immunofluorescence. Anxiety-like behaviour and short- and long-term memory were evaluated using the open field, novel object recognition, and passive avoidance tests.

RESULTS: Diabetic db/db mice exhibited increased intestinal Aβ and ApoB immunoreactivity and elevated total plasma Aβ42, Aβ oligomer and ApoB, accompanied by heightened BBB permeability and anxiety-like phenotype. HA1 reduced intestinal Aβ and lowered plasma Aβ42 and Aβ oligomer, prevented IgG extravasation, and improved anxiety. APOC3 siRNA lowered plasma ApoB and plasma Aβ42 and attenuated neuroinflammation, but did not reduce IgG extravasation.

CONCLUSION: Dysregulated lipoprotein and Aβ metabolism are associated with neurovascular dysfunction and anxiety-like behaviour in diabetes. HA1 shows therapeutic potential by modulating Aβ metabolism and improving neurovascular and behavioural outcomes.},
}

@article {pmid42746219,
year = {2026},
author = {Samaiya, PK and Agrawal, A and Kesharwani, S and Sathe, R and Prajapati, SK and Majumdar, S},
title = {Microbiota-mitochondria axis in neurodegenerative disorders and retinal dysfunction: mechanisms and emerging therapeutic opportunities.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1889898},
pmid = {42746219},
issn = {1663-9812},
abstract = {The gut microbiota crucial role in maintaining host metabolism, immune homeostasis, intestinal integrity, and mitochondrial function. Emerging evidence suggests that dysregulation of the microbiota-mitochondria axis represents one of the key mechanisms linking gut dysbiosis to the development of neurodegenerative and ocular diseases. The dysbiosis causes disruptions in mitochondrial physiology due to lower levels of short-chain fatty acids, increased intestinal permeability, endotoxemia, oxidative stress, and inflammation. These mechanisms contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, and central serous chorioretinopathy. Environmental factors such as unhealthy dietary patterns, excessive antibiotic use, and prolonged exposure to artificial blue light may exacerbate dysbiosis and further disrupt mitochondrial homeostasis, thereby contributing to disease progression. We also elaborated the emerging therapeutic strategies targeting both the gut microbiota and mitochondrial function, including next-generation probiotics, postbiotics, dietary interventions, mitochondria-targeted antioxidants, NAD[+] precursors, and precision medicine approaches. Collectively, current evidence represents the microbiota-mitochondria axis as a one of the promising mechanistic and therapeutic targets for neurodegenerative and ocular diseases. However, most therapeutic evidence discussed in this review is derived from preclinical studies, with relatively limited clinical validation. Future well-designed longitudinal studies and randomized clinical trials are essential to establish efficacy, safety, and translational applicability in humans.},
}

@article {pmid42746331,
year = {2026},
author = {Hussain, JM and Lashari, A and Nageen, W and Siddiqui, A and Waris, A and Maliha, S and Mudasir, A and Rehman, MBA and Rahman, MHU},
title = {Cerebral oxygen extraction fraction as an emerging imaging biomarker in mild cognitive impairment and dementia.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250412},
pmid = {42746331},
issn = {1980-5764},
abstract = {The progressive onset of dementia and mild cognitive impairment (MCI) is a major global health concern due to its profound impact on quality of life. The challenge of identifying MCI and dementia lies partly in the high cost and invasiveness of some biomarkers. In this context, the oxygen extraction fraction (OEF) has emerged as a promising imaging biomarker. This review summarizes current evidence on cerebral OEF as a neuroimaging biomarker in MCI and dementia, focusing on pathophysiology, imaging techniques, comparison with established biomarkers, clinical applications, and future directions. A literature search was conducted from July 1-31, 2025, using the United States National Library of Medicine (PubMed), Scopus, and Web of Science. Search terms included "oxygen extraction fraction" OR "cerebral oxygen metabolism" AND ("mild cognitive impairment" OR "MCI" OR dementia OR "Alzheimer's disease" OR "vascular dementia") AND (qBOLD OR TRUST MRI OR mcQQ MRI OR 15O PET). English-language studies from the past ten years reporting OEF in cognitive impairment were included; case reports and non-human studies were excluded. OEF demonstrates distinct alterations across the spectrum of cognitive impairment. In MCI, reduced OEF has been linked to impaired neurovascular coupling and mitochondrial dysfunction. In dementia, patterns diverge - typically reduced in Alzheimer's disease but heterogeneous in vascular conditions, often elevated under chronic hypoperfusion yet reduced when vascular pathology coexists with Alzheimer's disease. Non-invasive techniques such as mcQQ magnetic resonance imaging (MRI) and TRUST MRI estimate OEF, while [15]O PET remains the gold standard. OEF shows promise as a neuroimaging biomarker for early detection, differential classification, and monitoring disease progression in cognitive impairment.},
}

@article {pmid42746597,
year = {2026},
author = {Qiu, J and Fan, M and Wu, C},
title = {Multicellular Exosomes as Therapeutic Modulators of Neuroinflammation: Mechanisms and Clinical Prospects.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {585449},
pmid = {42746597},
issn = {1178-2013},
mesh = {*Exosomes/metabolism ; Humans ; *Neuroinflammatory Diseases/therapy/immunology ; Animals ; Neurons/metabolism ; Cell Communication ; Neuroglia/metabolism ; Inflammation ; },
abstract = {Neuroinflammation is a fundamental pathological driver of diverse central nervous system (CNS) disorders, including Alzheimer's disease, stroke, and traumatic brain injury. This complex process is characterized by persistent neuronal damage and the orchestrated response of glial and peripheral immune cells. Intercellular communication during these inflammatory responses is increasingly attributed to exosomes, 30-150 nanometer (nm) extracellular vesicles that deliver bioactive lipids, proteins, and nucleic acids. These vesicles, secreted by neurons, glia, and mesenchymal stem cells, facilitate the sophisticated signaling networks necessary for maintaining neural homeostasis and immune regulation. However, while the individual roles of these vesicles are emerging, a comprehensive synthesis of how multicellular exosomal crosstalk collectively modulates the neuroinflammatory landscape remains elusive. This review systematically evaluates the bidirectional exchange of exosomes among diverse CNS cell populations and their specific roles in regulating inflammatory cytokine expression and immune cell phenotypes. We further examine the molecular mechanisms through which exosomal cargoes promote neural repair, alongside a critical analysis of current challenges in isolation, targeted delivery, and safety. By integrating these multicellular perspectives, this review provides a theoretical framework for utilizing exosomes as precision therapeutic modulators. Ultimately, it highlights the potential of exosome-based interventions to transform clinical outcomes for neuroinflammatory diseases.},
}

*Exosomes/metabolism
Humans
*Neuroinflammatory Diseases/therapy/immunology
Animals
Neurons/metabolism
Cell Communication
Neuroglia/metabolism
Inflammation

@article {pmid42746606,
year = {2026},
author = {Liu, AJ and Moghadam, AA and Alam, MS and Lutz, MW and Navarra, A and Luo, S and Wang, LA and Petrella, JR and Whitson, H and O'Brien, RJ and Johnson, KG and Parker, D and Beam, C and Sanfilippo, M and Al-Sahlani, H and Cobb, S and Liu, MY and Doraiswamy, PM},
title = {Clinical Practice Outcomes With Lecanemab for Alzheimer Disease.},
journal = {Neurology open access},
volume = {2},
number = {3},
pages = {e000121},
pmid = {42746606},
issn = {2998-7601},
abstract = {BACKGROUND AND OBJECTIVES: Lecanemab, an antiamyloid monoclonal antibody, received US Food and Drug Administration approval in July 2023 to treat amyloid-positive early stages of Alzheimer disease (AD) and has since been adopted in many countries. The primary objective was to assess amyloid-related imaging abnormality (ARIA) incidence and serious adverse events. Secondary objectives included identifying ARIA predictors and evaluating its effect on 12-month cognitive change.

METHODS: We performed a retrospective, single-site observational study in patients treated with lecanemab at the Duke University (May 2023-June 2025). Eligible patients met National Institute on Aging-Alzheimer's Association criteria for mild cognitive impairment or mild AD with confirmed amyloid pathology. Treatment protocols and MRI interpretations were standardized.

RESULTS: Among 230 patients (68% MCI; mean age 73.6; 50.9% female; 67.4% allele producing the ε4 type of apolipoprotein E [APOE ε4] carriers), the mean follow-up was 396 days (SD 183). Forty-nine patients (21% [95% CI 16.3%-27.3%]) discontinued treatment. ARIA occurred in 56 patients (24.3% [95% CI 19.1%-30.5%]). ARIA with edema (ARIA-E) and ARIA with microhemorrhages (ARIA-MH) generally had a peak incidence rate at ~10 weeks, with a smaller ARIA-E peak at ~25 weeks; most moderate-to-severe events occurred between 12 and 24 weeks. Clinically significant adverse events occurred in 72 patients (31.3% [95% CI 25.5%-37.8%]), including 5 deaths (2 ARIA-related). Twelve-month cognitive changes did not significantly differ by ARIA status, although there was a significant decline of 0.107 [95% CI 0.04-0.17] units per month in the Montreal Cognitive Assessment score. ARIA-E risk was elevated in APOE ε4 carriers (OR 4.81 [95% CI 1.17-21.45] for 2 copies, p = 0.014) and in men (OR 2.40 [95% CI 0.88-7.25], p = 0.075). Baseline ptau-181/amyloid beta 42, APOE ε4, and Fazekas scores showed high specificity (>90%) but low sensitivity (<25%) for ARIA. Initiation of treatment earlier in the disease course was associated with fewer ARIA events, particularly among APOE ε4 noncarriers and those with lower baseline amyloid burden.

DISCUSSION: Despite the limitations of a single-site cohort, these findings inform real-world lecanemab safety and efficacy. Dual ARIA-E peaks at ~10 and ~25 weeks underscore the need for ongoing MRI monitoring. Although several markers showed modest negative predictive value, none reliably predicted ARIA. Improved markers to predict and monitor ARIA are needed to optimize cognitive outcomes.},
}

@article {pmid42746628,
year = {2026},
author = {Chen, YS and Huang, HY},
title = {Designing intranasal formulations for Alzheimer's disease: A material-based perspective.},
journal = {Tzu chi medical journal},
volume = {38},
number = {4},
pages = {446-456},
pmid = {42746628},
issn = {2223-8956},
abstract = {Alzheimer's disease (AD) remains a major global health challenge, as currently available therapies have a limited impact on disease progression and rely largely on systemic administration. Effective treatment is further hindered by the blood-brain barrier, which restricts brain exposure for most therapeutic agents. Intranasal delivery offers a noninvasive nose-to-brain approach by utilizing olfactory and trigeminal pathways to bypass systemic circulation and first-pass metabolism. Clinically, intranasal insulin and mesenchymal stromal cell-derived exosomes have demonstrated feasibility and safety in mild cognitive impairment and AD, and imaging studies have confirmed direct brain uptake following intranasal dosing. However, variable clinical outcomes suggest that therapeutic efficacy is determined primarily by formulation properties rather than by the delivery route alone. This review adopts a material-centric perspective to summarize rational intranasal formulation strategies for AD, including chitosan derivatives, thermoresponsive poloxamer and amphiphilic block copolymer platforms, lipid-based nanocarriers, surface-engineered systems, and biomimetic nanovesicles. Key translational considerations are discussed with emphasis on quantitative validation of brain exposure and reproducibility. Emerging methodological tools are briefly noted as potential facilitators of formulation development, without detracting from the central role of rational material design.},
}

@article {pmid42746710,
year = {2026},
author = {Russo, MJ and Bueri, J and Alba-Ferrara, L and Sevlever, G and Allegri, RF},
title = {Recognition memory as a neuropsychological marker of progression in early-stage Alzheimer's disease: a 24-month prospective cohort study.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/13803395.2026.2732062},
pmid = {42746710},
issn = {1744-411X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia, and amnestic mild cognitive impairment (a-MCI) is considered its prodromal stage. Recognition memory is commonly assessed with yes/no tasks, although conventional scoring often overlook false alarms. Signal Detection Theory (SDT) measures, particularly discriminability (d-prime), may better detect early recognition deficits and predict progression to AD dementia.

METHOD: In this prospective cohort study, 278 older adults with a-MCI were followed for 24 months. Participants underwent clinical and neuropsychological assessment, including the Rey Auditory Verbal Learning Test. Recognition was decomposed into hits, false alarms, and d-prime. A subsample underwent amyloid and tau biomarker assessment by cerebrospinal fluid and/or imaging. Mixed-effects models examined longitudinal change and prediction of conversion to AD dementia.

RESULTS: Delayed recall, recognition hits, and d-prime declined significantly over time, with steeper trajectories among converters. Converters showed an early and marked d'prime reduction during the first 12 months, mainly related to increased false alarms. Lower baseline d-prime and greater early decline independently predicted conversion after adjustment for demographic, global cognition, and AD biomarkers.

CONCLUSIONS: SDT-derived recognition indices, especially d'prime, provide clinically relevant prognostic information in a-MCI. Adding d' to delayed recall and biomarkers may improve risk stratification, follow-up planning, and selection for disease-modifying trials.},
}

@article {pmid42746891,
year = {2026},
author = {Silva, MG and Vasconcelos, MB and Silva, RG and Feitosa, MÁL},
title = {Response: Beyond Oral Hygiene: Medication Burden, Oral Function, and Dysphagia in Alzheimer's Disease.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {5},
pages = {e70258},
doi = {10.1111/scd.70258},
pmid = {42746891},
issn = {1754-4505},
support = {001//CAPES-Brazilian Coordination for the Improvement of Higher Education Personnel/ ; },
}

@article {pmid42746961,
year = {2026},
author = {McEvoy, AM and Reeve, E and Ride, J and Langford, AV and Lee, KMK and Loh, S and Turner, J},
title = {Insomnia treatment preferences of older adults and people living with dementia: A qualitative study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487350},
doi = {10.1177/13872877261487350},
pmid = {42746961},
issn = {1875-8908},
abstract = {BackgroundInsomnia is common in people living with dementia and older adults. While clinical guidelines recommend non-pharmacological treatment as first-line therapy, insomnia is often managed with benzodiazepine receptor agonists (BZRAs), which carry a significant risk of medication-related harm.ObjectiveTo explore what influences decisions to engage with pharmacological and non-pharmacological insomnia treatments among older adults, people living with dementia and their carers.MethodsSemi-structured interviews were conducted with three participant groups (people living with dementia, their carers, and older adults). The interviews were conducted and transcribed in Zoom. Participants identified and prioritized factors that influence their treatment decisions. Thematic analysis was conducted in NVivo to generate themes that described how participants' beliefs and experiences influenced their preferences.ResultsFrom 19 interviews with 20 participants (Median age range = 65-74 years, 37% female), 14 factors were identified. Risk of side effects (n = 10) and effectiveness (n = 7) were most commonly prioritized and frequently reported across all participant groups. Medication side effects on cognition and daytime sedation were frequent concerns. Underpinning these factors were five main themes determined from thematic analysis, including: beliefs about sleep and insomnia, treatment expectations and experiences, external influences, treatment characteristics, and barriers to treatment.ConclusionsDecisions about insomnia treatments are influenced not only by expected and/or experienced treatment effectiveness, but also by perceived risks and health beliefs. Integrating these perspectives into clinical decision-making may help reduce medication-related harm and promote safer, acceptable alternatives.},
}

@article {pmid42746964,
year = {2026},
author = {Than-Trong, E and Torres, L and Gaudin-Guérif, M and Jan, C and Ghettas, A and Amadio, A and , and Oliet, SHR and Panatier, A and Bonvento, G},
title = {L-serine-enriched diet restores impaired adult neurogenesis in the hippocampus of 3xTg-AD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487394},
doi = {10.1177/13872877261487394},
pmid = {42746964},
issn = {1875-8908},
abstract = {BackgroundAltered adult neurogenesis occurs in Alzheimer's disease (AD) in humans and rodent models, though the mechanisms remain unclear. L-serine, a non-essential amino acid critical for cell proliferation and survival, is produced by neuroepithelial cells and radial glia in the developing brain, and by astrocytes and neural precursors in the adult brain. Its production is altered in AD, particularly in the hippocampus.ObjectiveTo determine whether reduced L-serine availability contributes to impaired adult neurogenesis in AD.MethodsWe examined the expression of phosphoglycerate dehydrogenase (PHGDH), an enzyme in L-serine biosynthesis, in neural stem cells (NSCs) of mouse and human dentate gyrus (DG). Adult neurogenesis was assessed by quantifying proliferating neural precursors and immature neurons in 7- and 12-month-old 3xTg-AD mice and age-matched controls. Mice received an L-serine-enriched diet for 4 or 8 months, after which plasma serine levels, neurogenesis markers, and amyloid pathology were evaluated.ResultsPHGDH was expressed by NSCs in the mouse DG and by cells in the subgranular zone (SGZ) of the human DG showing radial morphology typical of rodent NSCs. Twelve-month-old 3xTg-AD mice showed a significant reduction in proliferating (PCNA-positive) precursors and immature (DCX-positive) neurons in the DG relative to controls. L-serine supplementation significantly raised plasma L- and D-serine levels and partially rescued neurogenesis deficits in 3xTg-AD mice, without affecting amyloid pathology.ConclusionsWe suggest that impairment of L-serine metabolism and the resulting reduction in D-serine availability contributes to impaired adult neurogenesis, potentially via reduced survival of newborn neurons in the DG of 3xTg-AD mice.},
}

@article {pmid42746979,
year = {2026},
author = {Sánchez-Soblechero, A and Villarejo, A and Carreras, MT and Berbel, Á and Puertas, C and Fernández-Bullido, Y and Vieira, A and Gundín, I and Blanco-Palmero, V and González-Sánchez, M and Llamas, S and Lapeña, T and de Luis, P and Lucio, B and Ibáñez, MD and Heredia, P and Grandas, F and Olazarán, J},
title = {Validation of plasma core biomarkers of Alzheimer's disease: A multicenter study in usual practice conditions.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487171},
doi = {10.1177/13872877261487171},
pmid = {42746979},
issn = {1875-8908},
abstract = {BackgroundThe new anti-amyloid therapies have brought the challenge of early and feasible identification of Alzheimer's disease (AD). Plasma biomarkers are promising tools, but real-world evidence remains limited.ObjectiveWe aimed to evaluate the diagnostic performance of plasma core AD biomarkers, while accounting for potential confounding factors.MethodsCross-sectional study of 285 patients (mean age 69.9 [range 50-85] years, 50.9% female) from five centers of the ReDeMa cohort. The diagnostic performance of plasma Aβ42/Aβ40, p-tau181, p-tau217, and p-tau217/Aβ42 was tested against cerebrospinal fluid (CSF) amyloid (A) and tau (T) pathology using a centralized, chemiluminescence-based platform (Lumipulse[©]). The potential influence of comorbidities, medications, neuropsychological variables, and apolipoprotein E gene (APOE) ε4 allele was analyzed, and center-related variability was examined.ResultsCSF amyloid (A+) was present in 216/285 (75.8%), while amyloid and tau pathology (A + T+) occurred in 191/283 (67.5%) patients. p-Tau217 displayed the best performance for detecting both A + (AUC 0.956) and A + T + (AUC 0.903). The optimal cutoff for A + was 0.234 pg/mL (95% CI 0.168-0.237), with an overall agreement of 95.8%. p-Tau217 performance showed some variability across centers (AUCs 0.916 to 1.000), but confidence intervals overlapped. APOE ε4 status (r = 0.272), female sex (r = 0.231), and cognitive performance (r = -0.399) were associated with p-tau217, but multivariate models did not improve the diagnostic performance of p-tau217 alone. Significant associations were not found between p-tau217 and comorbidities or medications.ConclusionsPlasma p-tau217 is established as a first-choice biomarker for the early detection of AD pathology in specialized clinical settings, displaying excellent diagnostic accuracy and minimal site-related variability.},
}

@article {pmid42747062,
year = {2026},
author = {Demmer, RT and Watson, D and Goh, CE and Slashcheva, LD and Tom, SE and Zhou, MX and Kebschull, M and Sen, S and Noble, JM and Papapanou, PN},
title = {Periodontitis, Tooth Loss, and Risk of Cognitive Impairment and Dementia: A Systematic Review With Meta-Analysis.},
journal = {Journal of periodontal research},
volume = {},
number = {},
pages = {},
doi = {10.1111/jre.70177},
pmid = {42747062},
issn = {1600-0765},
support = {P30 AG066462/NH/NIH HHS/United States ; U19AG078558/NH/NIH HHS/United States ; R01AG076015/NH/NIH HHS/United States ; },
abstract = {AIM: To systematically review and meta-analyze cohort studies evaluating associations of gingival inflammation, periodontitis, and tooth loss with cognitive decline and incident mild cognitive impairment or dementia.

METHODS: PROSPERO-registered searches of MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library identified cohort studies from inception through October 10, 2025, with a PubMed update on June 24, 2026. Random-effects meta-analyses pooled adjusted hazard ratios (HRs) for dementia/MCI; cognitive function outcomes were summarized qualitatively. Risk of bias (RoB) was assessed using the Newcastle-Ottawa Scale.

RESULTS: Fifty-nine studies met inclusion criteria; 28 contributed to dementia/MCI meta-analyses. Severe periodontitis (HR: 1.16; 95% CI: 1.06-1.27; I[2] = 0%; Q-test p = 0.49), periodontitis of unspecified severity (HR: 1.45; 95% CI: 1.21-1.73; I[2] = 98%; Q-test p < 0.001), edentulism (HR: 1.26; 95% CI: 1.19-1.33), and low tooth count (HR: 1.27; 95% CI: 1.14-1.42; I[2] = 94%; Q-test p < 0.001) were associated with elevated dementia/MCI risk. RoB was low in 31 studies (53%), moderate in 25 (42%), and high in 3 (5%); inadequate confounder adjustment was common. Meta-regression showed stronger estimates for ICD-code periodontitis definitions (fold change (FC) = 1.44 95% CI: 1.04-2.01), older cohorts (FC per year = 1.02 95% CI: 1.00, 1.05), and weaker estimates with lower RoB (FC per NOS star = 0.81 95% CI: 0.73-0.92). Follow-up duration, cohort age, and RoB were not associated with tooth-count estimates.

CONCLUSION: Periodontitis and tooth loss are associated with modestly higher dementia/MCI risk and poorer cognitive function, but heterogeneity, residual confounding, and bias temper causal interpretation. Longitudinal studies with rigorous baseline cognition assessment and intervention studies are needed.},
}

@article {pmid42747078,
year = {2026},
author = {Yadav, P and Mishra, D and Singh, R},
title = {Advances in N- and S-Heterocycles as c-Jun-N-Terminal Kinase 3 Inhibitors for Alzheimer's Disease Treatment.},
journal = {Drug development research},
volume = {87},
number = {7},
pages = {e70381},
doi = {10.1002/ddr.70381},
pmid = {42747078},
issn = {1098-2299},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Mitogen-Activated Protein Kinase 10/antagonists & inhibitors/metabolism ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use ; Animals ; *Heterocyclic Compounds/chemistry/pharmacology/therapeutic use ; Structure-Activity Relationship ; Drug Design ; },
abstract = {c-Jun-N-terminal kinase 3 (JNK3) inhibitors are emerging as promising therapeutic agents for the treatment of Alzheimer's disease (AD). Predominantly expressed in the central nervous system (CNS), JNK3 plays a crucial role in neuronal apoptosis and inflammation, processes that are often dysregulated in neurodegenerative conditions. In recent years, a diverse range of heterocycle scaffolds has been explored as selective JNK3 inhibitors, demonstrating significant potential in modulating disease pathology. Structure-activity relationship (SAR) studies have further facilitated the rational design and optimization of these compounds, improving their potency, selectivity, and pharmacokinetic profiles. By selectively inhibiting JNK3, these small compounds can mitigate neuroinflammation and promote neuronal survival. The development of small molecule JNK3 inhibitors offers a targeted approach that may minimize side effects. This article explores various heterocyclic molecules such as pyrazoles, thiazoles, imidazoles, and thiophenes, evaluated for JNK3 inhibition. This review will help medicinal chemists to design and develop new molecules based on established data on isoform-selective JNK3 inhibitors.},
}

Humans
*Alzheimer Disease/drug therapy
*Mitogen-Activated Protein Kinase 10/antagonists & inhibitors/metabolism
*Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use
Animals
*Heterocyclic Compounds/chemistry/pharmacology/therapeutic use
Structure-Activity Relationship
Drug Design

@article {pmid42732414,
year = {2026},
author = {Rohatgi, S and Younan, CM and Martinez Imbett, RE and Ford, JN and Wleklinski, M and Zhu, S and Romero, J},
title = {Demographic and Clinical Characteristics of Patients Treated With Lecanemab Stratified by Amyloid-Related Imaging Abnormality Status.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114472},
pmid = {42732414},
issn = {2168-8184},
abstract = {Background Amyloid-related imaging abnormalities (ARIAs) are among the most important safety considerations during lecanemab treatment for Alzheimer's disease (AD). Although APOE ε4 carrier status is a recognized ARIA risk factor, the relationship between ARIAs and routine demographic and clinical characteristics in real-world practice remains incompletely characterized. This study evaluated demographic, vascular comorbidity, and APOE genotype characteristics among patients treated with lecanemab, stratified by ARIA status. Methodology We conducted a retrospective cohort study of patients with AD treated with lecanemab at a single academic institution from December 4, 2023, to October 28, 2025. Of 324 identified patients, 318 were included in the primary analysis. Demographic and clinical variables were extracted from the electronic health record. ARIA status and subtype were determined from clinical MRI interpretations by board-certified neuroradiologists. Patients were stratified by presence and type of ARIA development during treatment. Results Among 318 included patients, 98 (30.8%) developed ARIA and 220 (69.2%) did not. Among ARIA-positive patients, nine (9.2%) had ARIA-E only, 50 (51.0%) had ARIA-H only, and 39 (39.8%) had mixed ARIA-E/H. Age was similar between ARIA-positive and ARIA-negative patients (74.4 vs. 73.6 years; p = 0.437). ARIAs occurred in 33.9% of female patients and 26.8% of male patients (p = 0.218), and in 52.9% of non-White patients and 29.6% of White non-Hispanic patients (p = 0.078). Hypertension, hyperlipidemia, and diabetes were not associated with ARIA. APOE ε4 carriers had a higher incidence of ARIA than non-carriers (35.3% vs. 22.8%; p = 0.029), although differences across individual APOE genotypes did not reach statistical significance (p = 0.135). Conclusions In this real-world cohort of patients treated with lecanemab, ARIAs occurred in nearly one-third of patients. APOE ε4 carrier status was the only evaluated demographic, clinical, or genetic variable significantly associated with ARIAs. Sex- and race/ethnicity-related differences were exploratory and require validation in larger, more diverse prospective cohorts. These findings support genotype-informed ARIA surveillance while emphasizing the need for broader representation in studies of anti-amyloid therapy safety.},
}