@article {pmid42857600,
year = {2026},
author = {Moughamian, AJ and La Vallee, L and Kile, S and Urban, T and Momii, A and Manifield, M and Minton, J},
title = {The Advanced Therapeutics for Alzheimer's Disease Review Board: A multidisciplinary model to facilitate safe access to amyloid-targeting therapies in general neurology across the Sutter Health system.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70479},
pmid = {42857600},
issn = {2352-8729},
abstract = {Amyloid-targeting therapies (ATTs) require workup and monitoring that some general neurologists are uncomfortable with. Sutter Health treats over 3.5 million patients with more than 100 neurologists, but only 5 cognitive specialists. We developed the Advanced Therapeutics for Alzheimer's Disease (ATAD) Review Board, a system-wide model to address the shortage of specialists while enhancing safe access to ATTs across the health system. The ATAD Review Board comprises cognitive specialists, a neuroradiologist, a pharmacist, and a registered nurse program manager. Neurologists submit cases to the board for appropriate patient selection and re-review of cases with side effects. We reviewed 447 cases from 51 neurologists and 77% were eligible for treatment. The annual volume increased 148% in 2025. Total amyloid-related imaging abnormality rate was 17.4% for lecanemab and 28.8% for donanemab. We describe a system-wide review board model that supported ATT prescribing by general neurologists and expanded safe access to ATTs across a large integrated health system.},
}

@article {pmid42857741,
year = {2026},
author = {Shimazu, T and Hoshino, E and Nakaseko, M and Homma, K and Suzuki, S and Horikoshi, K and Maruki, Y},
title = {Caregiver-Reported Behavioral Changes After Donepezil Transdermal Patch Therapy in Alzheimer's Disease: An Exploratory Real-World Network Analysis.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {637015},
pmid = {42857741},
issn = {1176-6328},
abstract = {PURPOSE: To characterize caregiver-reported behavioral changes after donepezil transdermal patch therapy and to examine the descriptive connectivity of co-occurring improvements in patients with Alzheimer's disease (AD).

PATIENTS AND METHODS: This retrospective, single-center observational study included 26 patients meeting the 2011 National Institute on Aging-Alzheimer's Association criteria for probable AD dementia. Approximately 2-4 months after patch initiation, caregivers rated nine behavioral domains using routine, non-validated single-item change assessments as improved, unchanged, or worsened relative to the pre-treatment state. A descriptive co-improvement network was used solely to summarize pairwise co-occurrence of binary improvement indicators using phi-coefficients and observed strength centrality. Because of the small sample and sparse binary events, all network measures were treated as sample-specific descriptive quantities rather than inferential estimates.

RESULTS: The most frequently improved domains were smiling/positive affect (12/26, 46.2%), calmness (9/26, 34.6%), and night-time sleep (8/26, 30.8%). Calmness had the highest observed strength centrality (2.467), followed by grooming behavior (2.059), hobbies/interests (2.009), and housework/instrumental activities of daily living (1.938). Calmness remained the highest-strength node in all 26 leave-one-participant-out sensitivity analyses. No treatment discontinuations or serious adverse events were documented.

CONCLUSION: Caregiver-perceived calmness, assessed as a single non-validated change item, was the most highly connected domain in this small descriptive co-improvement network. The findings are exploratory and do not establish treatment efficacy, a validated agitation-related outcome, temporal direction, or mechanism. Prospective studies using standardized behavioral measures are needed.},
}

@article {pmid42857751,
year = {2026},
author = {Zhang, S and Ding, X and Caffo, B and Chen, J and Zhang, X and Kharrazi, H and Wang, Z},
title = {CROSS-ATTENTION FUSION OF STRUCTURAL AND DEFORMATION-BASED MRI FEATURES FOR ALZHEIMER'S DISEASE CLASSIFICATION.},
journal = {Proceedings. IEEE International Symposium on Biomedical Imaging},
volume = {2026},
number = {},
pages = {},
pmid = {42857751},
issn = {1945-7928},
support = {R01 AG068002/AG/NIA NIH HHS/United States ; },
abstract = {Accurate assessment of Alzheimer's disease (AD) using neuroimaging is important for understanding disease progression and supporting clinical research. Structural MRI (sMRI) is widely used for this purpose, but most deep learning approaches primarily rely on intensity-based features, which may not fully capture subtle morphological variations. Jacobian determinant maps (JSM) provide complementary information by describing localized brain deformations; however, conventional multimodal fusion strategies such as early or late fusion may not fully capture the interactions between these modalities. To address this, we explore a cross-attention fusion approach that explicitly models the relationship between sMRI intensity and JSM-derived deformation features for AD classification. Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we compare cross-attention with pairwise self-attention and four baseline fusion methods. The proposed approach achieved mean ROC-AUC scores of 0.903 (0.033) for AD vs. cognitively normal (CN) and 0.692 (0.061) for mild cognitive impairment (MCI) vs. CN under five-fold cross-validation. The proposed approach achieved the best performance among fusion strategies and achieved higher or comparable performance with only 1.56 million parameters. These findings suggest that cross-attention fusion may serve as a potentially useful approach for integrating structural and deformation-based MRI features in AD classification tasks.},
}

@article {pmid42857961,
year = {2026},
author = {Chandrakar, K and Panday, A and Patel, D and Poleboina, S},
title = {Neuroprotective effects of lithium and caffeic acid co-loaded liposomes in diabetes-induced Alzheimer's disease: association with GSK-3β and β-catenin.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17435889.2026.2743276},
pmid = {42857961},
issn = {1748-6963},
abstract = {AIM: To investigate the therapeutic effects of co-loaded lithium (Li) and caffeic acid (CA) liposomes in diabetes-induced Alzheimer's disease rats by improving cognitive dysfunction and attenuating neurodegeneration through the modulation of β-catenin/GSK-3β signaling.

METHODS: Li- and CA-co-loaded liposomes were prepared by the ethanol injection method and characterized. A diabetes-induced Alzheimer's disease model was established in male Wistar rats using a high-fat diet followed by low-dose streptozotocin (35 mg/kg) administered intraperitoneally. Li- and CA-co-loaded liposomes were given via the same route every day for 4 weeks. At the end of the experiment, the animals were sacrificed, and various biochemical and oxidative stress parameters, histopathological assessments, and ELISA analyses were performed.

RESULTS: Dual-drug-loaded Li and CA liposomal treatment significantly improved cognitive function, ameliorated metabolic dysfunction, and reduced oxidative stress by restoring antioxidant enzyme levels. Additionally, liposomes attenuated nitrite, acetylcholinesterase, and amyloid-β levels in diabetes-induced Alzheimer's rats. Histopathological assessment confirmed marked neuroprotective and pancreatic protective effects. Further, at a molecular level, Li and CA liposomal treatment reduced the expression of GSK-3β and increased the expression of β-catenin levels in rats.

CONCLUSION: This study provides the first evidence demonstrating the therapeutic potential of Li- and CA-co-loaded liposomes in attenuating diabetes‑associated cognitive dysfunction.},
}

@article {pmid42857983,
year = {2026},
author = {Smitasiri, T and Pongpitakmetha, T and Thanprasertsuk, S and Likitjaroen, Y},
title = {Prevalence and impact of cerebral small vessel lesions in mild cognitive impairment and mild dementia due to Alzheimer's disease patients in memory clinic: Preparation for anti-amyloid therapy in Thailand.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493065},
doi = {10.1177/13872877261493065},
pmid = {42857983},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) raises global concern with its impact on daily living. Anti-amyloid therapy (AAT) are specific treatments used in mild cognitive impairment (MCI) and mild dementia stage of AD (mild AD). Severe cerebral small vessel disease (SVD) lesions such as microbleeds, superficial siderosis, lacunes, white matter hyperintensities are listed as exclusions criteria for AAT. In Thailand, there is no prevalence study of SVD lesions specifically in these patient groups.ObjectiveThe purpose of this study is to report the prevalence of SVD burdens which are excluded in AAT, in MCI and mild AD patients in Thailand.MethodsThe study was carried out at Memory Clinic in King Chulalongkorn Memorial Hospital. Patients with amnestic MCI and mild AD were diagnosed using clinical criteria, cognitive tests and brain MRI. Visual rating scales were used to evaluate SVD burden based on STRIVE-2 criteria. Baseline characteristics and cognitive tests were retrieved from electronic medical records.ResultsThe study involving 102 patients, 73.5% had MCI, and 26.5% had mild AD. Twenty-one individuals (20.6%) had either more than 4 microbleeds, more than 2 lacunes, or Fazekas score of 3. There was no evidence of superficial siderosis. Individuals without microbleeds had a higher TMSE score (25.4 versus 23.5; p = 0.009).ConclusionsAmong patients with MCI and mild AD, 20.6% met the exclusion criteria for AAT, in part of SVD lesions. These findings provide important information for evaluating the cost-effectiveness of AAT, which become a treatment option for Thai AD patients.},
}

@article {pmid42858052,
year = {2026},
author = {Qiao, Y and Chen, H and Fan, K and Yang, X and Yu, Y and Wang, R and Xing, Y and Tang, Y},
title = {High-intensity transcranial alternating current stimulation improves sleep quality in patients with mild Alzheimer's disease: Findings from the TRANSFORM-AD study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261492561},
doi = {10.1177/13872877261492561},
pmid = {42858052},
issn = {1875-8908},
abstract = {BackgroundHigh-intensity transcranial alternating current stimulation (Hi-tACS) has shown beneficial effects on cognitive function in Alzheimer's disease (AD). However, data on the effects of hi-tACS on sleep quality and emotional state in patients with AD are still limited.ObjectiveThis study aimed to investigate the influences of hi-tACS on sleep quality and emotional state in AD.MethodsThe TRANSFORM-AD study was a double-blind, randomized-controlled trial that enrolled individuals with mild AD. Participants were randomized to receive hi-tACS group or sham stimulation group, and underwent 30 one-hour sessions of either 40 Hz tACS or sham stimulation over consecutive 15 consecutive days. Pittsburgh sleep quality index (PSQI), Hamilton anxiety Rating Scale (HAMA), Hamilton depression Rating Scale (HAMD) and Quality of life in Alzheimer's Disease scale (QOL-AD) were evaluated at baseline, and the end of the intervention.ResultsAmong 43 participants with complete baseline and post-intervention assessments, Hi-tACS reduced post-intervention PSQI scores compared with sham after adjustment for baseline PSQI (adjusted mean difference, -2.34 points; 95% CI, -3.63 to -1.05; p < 0.001). Baseline-adjusted effects for HAMA (-1.43; 95% CI, -2.89 to 0.02), HAMD (0.44; 95% CI, -1.28 to 2.15), and QOL-AD (2.07; 95% CI, -1.57 to 5.70) were imprecise and included the null.ConclusionHi-tACS improved subjective sleep quality in patients with mild AD. The present secondary analysis did not provide conclusive evidence of effects on anxiety, depression, or quality of life; these exploratory outcomes require confirmation in larger, adequately powered trials.Trial registration:ClinicalTrials.gov, NCT03920826.},
}

@article {pmid42858057,
year = {2026},
author = {Gu, Y and Liu-Ambrose, T and Falck, RS and Nagamatsu, LS and Tam, RC and Hsiung, GR and Ten Brinke, L and Bullock, A and Grant, S and Hsu, CL},
title = {Interaction of physical fitness and resting state functional connectivity on global cognitive function in older adults with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491995},
doi = {10.1177/13872877261491995},
pmid = {42858057},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) represents a prodromal stage of Alzheimer's disease. Physical fitness, including cardiorespiratory fitness and muscular strength, is associated with cognitive function in older adults. Resting-state functional connectivity (rsFC) is also linked to cognitive function; however, whether physical fitness modifies the association between rsFC and cognitive function remains unclear.ObjectiveTo examine associations of cardiorespiratory fitness and muscular strength with rsFC and their interaction on global cognitive function in older adults with MCI.MethodsA cross-sectional study of 95 older adults with MCI. Cardiorespiratory fitness was estimated by the 400-m walk; muscular strength was indexed using grip strength measured by hand dynamometer. Global cognitive function was indexed by the 13-item Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog-13). Using the Yeo 7-network atlas, we computed rsFC within and between seven canonical networks. Significant rsFC-fitness associations were entered into moderation analyses (X = rsFC, Y = ADAS-Cog-13) with cardiorespiratory fitness or grip strength as moderator, adjusted for covariates. Simple slopes were examined at ±1 SD from the mean of moderator.ResultsParticipants had a mean age of 73.49 years, and 53.7% were female. Cardiorespiratory fitness interacted with rsFC in relation to ADAS-Cog-13, whereas grip strength did not. Specifically, greater limbic-visual (standardized b = -0.22, p = 0.009), limbic-somatomotor (b = -0.20, p = 0.049), and limbic-ventral attention (b = -0.19, p = 0.020) rsFC were associated with better global cognitive function among individuals with higher cardiorespiratory fitness.ConclusionsHigher between-network rsFC is generally associated with worse cognitive function. Thus, higher cardiorespiratory fitness may attenuate the negative association between higher between-network rsFC and global cognitive function in MCI.},
}

@article {pmid42858060,
year = {2026},
author = {Ben Brik, S},
title = {Noise or clearance? Reframing plasma amyloid-β variability in Alzheimer's disease as a measurable clearance signal.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496533},
doi = {10.1177/13872877261496533},
pmid = {42858060},
issn = {1875-8908},
abstract = {Plasma biomarkers, and the amyloid-β 42/40 ratio in particular, are increasingly used to stage Alzheimer's disease and to stratify and monitor clinical trials, on the tacit assumption that a single measurement reflects a stable, steady-state level of pathology. A recent micro-longitudinal study that sampled plasma weekly for five weeks in people with Alzheimer's disease challenged that assumption, reporting that most participants varied by more than half in the amyloid-β 42/40 ratio over that short window. The reflexive response is to treat such movement as measurement noise to be averaged away. Here I argue that a meaningful part of it is unlikely to be noise. In healthy adults the same ratio is among the most stable plasma analytes, so instability concentrated in disease is difficult to attribute to the assay alone. Brain-to-blood clearance of amyloid-β is itself dynamic over days, rising with sleep and falling with fragmentation, apnoea, poor cerebral perfusion, autonomic dysregulation, and sedating or anticholinergic drugs. An instantaneous plasma value therefore partly reports the clearance state of the preceding night. This clearance account is kept distinct from analytical and pre-analytical variance, and from oligomeric amyloid-β dynamics, which are considered separately. The practical problem is not the variance itself but that we measure the molecule without measuring the physiological state that moves it. I propose that an inexpensive, repeatable, bedside index of that state, illustrated here with the Systemic BenBrik Geriatric Score, could be recorded alongside each plasma draw and modelled as a covariate, converting nuisance variance into interpretable signal. The prediction is falsifiable, and a validation design is outlined. This is a hypothesis, not a validated result; the illustrative index used here, the Systemic BenBrik Geriatric Score, is not a validated measure.},
}

@article {pmid42858061,
year = {2026},
author = {Zhou, Y and Zhu, L and Liu, Z and Zhang, Q and Wang, J},
title = {Multi-Dimensional Feature Adaptive Gating Network for Multi-View and Whole-Brain Magnetic Resonance Imaging-Based Alzheimer's Disease Classification.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73427},
pmid = {42858061},
issn = {1940-087X},
mesh = {*Alzheimer Disease/diagnostic imaging/classification/pathology ; Humans ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Cognitive Dysfunction/diagnostic imaging/classification ; *Neuroimaging/methods ; Convolutional Neural Networks ; Deep Learning ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with structural brain alterations detectable by structural magnetic resonance imaging (sMRI). Accurate classification of normal control (NC), mild cognitive impairment (MCI), and AD remains challenging because disease-related changes are subtle, spatially distributed across multiple brain regions, and difficult to interpret in a biologically meaningful manner. Existing deep learning methods often rely on either whole-brain volumetric features or two-dimensional slice-level representations, which may limit the integration of complementary structural information and reduce model interpretability. This study presents a reproducible and explainable deep learning framework, termed the multidimensional feature adaptive gating network (MDFAG-Net), for sMRI-based AD classification and neuroimaging analysis. The framework integrates multidimensional structural MRI representations by combining 2D slice-level features extracted from sagittal, coronal, and axial views using a Vision Transformer backbone with global whole-brain features extracted using a three-dimensional convolutional neural network. An Enhanced Sparse Multiple Instance Learning module is employed to identify informative slices and suppress redundant information in long slice sequences, while an adaptive gating module dynamically fuses multiview and whole-brain features according to sample-specific feature contributions. The framework was evaluated on 842 subjects from the Alzheimer's Disease Neuroimaging Initiative dataset for NC/MCI/AD classification. MDFAG-Net demonstrated competitive classification performance and outperformed representative two-dimensional, three-dimensional, and multibranch comparison models under the same experimental setting. The model achieved an area under the receiver operating characteristic curve of 0.798. Furthermore, Grad-CAM and DeepSHAP analyses revealed anatomically relevant regions associated with AD progression, including the hippocampus, amygdala, posterior cingulate gyrus, parahippocampal gyrus, and ventricular system.},
}

*Alzheimer Disease/diagnostic imaging/classification/pathology
Humans
*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/pathology
Cognitive Dysfunction/diagnostic imaging/classification
*Neuroimaging/methods
Convolutional Neural Networks
Deep Learning

@article {pmid42858065,
year = {2026},
author = {Özkurt, Ç},
title = {Single-cell gene networks nominate IKZF1 as an Alzheimer's disease microglial regulator.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496918},
doi = {10.1177/13872877261496918},
pmid = {42858065},
issn = {1875-8908},
abstract = {BackgroundMicroglia drive neuroinflammation in Alzheimer's disease (AD), yet no approved therapy targets this compartment. Human genome-wide association studies consistently implicate innate immune loci in AD risk, establishing microglial transcriptional programs as therapeutically relevant but pharmacologically underexploited targets.ObjectiveWe sought to identify transcription factors (TFs) governing microglial state transitions computationally and to nominate structurally tractable drug repurposing candidates.MethodsWe applied trajectory inference (PAGA), pseudobulk DESeq2, pySCENIC gene regulatory network (GRN) inference, CellChat, and virtual screening of 1962 approved compounds to 236,002 microglial nuclei from 84 donors (SEA-AD atlas).ResultsIKZF1 was the sole target TF retained under cisTarget v10 motif constraints, with peak regulon activity in LateAD-DAM (pseudotime ρ = + 0.309) and replication in an independent bulk cohort (GSE95587; adjusted p = 0.004). CellChat identified SLIT2→ROBO2 from multiple neuron subtypes (predominantly inhibitory interneurons) as the top predicted pathway to microglia. Tafamidis (→IRF8) and diflunisal (→PPARG) were top virtual screening hits; all evaluated compounds failed the pre-specified selectivity threshold.ConclusionsIKZF1 is prioritized as a candidate late-disease microglial TF, supported by six convergent evidence dimensions including independent bulk replication. Tafamidis and diflunisal are low-confidence repurposing hypotheses requiring experimental validation.},
}

@article {pmid42858068,
year = {2026},
author = {Wang, P and Ge, L and Gao, B and Jiang, S and Wang, S},
title = {Baseline and longitudinal trajectories of peak expiratory flow in relation to incident cognitive impairment among older adults: Evidence from CHARLS.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494159},
doi = {10.1177/13872877261494159},
pmid = {42858068},
issn = {1875-8908},
abstract = {BackgroundPrevious studies, including CHARLS analyses, have linked lower peak expiratory flow (PEF) with cognitive decline. Evidence regarding incident score-based cognitive impairment, longitudinal PEF patterns, and incremental prediction remains limited.ObjectiveTo examine associations of baseline PEF and exploratory PEF trajectories with incident score-based cognitive impairment and evaluate the incremental predictive value of PEF.MethodsThe primary analysis included 2604 CHARLS participants aged ≥60 years without score-based cognitive impairment at baseline. Cognitive impairment was defined as a global cognitive score ≥1 SD below the wave- and age-specific mean and was not a clinical diagnosis of mild cognitive impairment or dementia. Cox models, sensitivity analyses, prediction analyses, and exploratory trajectory modeling were performed.ResultsOver a median follow-up of 9.0 years, 636 participants developed score-based cognitive impairment. Each 1-SD increase in PEF was associated with lower risk in fully adjusted models (HR = 0.801, 95% CI 0.728-0.880) and after adjustment for baseline cognition (HR = 0.846, 95% CI 0.768-0.930). Nine-year cumulative incidence decreased from 35.6% to 16.6% across PEF quartiles. Adding PEF modestly improved 9-year AUC (ΔAUC = 0.011, p = 0.042). In the exploratory trajectory analysis, the moderate PEF group was not significantly associated with risk versus the high group (HR = 1.294, 95% CI 0.860-1.948), whereas the low PEF group had higher risk (HR = 1.817, 95% CI 1.172-2.817), with no clear graded pattern.ConclusionsLower baseline PEF was associated with wave-specific score-based cognitive impairment, but not under stricter definitions requiring subsequent confirmation with wave-specific or fixed thresholds. PEF trajectories were exploratory, and incremental predictive value was limited.},
}

@article {pmid42858079,
year = {2026},
author = {Yang, X and Ye, T and He, Y and Zhao, J and Wang, J and Cheng, X},
title = {Qi-Fu-Yin Attenuates Frailty by Regulating Gut Microbiota and Neuroendocrine Hormones in 5xFamilial Alzheimer's Disease Transgenic Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73003},
pmid = {42858079},
issn = {1940-087X},
mesh = {Animals ; *Alzheimer Disease/drug therapy/microbiology/blood/metabolism ; Mice, Transgenic ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/pharmacology/administration & dosage ; *Frailty/drug therapy/microbiology ; Female ; Male ; Disease Models, Animal ; },
abstract = {Frailty is a common and debilitating feature of Alzheimer's disease (AD), yet effective therapeutic strategies targeting both cognitive decline and physical frailty remain limited. Qi-Fu-Yin (QFY), a traditional Chinese herbal formulation, has been used to treat aging-related disorders, but its effects on frailty in AD and the underlying mechanisms are unclear. This study aimed to evaluate whether QFY alleviates frailty in 5xFamilial Alzheimer's Disease (FAD) transgenic mice and to explore the potential involvement of gut microbiota and neuroendocrine hormones. Mice were treated with QFY at low (2.8 g/kg), medium (5.6 g/kg), or high (11.2 g/kg) doses, or with donepezil as a positive control, for 194 days. Frailty-related behaviors were assessed using CatWalk gait analysis, grip strength, rotarod, nest-building, and aging scoring. Plasma hormone levels were measured, and fecal gut microbiota composition and function were analyzed by 16S rRNA sequencing and metagenomic analysis. QFY treatment significantly improved gait parameters, grip strength, motor coordination, nesting ability, and reduced aging scores in 5xFAD mice, with effects comparable to or superior to those of donepezil. QFY also restored aberrant levels of estradiol, testosterone, and corticosterone, and reshaped gut microbiota composition, particularly by increasing the abundance of Adlercreutzia, which negatively correlated with senescence and testosterone levels. Functional metagenomics revealed that QFY partially restored disease-associated microbial pathways, including those involved in carbohydrate metabolism and virulence. These findings suggest that QFY alleviates frailty in 5xFAD mice, with effects associated with concurrent modulation of gut microbiota and neuroendocrine function, though causal relationships require further validation. These findings support further investigation of QFY as a potential intervention for AD-associated frailty.},
}

Animals
*Alzheimer Disease/drug therapy/microbiology/blood/metabolism
Mice, Transgenic
Mice
*Gastrointestinal Microbiome/drug effects
*Drugs, Chinese Herbal/pharmacology/administration & dosage
*Frailty/drug therapy/microbiology
Female
Male
Disease Models, Animal

@article {pmid42858322,
year = {2026},
author = {Yang, Y and Zhang, X and Zan, X and Niu, C and Wei, X and Feng, P and Li, G and Gao, M},
title = {A Clearance-Repair-Activation Framework for Alzheimer's Disease: A Perspective and Validation Roadmap.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.1040},
pmid = {42858322},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is a heterogeneous clinicobiological syndrome involving impaired protein clearance, neuroinflammation, synaptic and cellular injury, network dysfunction, and progressive functional decline. Amyloid-directed antibodies provide an evidence-based treatment backbone for selected patients with early symptomatic AD, but adjunctive strategies may be needed to address other disease mechanisms. This Perspective proposes a clearance-repair-activation framework for hypothesis-driven research. Clearance includes established pharmacological treatment and risk management as well as investigational drainage approaches; lymphaticovenous anastomosis (LVA) and deep cervical lymphaticovenous anastomosis (dcLVA) are considered only as research options within this broader domain. Repair includes neural stem-cell (NSC), induced pluripotent stem-cell-derived, engineered-cell, and secretome-based strategies, for which AD evidence remains predominantly preclinical. Activation encompasses invasive and non-invasive stimulation, sensory entrainment, neurofeedback, brain-computer interface (BCI) monitoring, and cognitive rehabilitation; BCI is positioned mainly as an experimental monitoring and adaptive rehabilitation platform. We define falsifiable links between clearance and repair readiness and between repair markers and activation responsiveness, consider adaptive and parallel alternatives to fixed sequencing, and integrate disease stage, heterogeneity, regulation, and combination-trial design. Informatics is limited to trial infrastructure and safety governance. The validation roadmap specifies success criteria, stop rules, interaction testing, clinically meaningful outcomes, and long-term surveillance.},
}

@article {pmid42858330,
year = {2026},
author = {Zhang, K and Zhang, Y and Jiang, X and Chen, X},
title = {Neuroimmune State Configurations at the Amyloid-Tau Interface in Alzheimer's Disease: A Testable Framework.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0888},
pmid = {42858330},
issn = {2152-5250},
abstract = {Neuroimmune mechanisms are central to Alzheimer's disease (AD), but a single continuum of "more inflammation" does not explain why similar amyloid-β (Aβ) and tau burdens are associated with different clinical trajectories, tissue responses, and treatment risks. We present a testable neuroimmune-state framework that integrates, rather than replaces, the AT(N) system, cellular-phase models, and transcriptional descriptions of disease-associated microglia and reactive astrocytes. The framework treats neuroimmune states as multidimensional, regionally heterogeneous configurations defined by pathological substrate, cellular program, biological target, vascular and aging context, and measurable patient-level readouts. We distinguish four meanings of the amyloid-tau interface: a biomarker interface, a spatial tissue interface, a cellular-state interface, and a clinical-progression interface. We then examine the hypothesis of phagocytic target switching, in which clearance pathways that support plaque compaction or debris removal may, under selected tau- and complement-rich conditions, contribute to removal of stressed but potentially functional synapses. We explicitly separate evidence from longitudinal human studies, cross-sectional biomarkers, human genetics, postmortem tissue, animal models, and in vitro systems. Current biomarkers cannot yet assign patients to validated discrete neuroimmune states; proposed state readers should therefore be probabilistic, allow regional coexistence and parallel vascular-immune trajectories, and be tested for incremental value beyond established AD biomarkers and co-pathologies. Finally, we organize immune-directed interventions by clinical evidence level and frame stage matching as a research strategy rather than a treatment algorithm. The model is useful only if its predictions can be prospectively supported or falsified.},
}

@article {pmid42858800,
year = {2026},
author = {Changjian, W and Furui, W and Yanyu, F and Yu, Y and Jianshe, W},
title = {Beyond the brain-centric view: A systems physiology framework for exercise-induced neuroprotection in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116058},
doi = {10.1016/j.expneurol.2026.116058},
pmid = {42858800},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is regarded as a multifactorial disease that combines central pathological changes and peripheral organ dysfunction. Its core features include Aβ protein deposition, tau protein pathology, synaptic dysfunction, and neuroinflammation. Exercise has been proven to be one of the most effective non-pharmacological intervention measures. However, its mechanism of action in AD has not been fully elucidated from the traditional brain-centered research perspective. Moreover, most existing studies focus on isolated organ systems or a single signaling pathway, failing to fully reflect the overall peripheral-cerebral physiological interaction mechanism required for neuroprotective effects of exercise. This article provides a structured narrative synthesis of current evidence regarding how exercise may influence AD-related pathological processes through multiple peripheral organ systems. It clarifies the communication mechanisms between these systems and the central nervous system through endocrine, immune, metabolic, neural, and vascular pathways. The study shows that exercise functions by coordinating the regulation of peripheral physiological functions, rather than relying on a single target mechanism. Exercise can regulate multiple signaling pathways such as muscle-brain, gut-brain, liver-brain, adipose-brain, bone-brain, and immune-brain, improving overall metabolic flexibility, inflammation regulation, vascular function, and neuroimmune homeostasis; these peripheral adaptive changes further act on the central nervous system, regulating blood-brain barrier(BBB) integrity, microglial cell activity, neuronal energy metabolism, neurovascular coupling, and synaptic plasticity. In summary, the neuroprotective effect induced by exercise stems from the integration of multiple systems' physiology, rather than isolated molecular signal transduction. This review synthesizes current evidence on exercise-induced peripheral-central interactions in AD from a systems physiology perspective, highlighting the significance of integrating peripheral biomarkers, multi-organ interactions, and central outcomes. It provides a theoretical framework for future personalized and mechanism-oriented exercise intervention studies.},
}

@article {pmid42858944,
year = {2026},
author = {Patel, DR and Rangasamy, SB and Gorai, S and Paidi, RK and Pahan, K},
title = {Glyceryl tribenzoate, a flavoring agent, stimulates hippocampal plasticity and protects memory via PPARα.},
journal = {Neurochemistry international},
volume = {201},
number = {},
pages = {106270},
doi = {10.1016/j.neuint.2026.106270},
pmid = {42858944},
issn = {1872-9754},
abstract = {Glyceryl tribenzoate (GTB) or tribenzoin is a flavoring agent with characteristic anti-microbial property. We have already delineated GTB's immunomodulatory role via the enrichment of regulatory T cells in mouse models of multiple sclerosis and anti-neuroinflammatory role via the reduction of glial activation in a monkey model of Parkinson's disease and a mouse model of Huntington's disease. However, its role has never been explored in Alzheimer's disease (AD), the most common neurodegenerative disorder in human. This study underlines the importance of GTB in promoting the growth and function of hippocampal neurons via upregulation of plasticity-associated genes, enrichment of dendritic spines and stimulation of inotropic calcium influx. Accordingly, oral GTB improved hippocampal plasticity and protected memory and learning in 5xFAD mice. Similarly, GTB treatment also reduced cerebral plaque load and increased the life span of aged 5xFAD mice. Interestingly, we observed that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, served as a receptor of GTB. Consequently, GTB was shown to improve hippocampal plasticity and increase cognitive functions in 5xFAD, but not 5xFAD/Ppara-null, mice, indicating an important role of PPARα in GTB-mediated neuroprotection. These results suggest that oral GTB may have therapeutic importance for improving hippocampal functions in AD patients.},
}

@article {pmid42859261,
year = {2026},
author = {Maglio, GM and de Melo, NC and de Carvalho, LM},
title = {Integrative Transcriptomic and Interactome Analyses Prioritize Candidate Genes for Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42859261},
issn = {1559-1182},
support = {2024/21955-3//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
mesh = {*Alzheimer Disease/genetics ; Humans ; *Transcriptome/genetics ; Aging/genetics/pathology ; *Protein Interaction Maps/genetics ; *Gene Expression Profiling ; Signal Transduction/genetics ; Gene Regulatory Networks ; *Genetic Association Studies/methods ; *Genetic Predisposition to Disease ; },
abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder characterized by complex molecular alterations and diverse cognitive, behavioral, and neuropsychiatric manifestations. Although transcriptomic studies have identified several pathways associated with AD, the integration of molecular signatures with disease-related phenotype annotations and pathological aging remains incompletely understood. Therefore, this study aimed to integrate transcriptomic profiling, protein-protein interaction (PPI) network analysis, pathological aging assessment, and curated clinical phenotype annotations to prioritize candidate molecular signatures associated with AD. Differential expression analyses and network-based approaches were applied to publicly available transcriptomic datasets derived from distinct brain regions. Candidate genes and pathways were prioritized through interactome reconstruction, functional enrichment analyses, cluster-based analyses, and independent validation in an external dataset. In addition, transcriptomic signatures were integrated with curated clinical phenotype annotations using a knowledge-based gene overlap strategy. The analysis identified molecular signatures associated with neuroinflammatory signaling, synaptic dysfunction, endocytosis, and pathological aging. Pathways related to MAPK, PI3K/Akt, NF-κB, and TGF-β1 signaling emerged as candidate dysregulated pathways in AD. Comparative analyses of physiological aging and the AD aging comparison enabled the prioritization of candidate genes potentially more closely associated with the AD condition than with aging alone, including FOS and TAB2. Independent validation reinforced the reproducibility of several prioritized genes, including GFAP, CXCR4, CCL2, HSPA1A, FCGR2A, TLR2, CD44, TLR4, FOS, TAB2, CDC42, and SH3GL2. Integration with curated clinical phenotype annotations suggested partially overlapping molecular signatures across neuropsychiatric and cognitive phenotype annotations in AD. Together, these findings demonstrate the utility of integrative bioinformatics approaches for prioritizing candidate genes, pathways, and molecular signatures associated with AD. This systems-level framework may contribute to future mechanistic studies aimed at understanding the molecular heterogeneity of AD and its associated phenotypic complexity.},
}

*Alzheimer Disease/genetics
Humans
*Transcriptome/genetics
Aging/genetics/pathology
*Protein Interaction Maps/genetics
*Gene Expression Profiling
Signal Transduction/genetics
Gene Regulatory Networks
*Genetic Association Studies/methods
*Genetic Predisposition to Disease

@article {pmid42859279,
year = {2026},
author = {Solar, KG and Kashyap, S and Deom, N and Uludağ, K and Zotovic, L and Lanctôt, K and Black, SE and McAndrews, MP},
title = {Characterizing hippocampal activation during pattern separation with multi-echo fMRI in cognitively normal older adults.},
journal = {Brain imaging and behavior},
volume = {20},
number = {5},
pages = {},
pmid = {42859279},
issn = {1931-7565},
support = {CT200401//Weston Family Foundation/ ; },
mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Aged ; Male ; Female ; *Hippocampus/physiology/diagnostic imaging ; Brain Mapping/methods ; Memory, Episodic ; *Cognition/physiology ; Neuropsychological Tests ; Aged, 80 and over ; Alzheimer Disease ; Aging/physiology ; Dentate Gyrus/physiology/diagnostic imaging ; Image Processing, Computer-Assisted ; },
abstract = {Hippocampal hyperactivity, detected with mnemonic similarity task (MST) fMRI, is both a promising marker of risk and a probable driver of degeneration in Alzheimer's disease (AD). However, implementation of such fMRI in interventional research is limited by long scan times and the absence of a framework for identifying prospective participants with hyperactivity who could be targeted with therapeutic approaches aimed at reducing this activity. We used multi-echo fMRI during the MST, an episodic memory task previously shown to engage hippocampal subfields CA3 and dentate gyrus (DG), to characterize activity profiles in 33 cognitively normal older adults. We compared MST-related CA3 and DG activation and behavioural performance across subsets of eight task runs. Behavioural and activation effects were equivalent for the first set of four runs (Runs-A) and the second set (Runs-B), suggesting that robust data can be obtained with four runs. Left and right CA3 + DG activation did not differ. We provide an exemplar framework for the derivation of a threshold for single-participant classification of elevated hippocampal activation as an indicator of AD risk in cognitively normal older individuals. Scalable (~22 min) multi-echo MST fMRI robustly captures hippocampal activation and provides a framework for individual-level characterization of hippocampal function in cognitively normal older adults. This enables individualized detection of elevated hippocampal activation as a modifiable risk factor and may guide enrolment into prevention trials targeting preclinical AD.},
}

Humans
*Magnetic Resonance Imaging/methods
Aged
Male
Female
*Hippocampus/physiology/diagnostic imaging
Brain Mapping/methods
Memory, Episodic
*Cognition/physiology
Neuropsychological Tests
Aged, 80 and over
Alzheimer Disease
Aging/physiology
Dentate Gyrus/physiology/diagnostic imaging
Image Processing, Computer-Assisted

@article {pmid42859348,
year = {2026},
author = {Lin, W and Shu, Z and Liu, G and Fang, J and Ding, S},
title = {The Gut-Brain Axis and Neurodegenerative Diseases: From Mechanistic Pathways to Therapeutic Interventions.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42859348},
issn = {1867-1314},
support = {2024RC2053//Yuelushan Laboratory joint talent introduction project/ ; Grant No. kq2502176//Natural Science Foundation of Changsha, China/ ; 24B0219//Scientific Research Project of Hunan Provincial Department of Education/ ; 2025JGZD053//Hunan Province Postgraduate Education Teaching Reform Research Project/ ; 2023YFD1301200//National Key Research and Development Program of China/ ; HARS-06//Hunan Poultry Industry Technology System/ ; },
abstract = {As the global population ages, the incidence of neurodegenerative diseases (NDDs) has increased. Neurodegenerative diseases have complex pathogenesis and currently lack fundamental treatment methods. The gut-brain axis (GBA) participates in the pathogenesis of NDDs through bidirectional communication between the gut microbiota and the central nervous system (CNS). This review systematically introduces the pathogenic characteristics of representative NDDs such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), as well as the association mechanisms between these diseases and GBA. The pathogenic characteristics of NDDs are closely related to changes in the composition of the gut microbiota and differences in gut microbiota metabolites (such as short-chain fatty acids (SCFAs), neurotransmitters, tryptophan metabolites, etc.). These changes influence the CNS through multiple pathways, including neuroendocrine, vagus nerve, and immune regulation, ultimately contributing to the onset and progression of the diseases. Furthermore, we have collected and summarized preclinical and clinical evidence from recent years regarding therapeutic interventions based on the GBA mechanism, including probiotics, prebiotics, and fecal microbiota transplantation (FMT). Nevertheless, major knowledge gaps remain, particularly regarding causality between gut microbiota changes and NDDs, the underlying molecular mechanisms, and the clinical efficacy of GBA-targeted therapies. This article aims to review the mechanisms of the interaction between the gut microbiota and the brain in neurodegenerative diseases, and based on the existing experimental evidence, provide theoretical basis and future development directions for future prevention and treatment strategies targeting GBA.},
}

@article {pmid42859693,
year = {2026},
author = {Noh, S and Shin, HE and Shim, Y},
title = {Cerebral Hemodynamic Changes in Older Adults With Cognitive Complaints According to the Presence of Peripheral Artery Disease.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {},
number = {},
pages = {},
pmid = {42859693},
issn = {2475-0360},
abstract = {OBJECTIVE: As a systemic expression of atherosclerosis, peripheral artery disease (PAD) has the potential to alter cerebral hemodynamics in elderly individuals presenting with cognitive concerns. However, how PAD status shapes the longitudinal trajectory of cerebral hemodynamics has not been well characterized.

METHODS: We conducted a single-center longitudinal observational study enrolling 132 participants (21 controls, 39 mild cognitive impairment, 72 mild Alzheimer's disease). All participants underwent transcranial Doppler (TCD) ultrasonography, ankle-brachial index (ABI) measurement, brain MRI, and cognitive assessments at baseline and follow-up (~13.45 months). PAD was defined as ABI < 0.90. Bilateral mean flow velocity (MFV), pulsatility index (PI), and resistance index (RI) of the middle cerebral artery (MCA) were tracked longitudinally across both time points.

RESULTS: PAD was identified in 13 participants (9.8%). Baseline TCD parameters, vascular risk factors, white matter lesions on brain MRI, and cognitive measures were comparable between groups. At follow-up, the PAD group showed significantly higher MCA MFV after age adjustment (left p < 0.001; right p = 0.005). MFV increased in the PAD group (left +16.45 cm/s) but decreased in the non-PAD group (left -3.37 cm/s), with a significant between-group difference. PI and RI did not change in either group. Cognitive and functional outcomes were similar across groups throughout the study.

CONCLUSION: These findings identify PAD as a condition associated with progressive MCA MFV elevation in the context of preserved cognition, implying that subclinical cerebrovascular changes are detectable by TCD before overt clinical worsening. Future research involving larger cohorts and extended follow-up is required to determine whether such hemodynamic changes forecast eventual cognitive deterioration.},
}

@article {pmid42859768,
year = {2026},
author = {Jimenez-Maggiora, GA and Bruschi, S and Abdel-Latif, S and Aisen, PS and Rissman, RA},
title = {ATRI LIMS: a cloud-native open-source laboratory information management system for biomarker-driven Alzheimer's disease clinical trials.},
journal = {JAMIA open},
volume = {9},
number = {5},
pages = {ooag198},
pmid = {42859768},
issn = {2574-2531},
abstract = {OBJECTIVES: This article summarizes the architecture, design principles, and implementation strategy of the ATRI Laboratory Information Management System (LIMS), a cloud‑native, open‑source platform supporting biomarker‑driven Alzheimer's disease (AD) clinical research. The system addresses challenges associated with managing large‑scale, multimodal biomarker, and biobanking data across multisite studies.

METHODS: The ATRI LIMS employs a Model-View-Controller architecture implemented in Django, with Single‑Page Application interfaces built in ReactJS. A hybrid database model integrates a normalized core schema with study‑specific extensions. Deployment on Amazon Web Services incorporates multifactor authentication, encryption, and a web application firewall. Regulatory support is provided through audit trails and electronic signatures. Development relied on collaboration between informatics engineers and laboratory personnel, with user acceptance testing guiding workflow and interface refinement.

RESULTS: As of February 2026, the ATRI LIMS supports seven clinical trials and observational studies and manages more than 1.2 million biospecimens. The platform synchronizes biospecimen metadata and assay outputs with clinical datasets, improves operational efficiency through automated workflows and quality control, and facilitates compliant sample sharing for secondary research. AI‑assisted development accelerated feature delivery while maintaining code quality.

DISCUSSION: The ATRI LIMS offers a scalable, adaptable informatics framework for biomarker‑intensive AD research. Its modular design, cloud‑native architecture, and comprehensive data management capabilities support accurate specimen tracking and coordinated data integration. An open-source release is planned to enable adoption and adaptation by other research programs.

CONCLUSIONS: The ATRI LIMS enhances informatics infrastructure for modern AD research by enabling scalable, efficient, and compliant biomarker and biospecimen workflow management.},
}

@article {pmid42860159,
year = {2026},
author = {Wang, M and Zhao, H and Lin, X and Ye, Z and Tu, B and Yang, Y and Wang, C and Fang, X and Fang, Q},
title = {Field-assisted interfacial passivation: Microwave-enhanced EGCG remodeling of amyloid-β42 aggregates.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154811},
doi = {10.1016/j.ijbiomac.2026.154811},
pmid = {42860159},
issn = {1879-0003},
abstract = {Amyloid misfolding and self-assembly are central pathological events of Alzheimer's disease and related proteinopathies. Although soluble oligomers are widely considered as the primary toxic species, how therapeutic modulators alter toxicity-relevant aggregate surfaces remains poorly understood. Here, we combine cell viability assays, thioflavin T (ThT) aggregation kinetics, circular dichroism (CD), transmission electron microscopy (TEM), and atomistic molecular dynamics (MD) simulations to investigate how microwave-assisted Epigallocatechin gallate (EGCG) remodels Aβ42 aggregates. We show that microwave exposure markedly enhanced EGCG-mediated cytoprotection in BV2 microglial cells while concurrently suppressing the formation of canonical ThT-responsive amyloid species. MD simulations revealed that oscillating electric fields promote a constrained, interface-selective remodeling of protofibrillar-like aggregates rather than catastrophic depolymerization. In the initial trajectory pair, field assistance redistributed EGCG contacts across more surface residues, accompanied by reduced overall and hydrophobic protein-only solvent-accessible surface area. At a key hydrophobic interface identified by contact-occupancy analysis, the combined treatment decreased local water density and solvent accessibility, indicating reduced local hydration. We define this collective surface state- characterized by expanded EGCG coverage, reduced hydrophobic exposure, and diminished solvent accessibility - as interfacial passivation. Moreover, simulation analysis revealed that the field-assisted EGCG adsorption state remains stable for at least 500 ns after field removal, suggesting that the electric field facilitates formation of a kinetically stable surface-bound configuration. Together, these findings support field-assisted interfacial passivation as a possible mechanism for amyloid modulation and suggest that passivating toxicity-relevant aggregate surfaces, rather than achieving complete depolymerization, may represent a promising therapeutic strategy.},
}

@article {pmid42860235,
year = {2026},
author = {Ma, C and Lu, W and Guo, R},
title = {Exploratory bone-brain transcriptomic associations and an ODE-based digital-twin framework for fracture healing.},
journal = {Brain research},
volume = {},
number = {},
pages = {150597},
doi = {10.1016/j.brainres.2026.150597},
pmid = {42860235},
issn = {1872-6240},
abstract = {Fracture healing is generally viewed as a local tissue-regeneration process, although skeletal injury can also elicit systemic immune, vascular, and neural responses. We used a stratified analytical strategy combining reanalysis of public transcriptomic datasets, descriptive single-nucleus profiling, and an ordinary differential equation (ODE)-based simulation of fracture healing to examine possible associations between adverse bone phenotypes and Alzheimer disease. In the primary random-effects meta-analysis of three retained human bone-related binary cohorts, 72 prespecified panel genes were measured in all three cohorts; BMP10 and ANGPT1 had the smallest adjusted P values. In the separate GSE48350 whole-brain dataset, 6 of 84 mapped target genes had nominal P < 0.05. Descriptive single-nucleus RNA-sequencing analysis of GSE138852 showed within-dataset, cell-type-specific expression patterns across annotated neural cell populations. The eight-state ODE prototype, built on prespecified assumptions, generated fracture-healing trajectories and scenario-dependent model outputs. Tissue-expression and genetic analyses provided additional exploratory context for the selected genes. These analyses define a hypothesis-generating framework for studying skeletal-neural associations after fracture.},
}

@article {pmid42860380,
year = {2026},
author = {Barthold, D and Zissimopoulos, J and Basu, A and Tysinger, B},
title = {The effects of improved access to diabetes medications on risk of Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71794},
doi = {10.1002/alz.71794},
pmid = {42860380},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; *Hypoglycemic Agents/therapeutic use ; *Dementia/epidemiology/prevention & control ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Female ; Aged ; Male ; Middle Aged ; Incidence ; *Health Services Accessibility ; *Diabetes Mellitus/drug therapy ; *Diabetes Mellitus, Type 2/drug therapy ; },
abstract = {INTRODUCTION: Diabetes is associated with elevated risk of Alzheimer's disease and related dementias (ADRD). Disease management with pharmaceutical therapies may mitigate this increased risk, but access and use of diabetes therapies are limited, especially for persons at highest risk of ADRD.

METHODS: Using 10 years of data on Americans aged 51 and older with diabetes, we employed dynamic microsimulation to analyze the impact of increased utilization of glucagon-like peptide 1 receptor agonists (GLP1s) and sodium-glucose cotransporter-2 inhibitors (SGLT2s) on ADRD incidence.

RESULTS: Over 10 years, utilization of GLP1s and SGLT2s by people with diabetes and HbA1c > 7 could avert 76,000-201,000 ADRD cases. The risk reduction is largest for Black and Hispanic individuals and individuals with HbA1c > 8.

DISCUSSION: This study shows that improving diabetes management can lead to large reductions in ADRD risk. Improved adherence and access for those with higher HbA1c and higher risk of ADRD will have the largest benefit.},
}

Humans
*Alzheimer Disease/epidemiology/prevention & control
*Hypoglycemic Agents/therapeutic use
*Dementia/epidemiology/prevention & control
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
Glucagon-Like Peptide-1 Receptor Agonists
Female
Aged
Male
Middle Aged
Incidence
*Health Services Accessibility
*Diabetes Mellitus/drug therapy
*Diabetes Mellitus, Type 2/drug therapy

@article {pmid42860384,
year = {2026},
author = {Tallapragada, B and Galna, B and Shishegar, R and Markovic, SJ and Brown, BM and Dore, V and Laws, SM and Porter, T and Burnham, S and Lim, YY and Hassenstab, J and Rowe, CC and Jin, L and Fripp, J and Doecke, JD and Tosun, D and Weiner, M and Martins, RN and Morris, JC and Masters, CL and Maruff, P and Sohrabi, HR and , },
title = {Data‑driven cognitive composites predict Aβ‑related decline and progression to MCI: the ADOPIC study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71917},
doi = {10.1002/alz.71917},
pmid = {42860384},
issn = {1552-5279},
support = {R01-AG058676-01A1/AG/NIA NIH HHS/United States ; 1132604//National Health and Medical Research Council/ ; 1140853//National Health and Medical Research Council/ ; 1152623//National Health and Medical Research Council/ ; 2 U19 AG024904.16//National Health and Medical Research Council/ ; 5U2CAG060426-04//National Health and Medical Research Council/ ; 5R01AG058676-02//National Health and Medical Research Council/ ; 1RF1AG059009-01//National Health and Medical Research Council/ ; R33 AG062867//National Health and Medical Research Council/ ; 1R01NS119651-01//National Health and Medical Research Council/ ; RF1AG062196//National Health and Medical Research Council/ ; R56AG075744-01A1//National Health and Medical Research Council/ ; /AG/NIA NIH HHS/United States ; //Department of Defense/ ; //California Department of Public Health/ ; //University of Michigan, Siemens, Biogen, Hillblom Foundation/ ; /ALZ/Alzheimer's Association/United States ; //Johnson & Johnson/ ; //Kevin and Connie Shanahan/ ; //Australian Catholic University/ ; //The Stroke Foundation, and the Veterans Administration/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/psychology ; Disease Progression ; *Amyloid beta-Peptides/metabolism ; Female ; Male ; *Neuropsychological Tests/statistics & numerical data ; Aged ; *Alzheimer Disease/diagnosis ; Psychometrics ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Cognitive composites offer greater sensitivity to amyloid beta (Aβ)-related decline compared to individual tests for tracking longitudinal cognitive change. We developed and validated data-driven composites from the harmonized Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study, addressing gaps in psychometric reporting and multi-cohort validation.

METHODS: The study included 1964 cognitively unimpaired (CU) participants at baseline (longitudinal subset = 1110). Principal component analysis-derived domain-specific and general cognitive composites were evaluated for psychometric properties, sensitivity to Aβ-related decline, and mild cognitive impairment (MCI) progression prediction compared to the Alzheimer's Disease Cooperative Study - Preclinical Alzheimer's Cognitive Composite (ADCS-PACC).

RESULTS: Proposed composites demonstrated good to excellent psychometric properties and sensitivity to differentiating CU Aβ trajectories (p < 0.001). General cognition demonstrated longitudinal sensitivity comparable to the ADCS-PACC (d = -0.20) and equivalent classification performance (area under the receiver operating characteristic curve = 0.70). All composites significantly predicted MCI progression (p < 0.001).

DISCUSSION: The composites perform comparably to the ADCS-PACC, developed for CU with Aβ, in longitudinal sensitivity while providing comprehensive psychometric characterization and domain-specific measurement, supporting their utility as outcome measures in preclinical Alzheimer's disease studies.},
}

Humans
*Cognitive Dysfunction/diagnosis/psychology
Disease Progression
*Amyloid beta-Peptides/metabolism
Female
Male
*Neuropsychological Tests/statistics & numerical data
Aged
*Alzheimer Disease/diagnosis
Psychometrics
Longitudinal Studies

@article {pmid42860522,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE lipidation state directs immunometabolic reprogramming of human microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71882},
doi = {10.1002/alz.71882},
pmid = {42860522},
issn = {1552-5279},
support = {R01AG079217-01/NH/NIH HHS/United States ; R01NS125591/NS/NINDS NIH HHS/United States ; T32 2T32DK120521-06//Strategic Infrastructure for Research Committee/ ; },
mesh = {Humans ; *Microglia/metabolism ; *Apolipoprotein E4/metabolism ; *Apolipoproteins E/metabolism ; *Lipid Metabolism ; Metabolic Reprogramming ; Mitochondria/metabolism ; Alzheimer Disease/metabolism ; *Apolipoprotein E3/metabolism ; Lipid Droplets/metabolism ; },
abstract = {INTRODUCTION: ApoE ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free (LF) or lipid-bound ApoE3 or ApoE4. Label-free, live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet (LD) dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged LDs and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to LF-ApoE, which was exacerbated by LF-ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas LF-ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}

Humans
*Microglia/metabolism
*Apolipoprotein E4/metabolism
*Apolipoproteins E/metabolism
*Lipid Metabolism
Metabolic Reprogramming
Mitochondria/metabolism
Alzheimer Disease/metabolism
*Apolipoprotein E3/metabolism
Lipid Droplets/metabolism

@article {pmid42860584,
year = {2026},
author = {Corbali, O and Menon, P and Corbali, HI and Jagannathan, R and Levey, AI},
title = {Diabetes-Associated Cognitive Impairment: Pathophysiology and Emerging Therapies.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70487},
pmid = {42860584},
issn = {2328-9503},
abstract = {Diabetes-associated cognitive impairment (DACI) is a common yet underrecognized condition, manifesting along a spectrum from mild cognitive impairment to dementia. DACI encompasses patients who develop vascular dementia (VaD) or Alzheimer's disease (AD) with diabetes as a risk factor; however, in certain patients, particularly those lacking clear VaD or AD features, diabetes may act as a primary driver of neurodegeneration. Mechanistically, DACI can be conceptualized as a neurovascular-metabolic disorder characterized by disruption of the neurovascular unit, impaired cerebral glucose metabolism, brain insulin resistance, and chronic neuroinflammation, contributing to small vessel disease, regional brain atrophy, and accelerated brain aging. In this narrative review, we synthesize current evidence on the clinical and imaging features of DACI, outline key mechanistic pathways linking diabetes to neurodegeneration, and discuss emerging therapeutic strategies, including GLP-1 receptor agonists and SGLT2 inhibitors, with potential neuroprotective effects. Greater recognition of DACI as a neurovascular-metabolic entity may facilitate earlier identification, inform biomarker development, and guide future trials aimed at preserving cognitive function in individuals with diabetes.},
}

@article {pmid42860632,
year = {2026},
author = {Rosahl, M and Kaplan, M and McKniff, M and Callahan, A and Chaturvedi, R and Giovannetti, T},
title = {Preliminary evidence for script generation as an efficient, objective measure of everyday function in older adults.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/13803395.2026.2743150},
pmid = {42860632},
issn = {1744-411X},
abstract = {INTRODUCTION: Mild difficulties performing everyday activities may emerge early in Alzheimer's disease and Alzheimer's disease-related dementias, creating a need for objective, efficient measures sensitive to subtle functional changes. This study investigated a script generation task (SGT), which required individuals to verbally describe the steps needed to complete familiar everyday activities, as a potential method for detecting mild functional difficulties in older adults with or without mild cognitive impairment (MCI). We examined both human-coded features of script generation and automated linguistic features using natural language processing (NLP).

METHODS: 83 community-dwelling older adults (mean age = 73.59 years; 67% female; 55% White; n = 57 cognitively unimpaired on testing [CU]; n = 26 MCI) completed the SGT, requiring them to describe the steps for four everyday tasks: making toast, preparing instant coffee, making a peanut butter and jelly sandwich, and preparing a lunchbox. SGT performance was scored by human coders for total steps, words, and errors and analyzed using NLP measures of pronoun-to-noun ratio, lexical density, and lexical sophistication. Participants also completed a performance-based test of everyday function (Naturalistic Action Test, NAT), self-report questionnaires regarding everyday function, and cognitive tests.  .

RESULTS: After controlling for age, education, and estimated IQ, participants with MCI generated significantly fewer SGT steps than CU participants and used more pronouns relative to nouns, reflecting less specificity in their speech. The ability to generate SGT steps was associated with cognitive tests of episodic memory, and both SGT steps and total words were associated with executive function. Participants who generated more SGT words also completed more steps on the NAT. These associations survived correction for multiple comparisons. By contrast, SGT measures were not significantly associated with self-reported everyday functioning after correction for multiple comparisons.

CONCLUSIONS: Findings provide support for the potential use of the SGT as an objective and efficient measure of mild functional difficulties in older adults. Future work is needed to evaluate the predictive validity of the SGT and to develop automated scoring programs to increase scalability.},
}

@article {pmid42860747,
year = {2026},
author = {Jackson, ML and Sangalang, S and Heyworth, NC and Stradford, J and Lyons-Jones, C and Delaney-Stewart, T and Foster, A and Williams, P and Harris, T and McKinney, W and Baker, C and Thames, AD and Norman, M and Sundermann, EE and Banks, SJ},
title = {A Community's Voice: Community Advisory Boards in ADRD Biomarker Research Among Older Black Women.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70721},
pmid = {42860747},
issn = {1532-5415},
support = {5R01AG077579-02/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's Disease and Related Dementias (ADRD) disproportionately affect Black/African American (BAA) women, yet this afflicted population remains underrepresented in ADRD biomarker research. As ADRD blood-based biomarkers become increasingly available, research must prioritize equity and inclusivity to determine their diagnostic specificity in minoritized groups. Community Advisory Boards (CABs) are pivotal in ensuring culturally responsive and community-engaged research. This article outlines the formation, operation, and maintenance of the Black Women: Inflammation and Tau Study (BWITS) CAB, which has played a crucial role in guiding the BWITS Research Team by refining research protocols and safeguarding the cultural contexts of the communities it represents. Motivated by a commitment to the BAA community, we advocate for a transformative shift in ADRD research on minoritized populations, emphasizing the need for CAB input to ensure accountability and the implementation of culturally responsive methods, benefiting both the scientific and target communities.},
}

@article {pmid42860874,
year = {2026},
author = {Gül, A and Yılmaz, F and Topal, F and Özgen, İ and Aydoğmuş, E and Arslanoğlu, H},
title = {In Vitro Antioxidant, Antibacterial, and Cholinesterase-Inhibitory Properties of an Aqueous Euphorbia macroclada Root Extract Obtained by Ultrasound-Assisted Extraction.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {10},
pages = {e71825},
doi = {10.1002/cbdv.71825},
pmid = {42860874},
issn = {1612-1880},
mesh = {*Euphorbia/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification ; *Antioxidants/pharmacology/chemistry/isolation & purification ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; Plant Roots/chemistry ; *Plant Extracts/chemistry/pharmacology/isolation & purification ; Microbial Sensitivity Tests ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Biphenyl Compounds/antagonists & inhibitors ; Water/chemistry ; *Ultrasonic Waves ; Benzothiazoles/antagonists & inhibitors ; Picrates/antagonists & inhibitors ; Sulfonic Acids/antagonists & inhibitors ; Dose-Response Relationship, Drug ; },
abstract = {In the present study, the aqueous extract obtained from the roots of Euphorbia macroclada via ultrasound-assisted extraction (Ult-ER) was evaluated for its anticholinesterase (AChE and BChE), antioxidant, and antibacterial activities. While the extract exhibited weak inhibition against AChE (IC50: 507.69 ± 17.95 mg/mL), it showed relatively greater inhibitory activity against BChE (IC50: 22.41 ± 0.49 mg/mL). In antioxidant assays, Ult-ER exhibited measurable antioxidant responses, with DPPH and ABTS[+] radical-scavenging capacities of 18.33 ± 0.49 and 119.59 ± 1.86 mg TE/L, respectively. Its Fe[3] [+] and Cu[2] [+] reducing capacities were 128.51 ± 12.57 and 670.33 ± 11.59 mg TE/L, respectively. The total phenolic and flavonoid contents were 84.80 ± 3.31 mg GAE/g and 60.67 ± 2.29 mg QE/g, while the total antioxidant capacity was 9.78 ± 0.44 mg TE/g and 15.62 ± 1.85 mg BHAE/g. In the antibacterial evaluation, Ult-ER at the highest tested concentration of 8 mg/mL exhibited inhibitory activity against all tested strains, including Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853, whereas no detectable inhibition was observed at lower concentrations.},
}

*Euphorbia/chemistry
*Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification
*Antioxidants/pharmacology/chemistry/isolation & purification
*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
Plant Roots/chemistry
*Plant Extracts/chemistry/pharmacology/isolation & purification
Microbial Sensitivity Tests
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Biphenyl Compounds/antagonists & inhibitors
Water/chemistry
*Ultrasonic Waves
Benzothiazoles/antagonists & inhibitors
Picrates/antagonists & inhibitors
Sulfonic Acids/antagonists & inhibitors
Dose-Response Relationship, Drug

@article {pmid42861391,
year = {2026},
author = {Zhang, X and Tang, X and Bo, Q and Ma, Y and Shi, F and Hou, H},
title = {Alzheimer's disease diagnosis based on gene selection and cross-tissue validation.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1890236},
pmid = {42861391},
issn = {1664-8021},
abstract = {BACKGROUND: Early and accurate diagnosis is critical for intervening in the progression of Alzheimer's disease (AD). However, traditional clinical diagnostic techniques, such as invasive cerebrospinal fluid punctures and expensive neuroimaging, struggle to meet the demands of large-scale early screening.

METHODS: This study proposes a novel transcriptomic-based diagnostic framework named DeepFS, which features an automated gene selection module to filter out redundant noise and identify high-value core gene targets for diagnosis.

RESULTS: DeepFS achieved high-precision identification of AD, yielding an ac-curacy of 89.45% and an AUC value of 0.9647 on brain tissue transcriptomic data. To further explore the methodological generalizability of the framework across different tissue types, we extended DeepFS to a peripheral blood transcriptomic dataset, where it consistently achieved reliable diagnostic classification performance. Furthermore, regarding the brain tissue transcriptomic data, the high-weight genes driven by the gene selection module were integrated with AD brain single-nucleus RNA sequencing data for quantitative analysis at single-cell resolution, further validating the biological efficacy of the module.

CONCLUSION: DeepFS not only exhibits competitive performance in AD diagnostic classification, but can also serve as a valuable prior reference for future AD biomarker research.},
}

@article {pmid42861417,
year = {2026},
author = {Guan, Y and Gu, P and Guo, D and Huang, L and Lian, D and Zhang, C and Feng, J and Peng, H},
title = {Multipath interaction network of annexin A2: multifaceted regulation and translational perspectives in neurological diseases.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1916220},
pmid = {42861417},
issn = {1664-8021},
abstract = {Annexin A2 (Anxa2) is a Ca[2+]-dependent phospholipid-binding protein whose functions are shaped by dynamic membrane association, post-translational regulation, and interactions with diverse molecular partners. Rather than acting as a conventional pathway-specific regulator, Anxa2 appears to operate within a multipath interaction network that links membrane organization, cytoskeletal remodeling, vesicular trafficking, extracellular proteolysis, and cellular stress responses. This Review examines how these interconnected functions contribute to neurological diseases, including Parkinson's disease, Alzheimer's disease, ischemic stroke, traumatic brain injury, and glioma. We critically evaluate evidence connecting Anxa2 with Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/AKT), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Transforming Growth Factor-beta (TGF-β) related signaling and distinguish direct molecular interactions from pathway-dependent or secondary signaling changes. Current evidence suggests that many Anxa2-associated signaling outputs may arise from changes in membrane trafficking, receptor organization, protein handling, and cellular state rather than from direct control of individual signaling cascades. This network-based view also provides a framework for interpreting apparently divergent effects of Anxa2 across neuronal, glial, endothelial, immune, and tumor contexts. From a translational perspective, Anxa2 is therefore a promising but challenging target: its broad physiological functions argue against indiscriminate inhibition and instead favor disease-, cell-, and interaction-specific modulation. Defining the molecular architecture and context-specific operation of Anxa2-centered networks will be essential for determining its value as a biomarker and therapeutic target in neurological disease.},
}

@article {pmid42861666,
year = {2026},
author = {Ding, L and Zheng, M and Wang, S and Liu, W and Liang, Y and Xie, S and Yang, T and Sheng, D and Wang, S and Sheng, J and Jia, J and , },
title = {Cross-cohort NULISAseq identifies tau-anchored CSF and plasma-specific signatures across the amyloid-positive Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71915},
doi = {10.1002/alz.71915},
pmid = {42861666},
issn = {1552-5279},
support = {STI2030-Major Projects - 2021ZD0201802//National Key Research and Development Program of China/ ; CX23YZ15//Chinese Institutes for Medical Research/ ; U20A20354//National Natural Science Foundation of China/ ; U19 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//U.S. Department of Defense (DOD ADNI)/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/blood ; *tau Proteins/cerebrospinal fluid/blood ; Female ; Biomarkers/cerebrospinal fluid/blood ; Male ; Aged ; Proteomics ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Cohort Studies ; },
abstract = {INTRODUCTION: ATN-stratified cerebrospinal fluid (CSF) proteomic signals may partly reflect classifier tau immunoassays; reproducible non-tau signals and CSF-plasma differences remain unclear.

METHODS: We profiled CSF from 60 A[+] Beijing patients with Alzheimer's disease (AD) and 875 A[+] Alzheimer's Disease Neuroimaging Initiative (ADNI) participants using the NULISAseq CNS Disease Panel. Differential expression was assessed using a false discovery rate (FDR) < 0.05 and |log2FC|≥0.5 across three ATN contrasts. We also analyzed ADNI plasma, protein-cognition correlations, tau-adjusted associations, and nested models comparing non-tau proteins with tau biomarkers.

RESULTS: Eight CSF proteins met the cross-cohort criterion within at least one matched contrast: pTau-217, pTau-181, pTau-231, MAPT, SMOC1, MDH1, VSNL1, and FABP3. NULISA tau correlated with INNOTEST (ρ = 0.75-0.85) and Elecsys (ρ = 0.65-0.68). T and N classifications agreed for 94.6% of ADNI participants (κ = 0.880); after adjustment for CSF pTau-217, all 12 associations involving the four non-tau proteins retained their direction and FDR support. In CSF, Elecsys p-tau181 and NULISA tau-family analytes had the strongest cognitive correlations (mean |ρ| = 0.35 and 0.29-0.34, respectively), followed by FABP3 (0.24). Adding the four-protein block after tau increased cross-validated R[2] across all three cross-sectional outcomes in models without diagnosis (+0.0101 to +0.0265), most clearly for the Alzheimer's Disease Assessment Scale-Cognitive Subscale, 13-item version (ADAS-Cog13); diagnosis-conditioned models showed no stable increment beyond tau and clinical characteristics. In plasma, pTau-217 was the only analyte that met both thresholds in all three contrasts.

DISCUSSION: CSF NULISAseq identified a reproducible tau-associated signature across A[+] cohorts that extended beyond the tau family. The four non-tau proteins extend the molecular profile associated with tau-defined disease state and merit further evaluation for biological stratification in independent cohorts.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/blood
*tau Proteins/cerebrospinal fluid/blood
Female
Biomarkers/cerebrospinal fluid/blood
Male
Aged
Proteomics
Amyloid beta-Peptides/cerebrospinal fluid/blood
Cohort Studies

@article {pmid42861684,
year = {2026},
author = {Lahlou, S and Ismail, Z and Smith, EE and Dang-Vu, TT and Badhwar, A},
title = {Vascular brain injury modifies the relationship between sleep duration, cognition, and white matter hyperintensity burden in the Alzheimer's disease continuum.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71838},
doi = {10.1002/alz.71838},
pmid = {42861684},
issn = {1552-5279},
support = {//Fonds de Recherche du Québec - Santé (FRQS)/ ; //Fonds de soutien à la recherche pour les neurosciences du vieillissement/ ; //Fondation Courtois/ ; //FRQS Chercheurs boursiers/ ; CNA-137794/CAPMC/CIHR/Canada ; CNA-163902/CAPMC/CIHR/Canada ; CND-193575/CAPMC/CIHR/Canada ; BCA 527734/CAPMC/CIHR/Canada ; //Gordie Howe CARES/ ; //UK National Institute for Health and Care Research Exeter Biomedical Research Centre/ ; //Vascular Training Platform/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/complications/physiopathology ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; *Sleep Duration ; Magnetic Resonance Imaging ; Aged ; *Cognition/physiology ; *Cognitive Dysfunction/pathology ; Aged, 80 and over ; Brain/pathology ; Cohort Studies ; },
abstract = {INTRODUCTION: Self-reported sleep duration is associated with dementia-risk and vascular brain injury markers, including white matter hyperintensities (WMHs), yet how additional cerebrovascular pathology alters these relationships remains unclear.

METHOD: In a deeply phenotyped cohort (735) including healthy and Alzheimer's disease (AD) continuum individuals (subjective and mild cognitive impairment [MCI], dementia [AD], MCI and AD with high vascular burden [+V]), sleep was assessed using the Pittsburgh Sleep Quality Index. Individuals were classified as WMH-only or WMH+ (WMHs with microbleeds, infarcts, or cerebral amyloid angiopathy). Linear models tested interactions between sleep duration, WMH+ status, and diagnostic group on WMH burden and cognition.

RESULTS: In MCI+V and AD, WMH+ significantly amplified the association between shorter sleep and greater WMH burden. In AD, longer sleep related to better cognition in WMH+ but worse cognition in WMH-only (exploratory).

DISCUSSION: Additional vascular brain injury modifies how sleep relates to WMH burden and cognition across the AD continuum, highlighting the importance of moving beyond WMHs alone.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/complications/physiopathology
*White Matter/pathology/diagnostic imaging
Male
Female
*Sleep Duration
Magnetic Resonance Imaging
Aged
*Cognition/physiology
*Cognitive Dysfunction/pathology
Aged, 80 and over
Brain/pathology
Cohort Studies

@article {pmid42861699,
year = {2026},
author = {Exalto, LG and van Alphen, JL and Barkhof, F and Teunissen, C and Vijverberg, EGB and Aarsland, D and Lemstra, AW},
title = {Dementia with Lewy bodies and amyloid pathology: Eligible for anti-amyloid treatment or not?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71907},
doi = {10.1002/alz.71907},
pmid = {42861699},
issn = {1552-5279},
mesh = {Humans ; *Lewy Body Disease/drug therapy/pathology ; *Alzheimer Disease/drug therapy/pathology ; *Amyloid beta-Peptides/metabolism ; },
abstract = {In the future, treatment of dementia will be personalized, targeted to contributing pathologies, rather than the clinical syndrome. Anti-amyloid drugs for Alzheimer's disease are the first approved drugs; however, the impact of co‑pathology on the treatment effects remains incomplete. Currently, only patients with a clinical diagnosis of Alzheimer's disease are eligible for these new drugs, but could they also be beneficial when amyloid is present in other neurodegenerative diseases? For example, roughly 50% of patients with dementia with Lewy bodies are amyloid-positive. In this perspective, we discuss the theoretical benefits and challenges of anti-amyloid drugs in patients with a clinical diagnosis of dementia with Lewy bodies and concomitant Alzheimer's disease pathology. We show that a significant portion of newly diagnosed dementia with Lewy bodies patients could be eligible. We advocate for the systematic collection of efficacy and safety data using innovative strategies to achieve adequate statistical power.},
}

Humans
*Lewy Body Disease/drug therapy/pathology
*Alzheimer Disease/drug therapy/pathology
*Amyloid beta-Peptides/metabolism

@article {pmid42861749,
year = {2026},
author = {Gigi, GP and Prema, S},
title = {Benzimidazole-based Multi-target Directed Ligands: A Comprehensive Review of Therapeutic Potential in Alzheimer's disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575491724260908101357},
pmid = {42861749},
issn = {1875-5607},
abstract = {Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline. Current treatments provide only symptomatic relief and fail to halt disease progression, underscoring the urgent need for disease-modifying interventions. The complex interplay among amyloid-β aggregation, tau hyperphosphorylation, cholinergic dysfunction, oxidative stress, metal dyshomeostasis, and neuroinflammation necessitates multi-target therapeutic strategies. Benzimidazole analogues have emerged as a promising scaffold in this context, owing to their structural flexibility, broad pharmacological activity, and demonstrated multi-target capability. This review critically analyses recent developments in the design, synthesis, and biological evaluation of benzimidazole-based compounds as potential anti-Alzheimer's agents. Particular emphasis is placed on structure-activity relationships governing interactions with key AD-relevant targets, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-secretase (BACE1), tau-related protein kinases, and metal chelation relevant to amyloid pathology. The neuroprotective, antioxidant, and anti-inflammatory properties of these derivatives are also discussed in the context of their potential disease-modifying relevance. The advantages of benzimidazole-based Multi-target Directed Ligands (MTDLs) over conventional single-target approaches are highlighted, particularly their capacity to address multiple pathological hallmarks of AD simultaneously. Key limitations, including pharmacokinetic challenges and the absence of clinical validation, are critically evaluated to provide a balanced perspective. Overall, this review establishes benzimidazole analogues as promising lead structures in AD drug discovery and aims to guide future medicinal chemistry efforts toward more effective, disease-modifying therapies.},
}

@article {pmid42861801,
year = {2026},
author = {Alpana, and Dewangan, HK},
title = {Crossing the Blood-brain Barrier: Emerging Nanotechnological Approaches for Neurodegenerative Disease Therapy.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454704261001071449},
pmid = {42861801},
issn = {1875-5739},
abstract = {Neurodegenerative disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD) are characterized by progressive neuronal degeneration and severe therapeutic limitations due to the Blood-Brain Barrier (BBB). Recent advances in nanotechnology have enabled the development of nanoscale drug delivery systems capable of improving BBB penetration and enhancing therapeutic efficacy. This review discusses recent progress in Lipid Nanoparticles (LNPs), polymeric nanoparticles, exosomes, magnetic nanoparticles, gold nanoparticles, graphene quantum dots, and RNAloaded nanocarriers for brain-targeted delivery. Special emphasis is placed on receptor-mediated transcytosis, intranasal delivery, magnetic targeting, and ionizable lipid nanoparticle systems for nucleic acid delivery. Recent nanoformulations including curcumin-loaded nanoparticles, siRNA- loaded lipid nanoparticles, dopamine-loaded liposomes, and lactoferrin-functionalized polymeric nanoparticles are critically compared based on BBB penetration, therapeutic efficacy, toxicity, and translational potential. Furthermore, current clinical challenges including nanotoxicity, pharmacokinetics, large-scale manufacturing, and regulatory barriers are discussed. Nanotechnology- based therapeutics represent a promising strategy for improving diagnosis and treatment of neurodegenerative disorders and may facilitate the future development of precision nanomedicine.},
}

@article {pmid42861804,
year = {2026},
author = {Borah, D and Devroy, P and Bala, A},
title = {Neuroimmune Dynamics of the Microglia-astrocyte Axis: Implications for Neurodegenerative Disorders as a Double-edged Sword.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X507671260924120425},
pmid = {42861804},
issn = {1875-6190},
abstract = {INTRODUCTION: Maintaining homeostasis in the Central Nervous System (CNS) requires constant, bidirectional molecular interactions between microglia and astrocytes. This intercellular communication, mediated by cytokines, extracellular vesicles, purinergic signals, and connexin hemichannels, synchronizes immune surveillance, neurogenesis, and synaptic pruning under physiological conditions. However, this interaction can drive persistent neuroinflammation in chronic Neurodegenerative Disorders (NDDs) such as Multiple Sclerosis (MS), Parkinson's Disease (PD), and Alzheimer's Disease (AD).

METHODS: Gene disease association analyses and review of existing literature were employed to identify shared glial regulators and molecular mediators across multiple neurodegenerative disorders, supported by schematic diagrams illustrating intercellular signaling dynamics Results: Deregulated astrocytes sustain microglial activation, creating self-amplifying inflammatory loops, while activated M1 microglia induce the conversion of astrocytes into neurotoxic A1 astrocytes via factors such as IL-1α, TNF-α, and complement C1q. Important mediators, such as prostaglandins, IL-1β, and IL-18, further contribute to demyelination, astrogliosis, and excitotoxicity. A convergent glial activation axis identifies shared regulators across several neurodegenerative disorders, including TREM2, GRN, LRRK2, and BDNF.

DISCUSSION: Active research targeting reactive astrogliosis and microglial reprogramming towards homeostatic phenotypes shows therapeutic promise. Nevertheless, CNS immune complexity, translational challenge, and inter-patient immunological variability underscore the need for individualized, combinatorial therapeutic strategies and human-relevant experimental models.

CONCLUSION: The microglia-astrocyte axis plays a dual role in neuro-immune homeostasis and neurodegeneration, representing critical therapeutic targets for NDDs and requiring further mechanistic and translational investigation.},
}

@article {pmid42861812,
year = {2026},
author = {Nour, H and Mounadi, N and Chtita, S},
title = {In silico Exploration of the Therapeutic Potential of Phytocannabinoids.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575510188260922092929},
pmid = {42861812},
issn = {1875-5607},
abstract = {Plant-derived cannabinoids exhibit remarkable structural diversity and have attracted increasing attention as bioactive compounds. Recent in silico studies have explored how these compounds interact with molecular targets involved in neurodegenerative, metabolic, oncological, and viral diseases. This review summarizes the available data on molecular docking, molecular dynamics (MD), and ADMET analysis published from 2023 to 2026 for selected phytocannabinoids. Analysis of the reviewed publications suggests that compounds such as Δ9-THC, CBN, THCV, and THCA are predicted to bind to numerous proteins implicated in disease pathogenesis, including acetylcholinesterase, butyrylcholinesterase, EGFR, BRAF/TGF-β, α-amylase, and SARS-CoV-2 Mpro. However, the docking scores obtained by different computational protocols are not directly comparable. Similarly, stable MD trajectories and favorable ADMET predictions provide computational evidence but do not guarantee the biological efficacy and safety of the studied compounds. This review highlights the importance of integrating molecular docking, molecular dynamics, pharmacokinetic prediction, and experimental validation. It also identifies methodological gaps and proposes a stepwise experimental strategy to validate the most promising computational hypotheses.},
}

@article {pmid42861935,
year = {2026},
author = {},
title = {Jacob Labonte, BS, and Michael L Alosco, PhD, are the recipients of the 2026 Alzheimer Award.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {112},
number = {4},
pages = {1573-1574},
doi = {10.1177/13872877261468905},
pmid = {42861935},
issn = {1875-8908},
}

@article {pmid42862019,
year = {2026},
author = {Stögmann, E and Haider, L and Leinkauf, J and Nakuz, T and Untersteiner, H and Farr, C and Silvaieh, S and Parvizi, T and Wurm, R and Kasprian, G and Berger, T and Gelpi, E and Sieczkowski, EB},
title = {Progressive Amyloid-Related Imaging Abnormalities After Discontinuation of Lecanemab in Early Alzheimer Disease in an APOE ε2/ε4 Carrier.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70779},
doi = {10.1111/ene.70779},
pmid = {42862019},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/diagnostic imaging ; Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Disease Progression ; *Antibodies, Monoclonal, Humanized/adverse effects ; Apolipoprotein E2/genetics ; Female ; Heterozygote ; Brain/pathology/diagnostic imaging ; Male ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are the most relevant adverse events associated with anti-amyloid therapies in Alzheimer's disease.

METHODS: We report a case of progressive ARIA after discontinuation of lecanemab in a patient with early-onset Alzheimer's disease carrying the rare APOE ε2/ε4 genotype.

RESULTS: After two infusions, mild ARIA-edema (ARIA-E) and ARIA-hemorrhage (ARIA-H) were detected on routine MRI, prompting treatment interruption. Despite partial radiologic regression, follow-up MRI 8 weeks after discontinuation demonstrated marked progression with multifocal ARIA-H displaying as superficial siderosis, while the patient remained clinically asymptomatic. Corticosteroid treatment was initiated and lecanemab permanently discontinued.

CONCLUSION: This case highlights that severe ARIA may progress beyond active treatment exposure and emphasizes the importance of continued MRI surveillance even after therapy cessation. Furthermore, the APOE ε2/ε4 genotype may represent a distinct risk factor for cerebral amyloid angiopathy-related vascular fragility and hemorrhagic ARIA.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/diagnostic imaging
Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Disease Progression
*Antibodies, Monoclonal, Humanized/adverse effects
Apolipoprotein E2/genetics
Female
Heterozygote
Brain/pathology/diagnostic imaging
Male

@article {pmid42862023,
year = {2026},
author = {DeCaro, RE and Smith, AM and Marin, A and Waskow, E and Turk, KW and Budson, AE},
title = {One year after spaced retrieval training: enduring memory enhancement for older adults with and without mild cognitive impairment.},
journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists},
volume = {41},
number = {7},
pages = {},
doi = {10.1093/arclin/acag081},
pmid = {42862023},
issn = {1873-5843},
support = {//Blank Slate Technologies/ ; CX002400//United States Department of Veterans Affairs, Merit Review Award/ ; AG072978//National Institutes of Health P30/ ; },
mesh = {Humans ; *Cognitive Dysfunction/rehabilitation/complications/psychology ; Aged ; Female ; Male ; *Mental Recall/physiology ; Neuropsychological Tests ; Alzheimer Disease/complications ; Cognitive Training ; Aged, 80 and over ; Mobile Applications ; Follow-Up Studies ; *Memory Disorders/etiology/rehabilitation ; },
abstract = {OBJECTIVE: Spaced retrieval training (SRT) can enhance memory in older adults with and without cognitive impairment, but the durability of these memories remains unclear. This study examined whether memory benefits from an app-based SRT program persisted one year after training in older adults with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and healthy controls.

METHOD: We recruited participants from a prior study in which they used a mobile app to engage in SRT for half of two sets of stimuli, verbal facts and face-name associations, across a four-week intervention. One year later, with no experimentally manipulated exposure to the stimuli, 12 participants with MCI and 13 controls completed follow-up memory testing of studied and nonstudied items. Memory accuracy was assessed separately for the two sets of stimuli.

RESULTS: Facts and face-name associations that were studied via SRT one year prior were remembered more accurately than nonstudied information in both participants with MCI and controls. We did not observe any significant interactions.

CONCLUSIONS: Our 4-week, app-based SRT program produced memory benefits that endured for one year in older adults with and without MCI due to AD. These findings highlight the promise of delivering SRT to older adults with and without MCI in an accessible, low-burden format that produces lasting memory benefits.},
}

Humans
*Cognitive Dysfunction/rehabilitation/complications/psychology
Aged
Female
Male
*Mental Recall/physiology
Neuropsychological Tests
Alzheimer Disease/complications
Cognitive Training
Aged, 80 and over
Mobile Applications
Follow-Up Studies
*Memory Disorders/etiology/rehabilitation

@article {pmid42862052,
year = {2026},
author = {Unnikrishnan, B and Anand, A and Fang, CN and Wu, SM and Wang, CC and Huang, CC and Chu, HW and Chang, HT},
title = {Carbon dot-based nanomaterials in neurodegeneration: addressing neurobiological barriers and targeting challenges.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03262a},
pmid = {42862052},
issn = {1364-548X},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a major global health challenge due to their progressive nature and limited therapeutic options. One of the primary obstacles to treating these disorders is the blood-brain barrier (BBB), which restricts the delivery of most therapeutic agents into the central nervous system. In recent years, carbon-based nanomaterials, particularly carbon dot (CD) nanostructures, have emerged as promising platforms for neurological applications owing to their ultrasmall size, BBB-crossing ability, and anti-inflammatory and neuroprotective properties, in addition to tunable surface chemistry, strong photoluminescence, and favorable biocompatibility. This review provides a comprehensive overview of recent research developments in the application of CD-based nanomaterials, including carbon nanodots, carbon quantum dots, graphene quantum dots, and carbon polymer dots, for the potential treatment of neurodegenerative diseases. The synthesis strategies and carbonization approaches used to produce these carbon nanomaterials are discussed, along with their physicochemical properties relevant to neurobiological applications, such as particle size, surface functionalization, heteroatom doping, optical properties, and stability in biological environments. Furthermore, the mechanisms by which CD-based nanomaterials can traverse the BBB are examined, including receptor-mediated and adsorptive-mediated transcytosis pathways. In addition, their applications are discussed, with particular focus on their roles in bioimaging, biosensing, inhibition of pathological protein aggregation, antioxidative activity, and targeted drug delivery. Finally, key challenges related to toxicity, biodistribution, large-scale synthesis, and clinical translation are discussed, along with future perspectives for the development of multifunctional theranostic platforms. Overall, use of CD-based nanomaterials represents a promising emerging strategy for overcoming neurobiological barriers and enabling the development of next-generation nanotherapeutics for the management of neurodegenerative diseases.},
}

@article {pmid42862138,
year = {2026},
author = {Ataka, T and Kimura, N and Ito, T and Kaneko, N and Masuda, T and Takeuchi, T and Miyagawa, T and Iwamoto, S and Matsubara, E},
title = {Psychological impact of the use of blood-based biomarkers for mild cognitive impairment in primary care.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494606},
doi = {10.1177/13872877261494606},
pmid = {42862138},
issn = {1875-8908},
abstract = {BackgroundBlood-based biomarker testing in primary care could contribute to the early diagnosis of Alzheimer's disease. The usefulness of using blood-based biomarker in the primary care has evaluated, but their psychological impact has not been examined.ObjectiveThe primary objective of this study is to investigate the psychological impact of disclosing results to patients and evaluate the changes in confidence of diagnoses by physicians. As a secondary objective, we compare the psychological impact with positron emission tomography.MethodsThis study included adults aged ≥50 years with suspected mild cognitive impairment or mild dementia. In total, 97 were analyzed in this study. All participants underwent blood-based biomarker testing and the results were disclosed by primary care physicians or specialists. Psychological impact was measured using the Impact of Event Scale-Revised 1 week after disclosure. Physician diagnostic confidence, changes in diagnosis and management actions were also recorded.ResultsNineteen participants had negative blood-based biomarker results but positive PET results. The Impact of Event Scale-Revised scores were low after blood-based biomarker disclosure and did not differ by health care provider. Blood-based biomarker results prompted changes in diagnosis in 41.9% of cases. The diagnostic confidence increased after disclosure of the blood-based biomarker. Physicians reported a moderate/strong impact on management in 81.5% of cases after the disclosure of blood-based biomarkers.ConclusionsIn this study, blood-based biomarker result disclosure to patients with mild cognitive impairment had minimal short-term psychological burden and informed clinical decisions. These findings support the integration of blood-based biomarker testing into dementia care.},
}

@article {pmid42853296,
year = {2026},
author = {Zhao, J and Bai, Y and Wang, C and Guo, P and Wang, Z and Du, G and Liu, A},
title = {Fraxetin Ameliorates Cognitive Impairment in STZ-Induced Mice: Involvement of Suppressed Microglial Hyperactivation and Improved Mitochondrial Dysfunction.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42853296},
issn = {1557-1904},
support = {2025177//Tianjin Municipal Research Project on Integrated Traditional Chinese and Western Medicine/ ; 2021-I2M-1-028//CAMS Innovation Fund for Medical Sciences/ ; 82574701//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Mice ; *Microglia/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; *Streptozocin/toxicity ; Male ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Coumarins/pharmacology/therapeutic use ; Mice, Inbred C57BL ; },
abstract = {Therapeutic for Alzheimer's disease (AD) remains a pressing medical challenge in the field of neuroscience. Natural compounds with structural diversity and multi-target regulatory properties have attracted increasing attention for the treatment of complex neurodegenerative disorders. ‌Fraxetin, previously identified through computer-aided virtual screening, C. elegans assays, and in vitro cellular models as a potential anti-AD natural compound, was further investigated in this study using established in vivo and in vitro systems to evaluate its efficacy in ameliorating cognitive function and elucidate underlying mechanisms. A sporadic AD mouse model was established by intracerebroventricular injection of STZ (3 mg/kg). Fraxetin (3, 10, and 30 mg/kg/day, po.) was administered until the mouse sacrifices. Cognitive performance was evaluated using the novel object recognition, passive avoidance, and Morris water maze tests. STZ induced cerebral energy metabolism disturbances accompanied by mitochondrial dysfunction, neuroinflammation, oxidative stress, neuronal and synaptic loss, and cholinergic system impairment. ‌Behavioral tests confirmed that fraxetin ameliorated cognitive deficits in STZ-induced mice. Further studies revealed that fraxetin preserved mitochondrial structural integrity and enhanced mitochondrial biogenesis, accompanied by upregulation of the Sirt1/PGC-1α/Nrf1/TFAM pathway. In parallel, fraxetin attenuated microglial overactivation and neuroinflammatory responses. Consistently, in LPS-stimulated BV2 microglial cells, fraxetin inhibited nitric oxide and inflammatory mediator release, which was associated with modulation of the TLR2/MYD88/NF-κB signaling pathway, while restoring cellular bioenergetic status, indicating coordinated regulation of inflammation-associated metabolic dysfunction. Importantly, fraxetin attenuated neurodegenerative alterations in STZ-treated mice, as evidenced by reduced neuronal loss and synaptic degeneration. These effects were associated with activation of the BDNF/TrkB/ERK/CREB neurotrophic pathway and inhibition of acetylcholinesterase activity, supporting preservation of synaptic and cholinergic function. This study provides experimental evidence supporting fraxetin as a promising natural multi-target candidate for the intervention of AD.},
}

Animals
Mice
*Microglia/drug effects/metabolism
*Mitochondria/drug effects/metabolism
*Streptozocin/toxicity
Male
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Coumarins/pharmacology/therapeutic use
Mice, Inbred C57BL

@article {pmid42853396,
year = {2026},
author = {Oberstein, TJ},
title = {[Anti-amyloid antibodies against Alzheimer's disease : Lecanemab and donanemab in practice-Clinical importance, patient selection and safety management].},
journal = {Der Nervenarzt},
volume = {},
number = {},
pages = {},
pmid = {42853396},
issn = {1433-0407},
abstract = {Lecanemab and donanemab are the first disease-modifying therapies for early Alzheimer's disease. These humanized IgG1 antibodies promote the clearance of aggregated amyloid-beta peptides and, in the pivotal CLARITY AD and TRAILBLAZER-ALZ 2 trials, significantly delayed cognitive and functional decline, with an approximately 30% relative risk reduction for the clinical stage progression; however, the clinical meaningfulness remains contested: critics point to the small between-group difference in relation to the total score. This is weighed against the first disease-modifying effect and the first pharmacotherapy for mild cognitive impairment due to Alzheimer's disease. A prerequisite is the biological diagnosis: the reference standard is cerebrospinal fluid (CSF) and amyloid positron emission tomography (PET), potentially complemented in the future by blood biomarkers such as plasma p‑Tau217. Amyloid-related imaging abnormalities (ARIA) are the key adverse event, manageable through patient selection, ApoE-ε4 genotyping and magnetic resonance imaging (MRI) monitoring. The indications and follow-up belong in specialized centers.},
}

@article {pmid42853420,
year = {2026},
author = {Salvadó, G and Groot, C and Wisse, LE and Vogel, JW and Beach, TG and Serrano, GE and Reiman, EM and Schneider, JA and Bennett, DA and Ossenkoppele, R and Hansson, O},
title = {Global and regional amyloid-β in explaining APOE-ε4 and sex associations with medial temporal tau: a neuropathology study.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42853420},
issn = {1432-0533},
support = {101061836//European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie action/ ; AARF-22-972612//Alzheimer's Association Research Fellowship/ ; A2024007F//BrightFocus Foundation/ ; AF-980942, AF-994514, AF-1012218//Alzheimerfonden/ ; AF-1010833//Alzheimerfonden/ ; ZonMW; project number: 10510022110010//Dementia Fellowship grant from Zorg Onderzoek Nederland - Medische Wetenschappen/ ; WE.03-2024-06//Alzheimer Nederland Early Career Grant/ ; KAW2020.0239//SciLifeLab & Wallenberg Data Driven Life Science Program/ ; 2024-03642//Swedish Research Council/ ; 2022-00775 and 2018-02052, 2021-02219//Swedish Research Council/ ; StG-101221737/ERC_/European Research Council/International ; ADG-101096455/ERC_/European Research Council/International ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610 and P30AG072980/AG/NIA NIH HHS/United States ; P30AG10161, P30AG72975, R01AG17917, R01 AG015819, U01 AG072572, U01 AG046152, and R01AG075927/AG/NIA NIH HHS/United States ; 211002//Arizona Department of Health Services/ ; 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; R01AG083740/AG/NIA NIH HHS/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ERAPERMED2021-184//ERA PerMed/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse/ ; AF-980907, AF-994229//Swedish Alzheimer Foundation/ ; FO2021-0293, FO2023-0163//Swedish Brain Foundation/ ; 1412/22//Parkinson foundation of Sweden/ ; WASP/DDLS22-066//WASP and DDLS Joint call for research projects/ ; 2025-2026-2024-2428//Bundy Academy at Lund University/ ; 2022-Projekt0080, 2022-Projekt0107//Swedish federal government under the ALF agreement/ ; },
mesh = {Humans ; Female ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; Male ; *Temporal Lobe/pathology/metabolism ; Aged ; *Apolipoprotein E4/genetics ; *Alzheimer Disease/pathology/genetics/metabolism ; Aged, 80 and over ; *Sex Characteristics ; Cohort Studies ; },
abstract = {The medial temporal lobe (MTL) is a key region in Alzheimer's disease (AD) pathogenesis, affected early by tau pathology. While female sex and APOE-ε4 are two known risk factors that affect tau levels, whether these factors drive tau in the MTL via amyloid-dependent or amyloid-independent mechanisms remains unclear. We investigated these relationships in two large neuropathological cohorts comprising 2550 participants from the Religious Orders Study/Memory and Aging Project (ROS/MAP; n=1587, main cohort) and Arizona Study of Aging and Neurodegenerative Disorders (AZSAND; n=963, replication cohort) covering the whole AD continuum. Neuropathological assessments of global neocortical and regional MTL amyloid-β burden were used to determine the extent to which amyloid-β pathology mediated associations of APOE-ε4 carriership and sex with MTL tau burden. In both cohorts, APOE-ε4 carriership and female sex were associated with significantly greater MTL tau pathology (all p<0.001). Adjustment for global amyloid-β attenuated but did not eliminate these associations (p≤0.024). However, after jointly accounting for global and MTL amyloid-β burden, the association between APOE-ε4 and MTL tau was no longer significant in either cohort (p≥0.19), whereas the association between female sex and MTL tau remained robust (p≤0.004). Models incorporating both global and regional MTL amyloid-β explained substantially more variance in MTL tau burden than models including only global amyloid-β, and results were replicated when further adjusting for diagnostic group or neocortical tau burden. These findings suggest that APOE-ε4 and female sex influence MTL tau accumulation through partially distinct pathogenic pathways, supporting an additional contribution of regional amyloid-β to the APOE-ε4-associated MTL tau burden while implicating additional amyloid-independent mechanisms in female vulnerability to tau accumulation.},
}

Humans
Female
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
Male
*Temporal Lobe/pathology/metabolism
Aged
*Apolipoprotein E4/genetics
*Alzheimer Disease/pathology/genetics/metabolism
Aged, 80 and over
*Sex Characteristics
Cohort Studies

@article {pmid42853677,
year = {2026},
author = {Yaman, Ü and Gustavsson, E and Lee, J and Ugolini, H and Macpherson, H and Mumford, P and Wiseman, F and Hardy, J and Salih, DA},
title = {Protocol for genome-wide differential methylation using long-read DNA sequencing in the cortex of a mouse model of Alzheimer's disease.},
journal = {STAR protocols},
volume = {7},
number = {4},
pages = {104827},
doi = {10.1016/j.xpro.2026.104827},
pmid = {42853677},
issn = {2666-1667},
abstract = {Third-generation sequencing enables direct detection of genome-wide 5-methylcytosine without bisulfite conversion. Here, we present a protocol for generating long-read DNA sequencing from mouse cortex and performing genome-wide differential methylation analysis. We describe steps for high-molecular-weight DNA extraction, data generation, and downstream analysis. We demonstrate the workflow in the App[NL-G-F] mouse model of amyloid pathology and provide a reproducible pipeline that links modified-base BAM (modBAM) files to annotated differentially methylated regions and functional enrichment results.},
}

@article {pmid42853714,
year = {2026},
author = {O Apos Connor, MK and Frank, B and Noah, HH and Harrington, SK and Metcalf, EE and DeCaro, R and Vives-Rodriguez, A and Hagan, B and Atlas, S and Hurley, L and Turk, KW and Budson, AE},
title = {Informant Presence Fails to Enhance Alzheimer's Diagnosis in Complex Veteran Cases.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag009},
pmid = {42853714},
issn = {1421-9824},
abstract = {INTRODUCTION: Informant reports are thought helpful for Alzheimer's disease (AD) diagnosis. We hypothesized that informants would improve diagnostic accuracy, operationalized as agreement between clinical impression and amyloid PET (aPET) findings.

METHODS: This study was a retrospective analysis of 168 Veterans referred for aPET due to diagnostic uncertainty or atypical presentation (Mage=69.3, SD=5.8). We examined the association between diagnostic accuracy and presence of an informant, patient's MoCA score, and informant type.

RESULTS: We found no evidence that informant presence was associated with diagnostic accuracy (OR = 0.92, 95% CI 0.48, 1.72), that this association varied by patient cognitive status as measured by MoCA (interaction OR = 1.13, 95% CI 0.97, 1.33), or that diagnostic accuracy differed by informant type (spouse/partner: OR = 1.23, 95% CI 0.55, 2.79; other: OR = 0.91, 95% CI 0.29, 2.71).

CONCLUSION: Our findings suggest informant presence does not necessarily enhance diagnostic accuracy for complex AD presentations. This highlights the continued value of aPET imaging in complex clinical presentations.},
}

@article {pmid42853744,
year = {2026},
author = {Zheng, Y and Ye, X and Zhang, J and Huang, Z and Tian, X and Mao, H},
title = {DeMorph: A Decoupled Deformation Model with Anatomical Guidance for Predicting Longitudinal Brain Atrophy.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3737688},
pmid = {42853744},
issn = {2168-2208},
abstract = {Modeling the longitudinal progression of brain atrophy in Alzheimer's Disease (AD) is critical for early diagnosis and prognosis, but remains challenging for existing generative models. Current methods either fail to preserve anatomical integrity or treat progression as an entangled process, where changes from normal aging are inseparably fused with AD pathology. This fundamentally limits their scientific utility. To address this, we propose DeMorph, a novel deformation-based framework that explicitly disentangles and accurately predicts longitudinal brain MRI changes. Our transformer-based architecture features two key innovations: (1) a Decoupled Feed-Forward Network (D-FFN) for separate aging and pathology deformation pathways; and (2) a Multi-Scale Anatomical Guidance Cross-Attention (MS-AGCA) module, which explicitly injects anatomical priors to ensure spatially precise and biologically plausible disentanglement. Extensive experiments on four datasets (ADNI, OASIS-3, AIBL, and an inhouse dataset) demonstrate that DeMorph achieves stateof- the-art performance in both image similarity and anatomical accuracy. Crucially, we validate the success of our framework through robust bidirectional counterfactual synthesis, demonstrating the ability to controllably induce and remove a quantitatively plausible, AD-specific pathological effect.},
}

@article {pmid42853952,
year = {2026},
author = {Hirbawi, J and Zaretsky, A and Zhu, H and Goshtchevsky, U and Dey, G and Merquiol, E and Siddiqui, AA and Cohen, I and Blum, G and Cohen, E},
title = {A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues.},
journal = {Science advances},
volume = {12},
number = {41},
pages = {eady6048},
pmid = {42853952},
issn = {2375-2548},
mesh = {*Proteostasis ; Animals ; *Signal Transduction ; *Neurons/metabolism ; *Neuropeptides/metabolism/genetics ; *Receptors, G-Protein-Coupled/metabolism/genetics ; Caenorhabditis elegans/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Proteolysis ; Gene Knockdown Techniques ; },
abstract = {The proteostasis network (PN) safeguards the integrity of proteins by promoting various cellular activities. However, with aging, the PN's competence declines and aggregated proteins accrue within cells. This process underlies the development of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. While the PN functions within cells, proteostasis is regulated across the organism by intertissue communication, which is partially governed by neurons. We previously found that reducing the expression of gtr-1, which encodes a neuronal heterotrimeric guanine nucleotide-binding protein-coupled receptor, mitigates the toxicity of the Alzheimer's disease cause, Aβ peptide. Here, we investigated the mechanism that is acted upon the knockdown of gtr-1 and found that it differentially modulates gene expression profiles, including of neuropeptide-coding genes, and dissimilarly modifies protein aggregation in worms that express distinct proteotoxic proteins. The knockdown of gtr-1 also enhances protein degradation. These findings highlight the roles of neuropeptides as organismal coordinators of proteostasis in the face of distinct proteotoxic challenges.},
}

*Proteostasis
Animals
*Signal Transduction
*Neurons/metabolism
*Neuropeptides/metabolism/genetics
*Receptors, G-Protein-Coupled/metabolism/genetics
Caenorhabditis elegans/metabolism/genetics
*Caenorhabditis elegans Proteins/metabolism/genetics
Proteolysis
Gene Knockdown Techniques

@article {pmid42854044,
year = {2026},
author = {Wen, P and Liu, W and Li, Y and Liao, M and Qin, H and Ye, J and Deng, Z and Cui, S and Zhao, Y and Wang, X and Huang, Y and Tang, H and Qin, H and Wang, K and Qin, Q},
title = {Tobacco-attributable burden of alzheimer's disease and other dementias in China and ASEAN: Temporal trends and projections - an observational study based on GBD 2021.},
journal = {Medicine},
volume = {105},
number = {41},
pages = {e50974},
doi = {10.1097/MD.0000000000050974},
pmid = {42854044},
issn = {1536-5964},
mesh = {China/epidemiology ; *Alzheimer Disease/epidemiology/mortality/etiology ; Humans ; *Dementia/epidemiology/mortality/etiology ; *Cost of Illness ; Disability-Adjusted Life Years ; Male ; Female ; },
abstract = {This study aimed to systematically analyze the disease burden of Alzheimer's disease and other dementias (ADOD) attributed to tobacco in China and ASEAN countries from 1990 to 2021, and predict the disease burden in the next ten years to characterize the disparities in disease burden between the 2 sides, and to conduct a preliminary exploration of factors that may be associated with these disparities. Data on ADOD deaths, mortality, DALYs and DALY rates attributed to tobacco in China and ASEAN countries were extracted from GBD 2021, and the trend of disease burden was analyzed using Joinpoint regression model. R software was used for data analysis and visualization, and Joinpoint regression model was used to calculate the APC of each indicator; the disease burden attributable to tobacco in China and ASEAN countries was analyzed through the SDI; and the ARIMA was used to predict ADOD from 2022 to 2035. In China, the number of ADOD deaths (1990: 8126.47, 95% CI: 1822.19-22,577.84), mortality rate, DALYs, and DALY rate attributable to tobacco all exhibited significant and sustained upward trends from 1990 to 2021, and consistently exceeded the corresponding levels in the other ten ASEAN countries. The APC for mortality and DALY rates showed a significant increase in China and most ASEAN countries, with particularly rapid increases in mortality in China, Thailand, Cambodia, and Indonesia. Correspondingly, the DALY rate rose in most countries, indicating a growing overall disease burden. An exception was Myanmar, where the burden decreased. The burden of tobacco-attributable ADOD was consistently higher among males than females in all countries. Analysis based on SDI revealed a lower and more stable disease burden in high-SDI areas, whereas medium- and low-SDI countries demonstrated an upward trend. ARIMA model projections for 2022-2035 suggest that while mortality trends are diverse, an increasing trend is anticipated in most countries. The disease burden of ADOD attributable to tobacco use has continued to rise in China and ASEAN countries. This trend suggests a potential role for tobacco control in the prevention of ADOD, and also points to the value of strengthening tobacco regulation and paying early attention to cognitive interventions.},
}

China/epidemiology
*Alzheimer Disease/epidemiology/mortality/etiology
Humans
*Dementia/epidemiology/mortality/etiology
*Cost of Illness
Disability-Adjusted Life Years
Male
Female

@article {pmid42854182,
year = {2026},
author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG},
title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {6},
pages = {e200663},
doi = {10.1212/CPJ.0000000000200663},
pmid = {42854182},
issn = {2163-0933},
}

@article {pmid42854385,
year = {2026},
author = {Ye, BS and VandeVrede, L and Jeon, S and Lee, S and Choi, M and Jeon, S and Shin, NY and Charters, B and Plastini, M and Kang, S and Rim, JH and Lim, JB},
title = {Clinical and biomarker predictors of α-synuclein seeding in cognitive impairment and motor parkinsonism.},
journal = {Parkinsonism & related disorders},
volume = {153},
number = {},
pages = {108956},
doi = {10.1016/j.parkreldis.2026.108956},
pmid = {42854385},
issn = {1873-5126},
abstract = {Dopamine transporter (DAT) imaging and α-synuclein seed amplification assay (SAA) are biomarkers for Lewy body disease (LBD). We aimed to identify clinical and biomarker factors associated with SAA positivity in patients with cognitive impairment and frequent motor parkinsonism. Dual-phase DAT positron emission tomography (PET) scans, cerebrospinal fluid (CSF) phosphorylated-tau/β-amyloid ratio (PTAR) measurement, and SAA were performed in 108 patients, including 99 with motor parkinsonism. Diagnoses, which were not mutually exclusive, included normal pressure hydrocephalus (NPH, N = 60), Alzheimer's disease (AD, N = 53), dementia with Lewy bodies (DLB, N = 43), vascular cognitive impairment (VCI, N = 23), progressive supranuclear palsy (N = 3), and semantic variant primary progressive aphasia (N = 1). We investigated clinical and biomarker factors associated with SAA positivity, including clinical diagnoses, clinical features, striatal DAT uptake, and log-transformed PTAR (LN-PTAR), and examined whether SAA positivity was associated with dopaminergic degeneration and regional perfusion measured by dual-phase DAT PET. SAA was positive in 50 patients (46.3%), including 30 of 43 (69.8%) with DLB and 47 of 99 (47.5%) with motor parkinsonism. Seven (14.0%) SAA-positive patients showed normal DAT uptake. Among clinical diagnoses, DLB and AD were associated with a higher likelihood of SAA positivity, whereas NPH and VCI were associated with a lower likelihood. Among clinical features, cognitive fluctuations and rapid eye movement sleep behavior disorder were independently associated with SAA positivity. Among biomarker measures, lower posterior putamen DAT uptake and a higher LN-PTAR were independently associated with SAA positivity. SAA positivity was associated with lower posterior putamen DAT uptake on delayed-phase DAT PET but not with perfusion changes on early-phase DAT PET. These findings suggest that SAA provides complementary information to clinical diagnosis and DAT imaging for evaluating possible LBD, particularly in patients with biomarker evidence of coexisting AD pathology.},
}

@article {pmid42854446,
year = {2026},
author = {Gasik, RE and Thierry, AD and Thorpe, RJ},
title = {Allostatic load measurement and cognitive function among midlife and older Black and White adults in the health and retirement study.},
journal = {Psychoneuroendocrinology},
volume = {194},
number = {},
pages = {108032},
doi = {10.1016/j.psyneuen.2026.108032},
pmid = {42854446},
issn = {1873-3360},
abstract = {Allostatic load (AL), a composite of biological measures, is frequently used to capture the physiological burden of chronic stress and is associated with cognitive decline. Black Americans are more likely to develop Alzheimer's disease and related dementias than White Americans, but racial disparities in the AL-cognition relationship have been under explored. Additionally, AL is not consistently measured in literature. The aim of this research was to examine racial variation of the AL-cognition relationship using various AL scoring methods. Data were from the 2006-2016 waves of the Health and Retirement Study, and the sample included 29,809 person-waves of White adults and 7612 person-waves of Black adults. Cognitive function was measured using a modified Telephone Interview for Cognitive Status (mTICS). AL calculation methods included quartile, z-score, and clinical cut-offs. Each measure defined biomarker levels as either high risk or low risk. For 'one-tailed' measures, higher values indicated higher risk for all biomarkers except HDL, for which lower values indicated higher risk. For quartile and z-scores, additional two-tailed measures were calculated which define risk at both unusually low and high biomarker levels. Mixed models were run examining both within-person and between-person change in allostatic load measures in relation to cognitive function. Two-tailed measures more strongly predicted cognitive function both within- and between-persons than traditional quartile or clinical cut-offs, particularly in the Black sample. Findings suggest that nonlinear relationships should be given greater consideration when examining AL, particularly in diverse populations of older adults.},
}

@article {pmid42854589,
year = {2026},
author = {Rawson, G and Howard, ME and Pase, MP and Jackson, ML},
title = {Obstructive sleep apnoea and Alzheimer's disease pathology: a review of plausible pathological mechanisms and potential modifying impact of hypertension.},
journal = {Sleep medicine},
volume = {149},
number = {},
pages = {109307},
doi = {10.1016/j.sleep.2026.109307},
pmid = {42854589},
issn = {1878-5506},
abstract = {Alzheimer's Disease (AD) is estimated to account for up to 75% of all dementia cases, of which there is a global prevalence of 50 million. There are no curative treatments available for AD dementia, therefore, early identification of risk factors is paramount. Up to 40% of all dementia cases may be attributable to modifiable risk factors. One such risk factor is poor sleep. Obstructive sleep apnoea (OSA) is a common sleep disorder characterised by repeated upper airway collapse, contributing to intermittent hypoxaemia and sleep fragmentation. Hypertension is frequently comorbid with OSA and is an established risk factor for dementia, with recent literature exploring potential mechanistic contributions to AD pathogenesis. Despite current literature exploring associations between OSA and hypertension on AD individually, little research has investigated the potential combined impact of these two pervasive disorders. To this end, this review will synthesise existing literature investigating potential pathogenic mechanisms between OSA and AD, including oxidative stress and altered sleep architecture. Further, shared pathophysiological consequences of OSA and hypertension will be reviewed in the context of AD to highlight the potential for effective management in mid-life to preserve neurological and cognitive health in late life.},
}

@article {pmid42854625,
year = {2026},
author = {Jansen, R and Arndt, P and Brüggemann, J and Dörner, M and Mattern, H and Meuth, SG and Lee, JI and Gliem, M and Schreiber, S},
title = {Exploratory synergistic diagnostic value of CSF neurofilament light chain and topographic cortical atrophy in differentiating cerebral amyloid angiopathy from Alzheimer's disease - a pilot study.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126200},
doi = {10.1016/j.jns.2026.126200},
pmid = {42854625},
issn = {1878-5883},
abstract = {BACKGROUND: Differentiating Cerebral Amyloid Angiopathy (CAA) from Alzheimer's disease (AD) in vivo is challenging due to overlapping amyloid pathology and limited availability sensitivity of hemorrhagic markers in memory clinic settings. We investigated whether integrating regional cortical atrophy with cerebrospinal fluid (CSF) neurofilament light chain (NfL), a marker of axonal injury, might have a diagnostic value.

METHODS: In this pilot study (n = 30, n = 12 CE and n = 18 probable CAA), cortical thickness was quantified via FreeSurfer MRI analysis and standardized into regional Z-scores. We applied a hypothesis-driven dual-region approach (entorhinal cortex vs. precuneus). Classification was performed using firth's penalized logistic regression because of sample size and validated via Leave-One-Out Cross-Validation (LOOCV).

RESULTS: AD exhibited widespread atrophy involving both medial temporal (entorhinal) and posterior parietal (precuneus) structures. In contrast, probable CAA presented with relative temporal preservation despite posterior involvement. CSF NfL was numerically higher in CAA (median 2830 pg/ml) than in AD (2105.5 pg/ml). A combined model (entorhinal, precuneus, and CSF NfL) achieved the highest in-sample discrimination (AUC = 0.86, 95% CI: 0.64-1.00), while LOOCV yielded an AUC of 0.61.

CONCLUSION: The multimodal integration of temporal neurodegeneration and axonal injury captures the divergent pathophysiological signatures of AD and CAA, serving as an exploratory, hypothesis generating pathophysiological profile rather than a generalized diagnostic algorithm.},
}

@article {pmid42854699,
year = {2026},
author = {Trouvé, R and Verstreken, P and Hoekstra, MMB},
title = {Tau phosphorylation from neuronal adaptation to Alzheimer's disease.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.08.032},
pmid = {42854699},
issn = {1097-4199},
abstract = {Tau phosphorylation is classically associated with neurodegeneration, yet similar phosphorylation patterns emerge during physiological states and acute stress responses. How these overlapping patterns of phosphorylated Tau (pTau) relate to neuronal adaptation and Alzheimer's disease pathology remains unresolved. We synthesize findings from human to rodent and fly brains and from neuronal cell models, across neurodevelopment, sleep, hibernation, cellular stress, and disease. Across these contexts, pTau changes are associated with altered Tau localization and functions involving synaptic transmission, mitochondrial activity, RNA metabolism, and genomic integrity. Physiological and acute stress responses are generally transient and reversible, whereas aging, repeated stress, and amyloid-β-associated stress can promote persistent pTau accumulation, impaired clearance, aggregation, and neurodegeneration. We propose that pathological Tau phosphorylation reflects dysregulation of a shared adaptive response rather than activation of an entirely distinct pathway. The critical determinants may be phosphorylation persistence, subcellular localization, proteoform composition, and the capacity to restore Tau homeostasis.},
}

@article {pmid42854778,
year = {2026},
author = {Nguyen, NH and Le, HT and Thi Nguyen, NT and Nguyen, TT and Vo, GV},
title = {Polysaccharide-based drug conjugates and related delivery systems for Alzheimer's disease: from molecular design to translational challenges.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.010},
pmid = {42854778},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) presents distinct extracellular, intracellular and vascular delivery targets, yet brain exposure of candidate therapeutics remains difficult to establish. This narrative review compares hyaluronic acid, chitosan, cyclodextrin, dextran, alginate and pectin systems by construct architecture, route, blood-brain barrier (BBB) evidence, cargo release and biological response. The literature includes covalent drug conjugates, loaded or coated carriers, host-guest complexes and intrinsically active polymers; evidence from one category cannot validate another. Clinical programs involving intravenous hydroxypropyl-β-cyclodextrin and a transferrin-receptor antibody shuttle provide context, but do not establish BBB transport for the conjugates reviewed. We examine how polymer size and degradation influence immune safety, particularly chitosan-associated NLRP3 activation and context-dependent responses to hyaluronic acid fragments. We distinguish endothelial or whole-brain signal from parenchymal active-drug exposure, and discuss payload-specific endosomal escape. Advancement requires a defined construct, quantitative target-site exposure, target engagement, comparison with free drug and a matched carrier, and route-appropriate safety data.},
}

@article {pmid42854795,
year = {2026},
author = {Aumont-Rodrigue, G and Picard, C and Sarty, I and Savard, M and Poirier, J and , },
title = {Scavenger receptors associate with Alzheimer's pathology, cholesterol metabolism and synaptic dysfunction.},
journal = {Neurobiology of disease},
volume = {230},
number = {},
pages = {107641},
doi = {10.1016/j.nbd.2026.107641},
pmid = {42854795},
issn = {1095-953X},
abstract = {This study investigated relationships between cerebrospinal fluid (CSF) scavenger receptors and early Alzheimer's disease (AD) pathology in cognitively unimpaired older adults at elevated familial risk, with complementary analyses in autopsied frontal cortex. In the PREVENT-AD cohort, CSF levels of the scavenger receptors MSR1, SCARB2, and SCARF2 were examined in relation to AD biomarkers and synaptic proteins. Complementary analyses, with the same scavenger receptors, used frontal cortex tissue from the Douglas-Bell Canada Brain Bank and targeted sterol/oxysterol mass spectrometry. Linear regression, longitudinal mixed-effects models, pathway enrichment, and mediation analyses were performed. Higher CSF concentrations of MSR1, SCARB2, and SCARF2 were strongly associated with synaptic markers (SNAP25, SYT1, GAP43), with SCARB2 showing the strongest relationships. Associations with Tau biomarkers (t-Tau and p-Tau181) were consistently stronger than those with Aβ species, and baseline receptor levels correlated with longitudinal increases in p-Tau181 over up to 12 years. In autopsied cortex, MSR1 was increased and SCARF2 decreased in AD, while APOB, MSR1 and SCARB2 were associated specific oxysterol levels. Proteomic enrichment linked APOB to vascular and extracellular matrix pathways, whereas scavenger receptor-associated proteins were enriched for synaptogenesis, myeloid activation, and MAPK/phosphorylation signaling. Mediation analyses showed by correlation that scavenger receptors, particularly SCARB2, partially or fully mediated numerous associations between Tau biomarkers and synaptic markers (SNAP25, SYT1 and GAP43). These findings identify MSR1, SCARB2, and SCARF2 as potential integrators of lipid, immune, and synaptic processes in early AD and highlight SCARB2 as a possible mediator of Tau-associated synaptic vulnerability, supporting further mechanistic and cell type-specific investigation.},
}

@article {pmid42855152,
year = {2026},
author = {Gerson, G and Nogueira, GN and Teixeira, MJ},
title = {Plasma p-tau217 as a biomarker for Alzheimer's disease: diagnostic and prognostic value in clinical and population-based studies.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {10},
pages = {1-8},
pmid = {42855152},
issn = {1678-4227},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; Biomarkers/blood ; *tau Proteins/blood ; Prognosis ; Predictive Value of Tests ; Sensitivity and Specificity ; Phosphorylation ; Reproducibility of Results ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, and blood-based biomarkers are emerging as accessible diagnostic tools. Plasma phosphorylated tau at position 217 (p-tau217) has shown promise in early detection.

OBJECTIVE: To evaluate the diagnostic accuracy, prognostic value, and applicability of plasma p-tau217 in AD compared with other biomarkers.

METHODS: We conducted an integrative review on the PubMed, Scopus, Embase, and Cochrane Library databases (2018-2024). Eligible observational and diagnostic studies assessing p-tau217 in plasma were included. Study selection and quality assessment followed the Standards for Reporting of Diagnostic Accuracy (STARD) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

RESULTS: We analized 9 studies involving more than 6 thousand participants analyzed. Plasma p-tau217 demonstrated high accuracy (area under the curve [AUC]: 0.86-0.94) for detecting tau and amyloid pathology, outperforming p-tau181. It was effective in diverse populations, asymptomatic individuals, and primary care settings. Longitudinal data suggest predictive value for cognitive decline.

CONCLUSION: Plasma p-tau217 is a reliable and non-invasive biomarker for AD, with applications in diagnosis, prognosis, and treatment monitoring. Standardization and multicenter validation are necessary before clinical implementation.},
}

Humans
*Alzheimer Disease/diagnosis/blood
Biomarkers/blood
*tau Proteins/blood
Prognosis
Predictive Value of Tests
Sensitivity and Specificity
Phosphorylation
Reproducibility of Results

@article {pmid42855713,
year = {2026},
author = {Zhang, X and Li, W and Sun, Z and Wang, X and Song, C and Wang, X and Niu, Y and Wei, D and Zhang, W and Zhang, G and Zhang, B and Wang, L and Liu, Z and Zhao, J and Jiang, W},
title = {Advantage of cerebellar intermittent theta-burst stimulation in Alzheimer's disease (ACT-AD): study protocol for a multicenter, randomized, double-blind, sham-controlled trial.},
journal = {Trials},
volume = {27},
number = {1},
pages = {},
pmid = {42855713},
issn = {1745-6215},
support = {2024LC2419//Clinical Research Program of the Fourth Military Medical University/ ; },
mesh = {Humans ; Double-Blind Method ; *Alzheimer Disease/therapy/physiopathology/psychology ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Treatment Outcome ; *Cerebellum/physiopathology ; *Theta Rhythm ; *Transcranial Magnetic Stimulation/methods/adverse effects ; Time Factors ; Female ; Aged ; Cognition ; Male ; Magnetic Resonance Imaging ; China ; Electroencephalography ; },
abstract = {INTRODUCTION: The cerebellum plays a crucial role in cognitive processing and thus presents a promising therapeutic target for Alzheimer's disease (AD). This trial aims to evaluate the efficacy and safety of long-term, neuronavigated cerebellar intermittent theta burst stimulation (iTBS) in patients with AD.

METHODS AND ANALYSIS: The ACT-AD trial is a multicenter, randomized, double-blind, sham-controlled study involving 100 participants with mild-to-moderate AD across 4 centers in China. Participants will be randomized to receive either cerebellar iTBS or sham stimulation for 4 weeks (daily sessions), followed by 8 weeks of weekly maintenance sessions. The primary outcome is the change in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score from baseline to week 12. Secondary outcomes include additional clinical scales. Exploratory outcomes include electroencephalogram (EEG), blood biomarkers and magnetic resonance imaging (MRI). Statistical analysis will follow intention-to-treat principles using mixed models for repeated measures (MMRM).

DISCUSSION: The ACT-AD trial will assess the efficacy and safety of long-term, neuronavigated cerebellar iTBS in treating patients with mild-to-moderate AD.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT06669182. Registered on 31 October 2024.},
}

Humans
Double-Blind Method
*Alzheimer Disease/therapy/physiopathology/psychology
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
Treatment Outcome
*Cerebellum/physiopathology
*Theta Rhythm
*Transcranial Magnetic Stimulation/methods/adverse effects
Time Factors
Female
Aged
Cognition
Male
Magnetic Resonance Imaging
China
Electroencephalography

@article {pmid42855737,
year = {2026},
author = {La, Y and Yuan, J and Chen, J and Lv, K and Wang, X and Gao, Q and Wang, Y and Wang, C and Xu, B and Yang, Y and Zhang, J},
title = {The glymphatic-lymphatic axis: known pathways, open questions, and emerging roles in neurodegeneration.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42855737},
issn = {2047-9158},
support = {LY24H090006//Natural Science Foundation of Zhejiang Province/ ; 82571418//National Natural Science Foundation of China/ ; 32530027//National Natural Science Foundation of China/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; },
mesh = {Humans ; *Glymphatic System/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology ; Animals ; *Lymphatic Vessels/metabolism/pathology ; *Brain/metabolism ; Lymphatic System ; Cerebrospinal Fluid/metabolism ; },
abstract = {The discovery of the glymphatic system and meningeal lymphatic vessels has transformed our understanding of brain fluid homeostasis and central-peripheral communication, highlighting the critical role of cerebrospinal fluid in brain clearance. While substantial progress has been made in defining the structural components and physiological regulators of brain clearance, major uncertainties remain regarding (1) how these systems interact as an integrated physiological network, (2) how they fail in disease, and (3) whether they can be therapeutically manipulated. In this review, we first summarize the anatomical and physiological organization of the glymphatic-lymphatic axis, with particular emphasis on its regulatory mechanisms in light of rapid advances in this field. We then discuss how the glymphatic-lymphatic axis functionally integrates with peripheral immune and metabolic systems and describe how impairment of these clearance pathways is associated with the accumulation of pathological proteins, neuroinflammation, and vascular dysfunction and may contribute to the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Finally, we discuss emerging therapeutic strategies and biomarkers targeting the glymphatic-lymphatic axis. By redefining the central-peripheral crosstalk, the glymphatic-lymphatic axis provides a unifying framework for understanding brain clearance, neurodegeneration, and future therapeutic interventions.},
}

Humans
*Glymphatic System/metabolism/pathology
*Neurodegenerative Diseases/pathology/metabolism/physiopathology
Animals
*Lymphatic Vessels/metabolism/pathology
*Brain/metabolism
Lymphatic System
Cerebrospinal Fluid/metabolism

@article {pmid42855813,
year = {2026},
author = {Alten, B and Gokcal, E and Sperling, RA and Shirzadi, Z and Chhatwal, JP and Gurol, ME and Kasner, SE and Greenberg, SM and Cucchiara, BL},
title = {Centrum Semiovale Perivascular Spaces Predict First Hemorrhagic Lesion in Asymptomatic Amyloid-Positive Individuals.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78388},
pmid = {42855813},
issn = {1531-8249},
abstract = {OBJECTIVE: Identification of cerebral amyloid angiopathy (CAA) before its hemorrhagic manifestations remains limited. We aimed to determine whether severe enlarged perivascular spaces in the centrum semiovale (EPVS-CSO) identify a prehemorrhagic stage of sporadic CAA by predicting the first appearance of CAA-related hemorrhagic lesions or incident cognitive decline in amyloid-positive, cognitively unimpaired, hemorrhage-free older adults.

METHODS: We performed a secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial, a phase 3 randomized study in cognitively unimpaired, amyloid-positive older adults. Participants with baseline hemorrhagic lesions were excluded. Baseline EPVS-CSO severity was dichotomized as severe versus nonsevere. Severe basal ganglia EPVS, more closely associated with hypertensive small vessel disease, was evaluated as a topographical negative-control exposure. The primary outcome was incident strictly lobar cerebral microbleeds or cortical superficial siderosis. The secondary outcome was longitudinal cognitive trajectories measured by the Preclinical Alzheimer Cognitive Composite.

RESULTS: Among 932 participants (mean age 71.7 ± 4.8 years; 61.3% female), 101 (10.8%) had severe EPVS-CSO at baseline. Over a median follow up of 5.1 years (IQR 3.3-5.5 years), 33.7% of those with severe EPVS-CSO developed incident CAA-related hemorrhagic lesions compared with 13.6% of those with nonsevere EPVS-CSO (adjusted HR 2.85, 95% CI 1.91-4.25; p < 0.0001). Severe basal ganglia EPVS was not associated with incident hemorrhagic lesions (adjusted HR 0.87, 95% CI 0.35-2.18; p = 0.77). Severe EPVS-CSO was not associated with early cognitive differences, and participants who developed incident hemorrhagic lesions showed more pronounced cognitive decline.

INTERPRETATION: These findings identify severe EPVS-CSO as a strong predictor of first appearance of CAA-related hemorrhagic lesions in amyloid-positive individuals, supporting integration of amyloid biomarkers into magnetic resonance imaging-based Boston criteria. Identifying markers of the transition of CAA from a nonhemorrhagic to a hemorrhagic stage provides a potential foundation for approaching primary prevention of CAA-related hemorrhage. ANN NEUROL 2026.},
}

@article {pmid42855977,
year = {2026},
author = {Bosco, N and Cappellato, V and Micalizzi, E},
title = {Negotiating Care Over Time: A Systematic Review of Alzheimer's Disease Caregiving Through a Life Course Approach.},
journal = {Sociology of health & illness},
volume = {48},
number = {8},
pages = {e70280},
doi = {10.1111/1467-9566.70280},
pmid = {42855977},
issn = {1467-9566},
mesh = {Humans ; *Alzheimer Disease/nursing ; *Caregivers/psychology ; Adaptation, Psychological ; *Negotiating/psychology ; },
abstract = {The global ageing of the population has significantly increased the demand for long-term informal care, particularly in the context of Alzheimer's disease (AD). Although research on caregiver burden and coping strategies is extensive, limited attention has been paid to the temporal evolution of caregiving roles and their intersections with caregivers' life trajectories. This systematic review, conducted across literature published between 2004 and 2024, examines how the life course perspective has been applied in sociological research on family caregiving for people with AD, aiming to analyse the interplay between caregiving timing, biographical transitions, and socio-institutional contexts. The selected studies reveal that caregiving is not a static or homogeneous role but evolves across the life span, shaped by transitions, linked lives and structural conditions. Adopting a life course perspective enhances the understanding of caregiving as a dynamic and socially embedded process. This approach underscores the need for policies that are temporally sensitive, culturally reflexive and capable of supporting caregivers across different life stages.},
}

Humans
*Alzheimer Disease/nursing
*Caregivers/psychology
Adaptation, Psychological
*Negotiating/psychology

@article {pmid42855983,
year = {2026},
author = {Khan, Y and Naeem, MU and Naqvi, SF and Fatima, B and Hussain, R and Uddin, H and Aziz, T and Binsaleh, AY and Al-Hoshani, N and Alwabsi, HA},
title = {Design, synthesis, and biological evaluation of pyrimidine linked fused thiazole-isoxazole conjugates as dual cholinesterase inhibitors for Alzheimer's disease.},
journal = {Zeitschrift fur Naturforschung. C, Journal of biosciences},
volume = {},
number = {},
pages = {},
pmid = {42855983},
issn = {1865-7125},
abstract = {Alzheimer's disease (AD) affects over 55 million individuals worldwide, yet approved pharmacotherapies remain limited to symptomatic relief. Dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) offers a validated approach to restoring cholinergic tone. However, structurally differentiated inhibitors with favorable selectivity profiles are critically needed. Here, we report a series of pyrimidine clubbed thiazolo[4,5-c]isoxazole framework that functions as potent dual cholinesterase inhibitors with low-micromolar activity against both AChE and BuChE. Lead compound-1 demonstrated IC50 values of 6.19 ± 0.60 μM (AChE) and 8.64 ± 0.91 μM (BuChE) showing promising performance over the reference donepezil (AChE IC50 = 19.38 ± 0.98 μM, BuChE IC50 = 27.54 ± 1.34 μM). Furthermore, structure-activity relationship analysis identified electron-withdrawing (p-CF3, p-F, o,p-Cl, p-NO2) and electron-donating (-OH) aryl substituents as principal modulators of inhibitory potency. Moreover, molecular docking against human AChE and BuChE crystal structures revealed dual engagement of the catalytic anionic site and peripheral anionic site through hydrogen-bonding and π-π stacking interactions. In silico ADMET profiling confirmed electronic reactivity and drug-likeness of lead compounds. These findings establish pyrimidine-clubbed thiazolo[4,5-c]isoxazole as a mechanistically grounded scaffold with translational potential for next-generation anti-Alzheimer therapeutics.},
}

@article {pmid42856097,
year = {2026},
author = {Lopez-Esquibel, N and Bettcher, BM and Gunn-Sandell, LB and Gonzalez, ME and Carlson, NE and Unger, JR and Holden, SK and Greher, MR and Lum, HD},
title = {Patient and care partner perspectives of a teleneuropsychology intervention: a mixed-methods evaluation.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/13854046.2026.2742406},
pmid = {42856097},
issn = {1744-4144},
abstract = {OBJECTIVE: While neuropsychological evaluations by telehealth are a valid alternative to face-to-face (FF) visits, teleneuropsychology has not been widely adopted. We explored patient and care partner perspectives on acceptability, appropriateness, feasibility, and use of teleneuropsychology to evaluate possible Alzheimer's disease.

METHODS: Using mixed methods, we evaluated patient and care partner's quantitative surveys and qualitative interviews after two neuropsychology modalities: Teleneuropsychology or FF. Surveys included acceptability, appropriateness, and feasibility measures, and the Unified Theory of Acceptance and Use of Technology questionnaire. Median scores and interquartile ranges were compared. Interviews focused on implementation outcomes and intention to use. Qualitative analyses identified salient themes, which were integrated with quantitative findings.

RESULTS: Patients and care partners (94 and 93% non-Hispanic white) reported similar positive (median score = 4.0 on a 5-point scale) ratings for Teleneuropsychology and FF. Interviews found that benefits of Teleneuropsychology were support for care partner involvement, minimization of logistical demands, reduced travel burden, and increased comfort within a patient's home. Benefits of FF included increased interpersonal connection, improved communication with the provider, and less stress with technology. Some patients tended to prefer FF, while some care partners tended to prefer Teleneuropsychology.

CONCLUSIONS: Patients and care partners in this homogeneous sample indicated that both modalities were acceptable, appropriate, and feasible. Although quantitative ratings were similar, the "appropriate" choice for a particular patient and care partner dyad seemed to be a personalized consideration of tradeoffs that they navigated together. When Teleneuropsychology is adopted, attention to preferences and feasibility among diverse patients is needed.},
}

@article {pmid42856127,
year = {2026},
author = {Grant, RA and Park, LHE and Wahl, D and LaRocca, TJ},
title = {Apigenin Improves Healthspan and Protects Against Alzheimer's Disease-Associated Proteotoxicity in C. elegans.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.23.753917},
pmid = {42856127},
issn = {2692-8205},
abstract = {Apigenin is an abundant, bioactive phytochemical with reported therapeutic potential and neuroprotective effects in a variety of age-related disease models. However, the extent to which apigenin may promote healthspan and protect against neurodegeneration-associated proteotoxicity has not been thoroughly investigated, and the biological processes/mechanisms that underlie its protective effects remain unclear. To determine if apigenin increases healthspan, we performed lifespan assays in conjunction with measures of aging-relevant physiological function in wild-type C. elegans . We found that chronic exposure to apigenin extended median lifespan and improved multiple readouts of healthspan, including pharyngeal pumping, locomotor activity, and age-related macromolecular damage accumulation. Additional analyses of transgenic reporter strains and transcriptomic profiling (RNA-seq) indicated that apigenin primarily modulated redox-sensitive stress signaling and pathways associated with cellular homeostasis in aging animals. Finally, in transgenic C. elegans strains expressing the pathological Alzheimer's disease-associated proteins amyloid-beta or tau, we found that apigenin had similar beneficial effects on lifespan, healthspan, and proteotoxicity-associated functional impairments. Together, our results support apigenin as a potential healthspan-promoting intervention that acts in part through reductions in oxidative stress-associated signaling, with beneficial effects that extend to models of Alzheimer's disease-associated proteotoxicity.},
}

@article {pmid42856154,
year = {2026},
author = {Zhan, Y and Yan, B and Zhang, A and Kellis, M and Sun, N},
title = {ProxiNet transfers spatially learned cellular proximity to dissociated single-cell transcriptomes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.25.754372},
pmid = {42856154},
issn = {2692-8205},
abstract = {Spatial transcriptomics reveals cellular organization within intact tissues, whereas dissociated single-cell RNA sequencing provides broad transcriptomic coverage but loses information about cellular proximity and neighborhood structure. Here, we developed ProxiNet , a spatially supervised framework that learns transcriptomic signatures of pairwise cellular proximity from spatial reference datasets and transfers these relationships to dissociated single-cell transcriptomes. ProxiNet predicted cellular proximity across brain regions and spatial technologies, including zero-shot cross-technology transfer, and gradient-based attribution identified genes and broader transcriptional programs associated with proximity predictions. In spatial datasets with known coordinates, ProxiNet-derived cellular neighborhoods recovered reproducible tissue organization and anatomical structure, providing independent spatial validation of the inferred proximity relationships. Applying the spatially calibrated model to dissociated scRNA-seq revealed heterogeneous cellular neighborhoods with distinct cell-type compositions and candidate communication programs. In an Alzheimer's disease dataset, ProxiNet further identified age-associated remodeling of inferred neighborhoods, including an AD-associated neighborhood at 8 months characterized by distinct astrocyte and neuronal transcriptional states and candidate intercellular communication programs. Together, these results establish pairwise cellular proximity as an interpretable and transferable representation for extending spatially learned tissue organization to dissociated single-cell transcriptomes.},
}

@article {pmid42856250,
year = {2026},
author = {Traxler, L and Borgogno, O and Champion, K and Herdy, JR and Dzieciatkowska, M and Reisz, JA and Petrosyan, A and Siler, C and Anderson, CC and Gorostieta-Salas, E and Lucciola, R and Galasko, D and Gage, FH and D'Alessandro, A and Mertens, J},
title = {Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.26.754222},
pmid = {42856250},
issn = {2692-8205},
abstract = {UNLABELLED: Metabolic alterations and dysregulated alternative RNA splicing are central layers of Alzheimer's disease (AD) pathogenesis, yet whether and to what extent these changes are mechanistically linked in adult human neurons in the aging brain remains unclear. To assess this, we generated induced neurons (iNs) by direct conversion of fibroblasts from sporadic AD patients and age-matched control donors. Fibroblast-derived iNs retaining donor-specific aging signatures have been shown to display several AD-related phenotypes. Metabolomic analysis revealed that AD iNs divert citrate toward ATP-citrate lyase (ACLY)-dependent citrate-to-acetyl-CoA flux, which drives increased nuclear levels of the high-energy metabolite acetyl-CoA. Acetyl-proteomics showed that acetyl-CoA accumulation leads to widespread hyperacetylation of RNA-binding proteins (RBPs) and splice regulators, suggestive of a direct mechanistic link between a metabolic shift and RNA processing. Indeed, single-cell long-read RNA sequencing identifies splicing alterations in AD-relevant transcripts whose isoform usage mirrors changes observed in post-mortem AD cortex samples. Subcellular acetyl-CoA imaging reveals that inhibition of ACLY enzymatic activity selectively reduces nuclear acetyl-CoA levels, and further improves citrate metabolic flux, normalizes RBP acetylation, and re-establishes a normal neuronal splicing landscape in AD iNs. Together, these findings reveal a nuclear acetyl-CoA-RNA processing axis that links age- and disease-related metabolic alterations to alternative splicing dysregulation in AD, and identify neuronal nuclear acetyl-CoA production as a causal and reversible node for restoring metabolic and RNA homeostasis in aging human AD neurons.

HIGHLIGHTS: Sporadic Alzheimer's disease (AD) patient-derived directly induced neurons (iNs) shift metabolism toward nuclear acetyl-CoA production via ATP-citrate lyase (ACLY).Elevated nuclear acetyl-CoA causes hyperacetylation of RNA-binding proteins (RBPs).Patient iNs show pathogenic RNA splicing patterns similar to post-mortem AD brains.Inhibition of ACLY normalizes neuronal acetyl-CoA metabolism and restores RNA splicing homeostasis.},
}

@article {pmid42856312,
year = {2026},
author = {Mukherjee, S and Barthélemy, NR and Atri, T and Li, Y and Yen, D and He, Y and Coyle, R and Ovod, V and Franklin, EE and Xiong, C and Wang, G and Xu, J and Farsad, H and Mummery, CJ and Masters, CL and Sanchez-Valle, R and Masellis, M and Hsiung, GR and Guthier, S and Lah, JJ and Berman, SB and Roberson, ED and Surti, G and Honig, LS and Clarnette, R and Vitali, P and Ringman, J and Bird, TD and Brooks, WS and Fox, NC and Suzuki, K and Black, SE and Levin, J and Farlow, MR and Chhatwal, J and Aggarwal, NT and Jucker, M and Frosch, MP and Kofler, JK and White, C and Keene, CD and Chen, J and Glass, J and Gearing, M and Ryan, NS and Aguillón, D and Supnet-Bell, C and Gordon, BA and Benzinger, TLS and Sims, J and Yaari, R and Bittner, T and Klein, G and Delmar, P and Morris, JC and Llibre-Guerra, J and Clifford, DB and Karch, CM and McDade, E and Perrin, RJ and Bateman, RJ and , and , },
title = {Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.22.26363432},
pmid = {42856312},
abstract = {UNLABELLED: Therapeutic strategies targeting amyloid-β (Aβ) in Alzheimer disease (AD) include antibodies directed against fibrillar amyloid plaques or soluble amyloid-β (Aβ) species, yet how these approaches reshape brain pathology remains poorly understood. Postmortem neuropathological assessment is crucial for evaluating the degree of Aβ removal, providing information and context that fluid biomarkers and positron emission tomography (PET) alone cannot, and guiding development of more effective disease modifying therapies for AD. In this study, using high resolution mass spectrometry we quantitatively measured Aβ and tau proteoforms in postmortem brain tissue homogenates to evaluate the impact of long-term treatment with anti-Aβ monoclonal antibodies gantenerumab or solanezumab in a clinical trial of dominantly inherited Alzheimer disease (DIAD). Symptomatic DIAD participants who had been treated for ∼ 4 years with anti-Aβ monoclonal antibodies (gantenerumab, n=4 or solanezumab, n=4) were compared with untreated, symptomatic DIAD mutation carriers (n=40) and with age-relevant non-DIAD controls with modest or no plaque pathology (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab-treated participant samples showed significantly lower levels of specific Aβ proteoforms (Aβ 42 , Aβ 40) in the insoluble plaque associated pool (range: 60-80 % reduction); they also showed lower levels of post-translationally modified Aβ proteoform Aβ 3pGlu in both the insoluble and soluble pool, compared to untreated DIAD participants, but without reaching the levels found in non-DIAD controls. Samples from gantenerumab-treated participants also showed regionally lower amounts of insoluble phosphorylated tau species (pT181, pT205, pT208) and MTBR tau species (354-369, 306-317, 299-317) without apparent differences in insoluble total tau levels. In contrast, brain tissue samples from solanezumab-treated participants did not show significant differences overall in soluble or insoluble levels of Aβ and tau proteoforms in comparison to those from non-treated DIAD individuals. These findings support that amyloid targeting treatment (ATT) with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.

KEY SUMMARY: Question: How do amyloid targeting treatments (ATT) affect the Alzheimer disease (AD)-related brain pathologies of soluble and aggregated amyloid-β and tau proteoforms in postmortem tissue?Background: Extracellular amyloid plaques and neurofibrillary tangles (NFTs) are the primary pathological hallmarks of AD. For the past three decades, active and passive immunization against cerebral amyloid-β (Aβ) has constituted one of the primary avenues of disease-modifying intervention in AD. Recently, passive immunizations using anti-Aβ targeting antibodies have demonstrated slowing of cognitive decline in sporadic AD and possibly in dominantly inherited AD (DIAD). In these clinical trials, target engagement has been inferred from Aβ-positron emission tomography (PET) and/or biofluid biomarkers during life. However, to confirm evidence of target engagement more directly, identify which pathological proteoforms are affected, quantify the dose dependent treatment effects of these treatments, and begin to evaluate their putative downstream effects on AD pathophysiology, quantitative biochemical comparisons of amyloid plaques and tau pathology (soluble and insoluble Aβ and tau species) in postmortem brain tissue of treated and untreated AD are needed.Findings: In this study, using high resolution mass spectrometry we measured the soluble and insoluble Aβ and tau proteoforms in the postmortem brain tissue homogenates from DIAN-TU-001 trial participants who were symptomatic and had been treated for ∼ 4 years with gantenerumab (n=4) or solanezumab (n=4), two antibodies that bind to insoluble and soluble Aβ, respectively. Intervals between treatment discontinuation and death ranged from 5 months to 3 years. Comparisons were made with postmortem brain tissue samples from untreated, symptomatic DIAD participants of the DIAN-Obs study (n=40) and from age-relevant, cognitively normal, non-DIAD controls with or without only modest burdens of diffuse Aβ plaques (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab significantly decreased specific Aβ (Aβ 42 , Aβ 40) proteoforms in the insoluble plaque associated pool (range: 60-80% reduction) compared to the untreated DIAD participants, but without reaching the levels found in the non-DIAD controls. Samples from gantenerumab treated participants also showed significantly lower amount of post-translationally modified Aβ (Aβ 3pGlu) and regionally lower insoluble phosphorylated tau species (pT181, pT205 and pT208), without apparent differences in insoluble total tau levels. In contrast, solanezumab treatment did not show significant effect on the soluble or insoluble levels of Aβ and tau proteoforms in comparison to samples from non-treated DIAD individuals. Significance: These findings support that ATT with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.},
}

@article {pmid42856336,
year = {2026},
author = {Alsolami, S and Wang, M and Sabedot, TS and Singh, U and Kirk, B and Mitchell, L and Hernandez, M and Skvir, N and Bowman, C and Oiwa, K and Agarwal, R and Mahmoudi, M and Cuoco, MS and MacDonald, E and Cranston, S and Lucciola, R and Boassa, D and Herdy, JR and Jones, JR and Yoshikiyo, K and , and Mertens, J and Martinez-Trujillo, J and Jaremko, L and Murphy, GJ and Gage, FH},
title = {An age-preserving neuronal iSpheroid platform for modeling human aging and Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755853},
pmid = {42856336},
issn = {2692-8205},
abstract = {UNLABELLED: Aging is the strongest risk factor for Alzheimer's disease (AD), yet existing human neuronal models either erase age-associated features during reprogramming or fail to recapitulate three-dimensional organization of human neuronal tissue. Here, we establish directly induced neuronal spheroids (iSpheroids), a scalable three-dimensional platform generated by direct conversion of primary fibroblasts without pluripotency. iSpheroids generate long-lived, electrophysiologically active neurons from young, unimpaired aged, and sporadic AD donors while preserving donor-specific epigenetic age. Single-nucleus RNA sequencing revealed approximately 96% of cells acquired a neuronal identity and were distributed across multiple neuronal states, including a diversity of neurons. The platform supports incorporation of astrocytes and microglia and generation from non-human primate fibroblasts. AD iSpheroids spontaneously recapitulated neuronal degeneration, amyloid-β accumulation, progressive Tau pathology, and metabolic dysfunction. Integrated proteomic, metabolomic, and lipidomic profiling distinguished physiological aging from AD and revealed disease-associated metabolic remodeling. Oxaliplatin shifted AD iSpheroids toward oxidative metabolism, whereas a multi-compound screen identified trametinib as a modulator of inflammatory and age-associated programs.

HIGHLIGHTS: - Direct conversion generates age-preserving, functional human neuronal iSpheroids.- iSpheroids recapitulate molecular and pathological hallmarks of AD.- Multi-omics distinguishes physiological neuronal aging from AD.- Pharmacological screening identifies reversible metabolic and inflammatory phenotypes.},
}

@article {pmid42856350,
year = {2026},
author = {Petrican, R and Fornito, A and John, A and Pendered, S},
title = {Regional similarity to male-typical brain architecture links childhood ADHD to neurophysiological aging in later adulthood.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.754764},
pmid = {42856350},
issn = {2692-8205},
abstract = {Identifying early life biomarkers of suboptimal aging trajectories could help design interventions to delay or even prevent the onset of pathological conditions in older adulthood. To address this issue, we capitalize on evidence that the prevalence rates and presentation of neurodevelopmental and neurodegenerative conditions tend to vary between males and females, thereby raising the possibility that processes involved in sexual differentiation could help connect brain maturation and aging outcomes. Here, we focus on attention deficit hyperactivity disorder (ADHD), a neurodevelopmental condition with male-biased prevalence, and examine the relevance of its genetic risk and functional brain profile to aging outcomes. We analyzed multimodal data from a child sample enriched in ADHD cases and a neurologically intact adult sample. Among 6-to-12-year-olds (N =522), genetic vulnerability to pathological aging, indexed via polygenic risk scores (PRSs) for Alzheimer's Disease (AD), predicted ADHD diagnosis across sexes, regardless of psychiatric history and PRSs for multiple disorders (including ADHD). Irrespective of age, boys and girls diagnosed with ADHD showed preferential alignment with male-, rather than female-, typical functional connectivity patterns in metabolically active transmodal areas which are enriched in 5-HT 2,4 , D1, and mGLU5 receptors. In an independent sample aged 36-90 years (N = 345), the ADHD brain profile correlated with higher levels of testosterone, physiological markers of reproductive aging and poorer performance on AD-relevant cognitive tasks among older individuals of either sex. Our results imply that neurodevelopmental conditions could provide insights into vulnerability to suboptimal aging trajectories and could help guide early interventions targeting at-risk individuals.},
}

@article {pmid42856359,
year = {2026},
author = {Petrican, R and Fornito, A},
title = {Alignment with sex-typical brain architecture: Links to mood pathology, sex hormones and transcriptomics of neurodegenerative conditions.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.754773},
pmid = {42856359},
issn = {2692-8205},
abstract = {Understanding the mechanisms that underpin the pervasive sex bias in risk for specific psychiatric and neurodegenerative conditions could substantially advance efforts promoting personalized medicine. As a first step towards addressing this issue, we applied imaging transcriptomics and multivariate analysis techniques to data from an adolescent sample enriched in anxiety/depression cases, a child sample enriched in attention deficit hyperactivity disorder (ADHD) cases, and adult patients with treatment resistant major depressive disorder (MDD). We tested whether, across sexes, alignment with female-typical, rather than male-typical, patterns of neural functional connectivity (FC) would relate to a diagnosis (adolescent sample) or severity of symptoms (adult sample) associated with internalizing disorders, which tend to be more often diagnosed in females. To provide preliminary evidence on its functional specificity, we compared the sex-aligned FC profile that distinguished neurotypical adolescents from those diagnosed with depression/anxiety against the sex-aligned FC patterns that distinguished neurotypical children from those diagnosed with ADHD. All the analyses controlled for age within each sample and sex. Finally, we examined the spatial overlap between the sex-aligned FC profile linked to an internalizing diagnosis in adolescence and the transcriptomic maps of genes that show sex-dependent dysregulation in neurodegenerative conditions. Across sexes, increasing alignment with female-typical FC patterns, from sensory-perceptual to default mode regions, discriminated between typically developing and anxious/depressed teens and tracked longitudinal fluctuations in depressive symptoms within adult MDD patients. The identified internalizing-related gradient showed a negative correlation with risk for ADHD in the child sample. The brain regions most strongly aligned with female-, rather than male-, typical FC in depression/anxiety overlapped the spatial expression profiles of genes linked to gonadal hormone synthesis, as well as genes dysregulated in female autism spectrum disorder (ASD) and male neurodegenerative conditions, specifically, Alzheimer's Disease (AD), Huntington's Disease (HD) and Multiple Sclerosis (MS). The brain areas most strongly aligned with male-typical, rather than female-typical, FC patterns overlapped the transcriptomic maps of genes related to androgen and estrogen receptors, as well as of genes dysregulated in male ASD and female neurodegenerative conditions (i.e., AD, HD, MS). Our results raise the possibility that the link between mood pathology and neurodegeneration could reflect a partial, regional reversal of sex-normative functional brain profiles.},
}

@article {pmid42856370,
year = {2026},
author = {Tang, S and Younes, K and Penukonda, E and Hausle, I and Thropp, P and Lupo, JM and Tosun, D and , },
title = {Examining the Clinical Utility of Deep Learning Models for Perivascular Space Segmentation in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.26363725},
pmid = {42856370},
abstract = {Open-source deep learning models promise scalable quantification of MRI-visible perivascular spaces (PVS), an emerging marker of glymphatic dysfunction in Alzheimer's disease (AD). Whether these models remain valid when applied to heterogeneous AD cohorts and preserve ground-truth derived biological associations has not been established. We benchmarked five open-source nnU-Net-based PVS segmentation models (nnU-Net T1, nnU-Net T1+FLAIR, mcPVS-Net, MedNet-PVS, ADNI-PVS-Net) against manual labels in 60 multi-site ADNI-3 participants balanced across cognitively unimpaired, mild cognitive impairment, and AD dementia, and in 12 publicly available scans from the VAscular Lesions object-level and segmentatiOn (VALDO) challenge. We evaluated overall, voxel, object, and lesion-wise Dice; stratified performance by region, diagnosis, scanner, PVS severity, and white matter hyperintensity (WMH) burden; and tested whether model-derived PVS burden reproduced ground-truth derived associations with AD-related biomarkers. Despite high internal performance, all models showed a specialist-generalist trade-off: the AD-trained ADNI-PVS-Net achieved highest internal performance (overall Dice = 0.58±0.14) but degraded most externally (Dice ≤ 0.11), while MedNet-PVS and mcPVS-Net generalized externally (Dice 0.27-0.30) but systematically misestimated PVS burden. Models were relatively robust across scanner and diagnosis but inconsistent across PVS severity, and some misclassified up to 32% of WMH as PVS. Notably, only AD-trained models reproduced the expected PVS-amyloid biomarker relationship; other models returned a null result, despite comparable or superior Dice scores. These findings show that internal segmentation accuracy and external generalizability alone do not guarantee downstream inferential validity. Careful model selection and cohort-specific validation against manual labels should precede clinical inference in AD.},
}

@article {pmid42856420,
year = {2026},
author = {Geng, Z and Montembeault, M and Coulombe, V},
title = {Diagnostic Utility of Multi-Domain Language Measures Across the Alzheimer Disease Continuum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.28.26364143},
pmid = {42856420},
abstract = {OBJECTIVES: Alzheimer's disease (AD) progresses from a cognitively unimpaired stage through mild cognitive impairment (MCI) to dementia. Because language impairment often emerges before dementia, it is a candidate marker of disease stage. Yet the standard batteries of large AD research cohorts rely on a narrow set of tests that mainly evaluate the lexical-semantic domain (i.e., picture naming and verbal fluency), leaving other language domains, such as semantic memory, phonology, morphosyntax, and single-word reading, rarely assessed. We evaluated the diagnostic utility of standard and specialized language tests for distinguishing amyloid-positive MCI and dementia of the Alzheimer's type (DAT) from healthy controls (HC) and from each other.

METHODS: We included 286 participants from the National Alzheimer's Coordinating Center (125 HC, 53 MCI Aβ+, 108 DAT Aβ+) assessed with three standard tests from UDSv3 (semantic fluency, letter fluency, and Multilingual Naming Test [MINT]) and nine specialized tests from the FTLD Module (regular and irregular word reading, semantic word-picture matching, semantic associates, Northwestern Anagram Test - Short Form [NAT-S], Northwestern Naming Battery noun and verb naming, sentence repetition, and sentence reading). For each test, the area under the receiver operating characteristic curve (AUC) was computed for DAT vs. HC, MCI vs. HC, and DAT vs. MCI, and AUCs were compared between tests with DeLong's test.

RESULTS: Eight of 12 measures reached acceptable discrimination (AUC ≥ .700) for DAT vs. HC, five for MCI vs. HC, but only semantic fluency and NAT-S for DAT vs. MCI. Semantic fluency showed the highest discrimination in each contrast, though it did not significantly outperform the NAT-S for MCI vs. HC or DAT vs. MCI. MINT, letter fluency, and irregular word reading reached clinically meaningful accuracy in distinguishing MCI and DAT from HC, but not DAT from MCI. The remaining specialized tests reached it only for DAT vs. HC, or not at all. In a post hoc regression, adjusting for cognitive flexibility and working memory attenuated group differences; the DAT difference was no longer significant, whereas the MCI difference remained significant.

DISCUSSION: Semantic fluency was the strongest single language marker across the AD continuum. Among specialized tests, NAT-S was the most informative, challenging the view that syntax is spared in early AD. Its performance was partly explained by executive function, mainly in DAT, whereas a residual morphosyntactic component remained in MCI, and several specialized tests were limited by ceiling effects. Clinically, the NAT-S may complement semantic fluency for staging, and specialized tests may help characterize heterogeneous language profiles in MCI and DAT.},
}

@article {pmid42856437,
year = {2026},
author = {Harris, AS and Rouse, JA and Guo, G and Fernandez-Maestre, I and Pal, S and Oh, B and Li, S and See, WY and Anderson, A and Gewolb, J and Soethout, M and Habel, J and Utama, R and Vakoc, CR and Amor, C},
title = {CAR T cell targeting of inflammatory myeloid progenitors in the bone marrow remodels border-associated macrophages and reverses cognitive aging.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.754777},
pmid = {42856437},
issn = {2692-8205},
abstract = {Aging is associated with progressive neuroinflammation and cognitive decline, yet the cellular sources that sustain this process and whether they can be targeted peripherally remain unclear. Here, we identify inflammatory border-associated macrophages (BAMs) as key drivers of neuroinflammation in aging and show that their therapeutic and prophylactic elimination through intrathecal CAR T cell therapy restores cognitive performance in mouse models of aging and Alzheimer's disease. Furthermore, targeting of aged inflammatory bone marrow myeloid progenitors through either intravenous CAR T cells, which do not infiltrate the brain, or through transplantation of CAR T-treated progenitors is sufficient to reduce neuroinflammation and cognitive impairment. These findings reveal that bone marrow myeloid progenitors harbor a heritable inflammatory transcriptional state that is transmitted to their BAM progeny, driving neuroinflammation and cognitive deterioration, and conserved in human aging. Critically, this proinflammatory state is marked by the upregulation of surface proteins, enabling precise peripheral CAR T cell targeting of these progenitors for long-lasting therapeutic effects in cognitive aging.},
}

@article {pmid42856516,
year = {2026},
author = {Wang, N and Dang, L and Chang, W and Qi, H and Ban, J and Guo, H and Tang, S},
title = {Non-pharmacological interventions for cognitive function improvement in patients with Alzheimer's disease: a best evidence summary.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1888519},
pmid = {42856516},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Cognitive Training ; Cognitive Enhancement ; *Cognition ; Music Therapy ; },
abstract = {OBJECTIVE: This study aimed to systematically retrieve, analyze, and synthesize evidence on non-pharmacological interventions to improve overall cognitive function in patients with Alzheimer's disease (AD), providing evidence-based references for selecting and optimizing these interventions.

METHODS: This review followed the PRISMA-ScR guidelines and the JBI scoping review framework. The evidence-based question was developed using the PIPOST framework. Databases and professional platforms were systematically searched from inception to January 30, 2026, using the "5S" model. Included studies were quality-appraised; eligible evidence was extracted, synthesized, graded, and assigned recommendation levels.

RESULTS: Following a strict literature screening strategy, a total of 15 studies were included, comprising 1 guideline, 7 expert consensus reports, 6 systematic reviews, and 1 randomized controlled trial. A total of 18 best evidence items were summarized and categorized into six dimensions: cognitive training (CT) and digital therapy, neuromodulation techniques, exercise interventions, lifestyle and reminiscence therapy interventions, music and sensory stimulation, and acupuncture and combined interventions.

CONCLUSIONS: This study consolidated the best evidence on non-pharmacological interventions to improve overall cognitive function in patients with Alzheimer's disease, providing references for clinical practice. Clinical healthcare professionals should select appropriate interventions based on the actual clinical scenarios and individual patient conditions, and strengthen quality control during implementation.},
}

Humans
*Alzheimer Disease/therapy/psychology
Cognitive Training
Cognitive Enhancement
*Cognition
Music Therapy

@article {pmid42856517,
year = {2026},
author = {Pinamonti, M and Moretto, M and Pieperhoff, L and Arunachalam, P and Barkhof, F and Wink, AM and Lorenzini, L and Veronese, M},
title = {Normative Modeling of Molecular-Enriched Functional Connectivity for Detecting Deviations from Healthy Brain Aging.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.28.754989},
pmid = {42856517},
issn = {2692-8205},
abstract = {INTRODUCTION: Inter-individual variability in adult brain aging can obscure early pathological alterations and is only partly represented by population-average or scalar brain-aging measures. We combined Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) with normative modeling (NM) to derive spatially resolved, molecularly informed deviation scores for dopamine transporter (DAT)-, norepinephrine transporter (NET)-, and serotonin transporter (SERT)-enriched resting-state functional connectivity (FC). We first evaluated whether these normative models could be transferred to independently processed external data through local calibration and then explored whether the resulting deviation profiles differed with cerebral amyloid burden in cognitively unimpaired older adults.

METHODS: Hierarchical Bayesian regression (HBR) models with a sinh-arcsinh likelihood (SHASHb) were estimated separately for 204 cortical molecular-enriched FC features in 4,152 healthy adults (18.0-89.8 years) from seven publicly available neuroimaging datasets and evaluated in a held-out healthy test set. Pretrained models were locally adapted to three Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study (AMYPAD-PNHS) acquisition batches using cognitively unimpaired, amyloid-negative participants (global Clinical Dementia Rating (CDR) = 0; Centiloid (CL) < 10). The independent primary comparison contrasted participants with intermediate amyloid burden (10 ≤ CL < 30; n = 111) and amyloid-positive participants (CL ≥ 30; n = 66); secondary analyses tested linear associations with continuous CL within participants with CL ≥ 10.

RESULTS: Of 204 normative reference models, 199 (97.5%) met the predefined diagnostic criteria; median held-out explained variance (EXPV) was 0.174. Of 612 feature-by-batch transfers, 541 (88.4%) met the strict transfer-diagnostic criteria. In the primary false discovery rate (FDR)-controlled regional analysis, DAT-enriched right caudal middle frontal cortex showed lower locally standardized deviation scores in the intermediate-amyloid-burden group than in the amyloid-positive group (adjusted difference = -0.582, q = 0.016). DAT extreme-deviation burden was also greater in the intermediate-amyloid-burden group (difference = 0.032, q = 0.044). The right frontal effect was reproduced with model-native scores across the three acquisition batches (pooled standardized effect = -0.698, q = 0.010). No NET- or SERT-enriched regional difference between these two groups survived FDR-correction, and no regional or subject-level linear association with continuous CL values survived FDR-correction in the CL ≥ 10 group.

CONCLUSION: NM can provide spatially resolved reference distributions of molecular-enriched FC that are deployable in independently processed external data when local adaptation, calibration, and feature-level transfer diagnostics are incorporated. The AMYPAD-PNHS application identified modest, spatially selective, and molecular-system-specific categorical differences during a cognitively unimpaired stage of amyloid accumulation, while continuous analyses within CL ≥ 10 did not support linear association. These findings support a methodological basis for distributed application of molecular-enriched normative models and motivate independent and longitudinal evaluation of their biological relevance.

KEY POINTS: Hierarchical normative models characterized 204 regional DAT-, NET-, and SERT-enriched FC features across 4,152 healthy adults; 199/204 models met the predefined normative-reference-model diagnostic criteria.Local hierarchical adaptation enabled the pretrained normative models to be applied to independently processed AMYPAD-PNHS data without centralized reprocessing of the target raw images or explicit feature-level harmonization; 541/612 feature-batch transfers met the strict transfer criteria.In cognitively unimpaired AMYPAD-PNHS participants, the exploratory amyloid application identified a spatially selective DAT-enriched right frontal difference and greater DAT extreme-deviation burden in the intermediate-amyloid-burden group than in the amyloid-positive group. No FDR-corrected regional NET or SERT differences between these groups and no FDR-corrected linear associations with continuous CL were identified.},
}

@article {pmid42856537,
year = {2026},
author = {Brown, BRP and Li, X and Grasty, MR and Miranker, AD and Gürsoy, G},
title = {Integrating CSF and EV Proteomes Enhances Biomarker Discovery by Capturing Shared Variation Across Compartments.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.754912},
pmid = {42856537},
issn = {2692-8205},
abstract = {Cerebrospinal fluid (CSF) contains brain derived proteins that can be leveraged as biomarkers for Alzheimer's disease (AD) and other neurodegenerative diseases. However, converting protein intensities to a disease signal remains a challenge because physiology driven changes to the localization of proteins across CSF subcompartments are obscured when CSF is analyzed alone. Where subcompartment data, such as that from extracellular vesicles (EVs), are also measured, separate but parallel analyses of EVs and CSF can obscure their shared disease signal. Here, we present an integrated matrix factorization approach that combines proteomic signals from matched CSF and phosphatidylserine exposed EVs and nanoparticles (EV ps). In a ROS/MAP cohort of 48 participants, integrating CSF and EV ps signals improved biological concordance across compartments and increased the number of candidate proteins distinguishing participants with AD from controls. Notably, the joint signal identified as many brain-related biomarker candidates as studies using substantially larger cohorts. By demonstrating that integration of CSF and EV ps proteomes maximizes information from limited samples, this framework offers a path toward more efficient biomarker discovery across two compartments increasingly leveraged in neurodegenerative disease research.},
}

@article {pmid42856593,
year = {2026},
author = {Zheng, L and Ghanbarian, E and Albarrán Morillo, C and Younes, K and Glover, CM and Rabin, LA and Grill, JD and Ewers, M and Sajjadi, SA and Ezzati, A and , and , and , },
title = {Tau-PET subtype modifies the association between plasma p-tau217 and memory in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.25.26363629},
pmid = {42856593},
abstract = {INTRODUCTION: Plasma p-tau217 is associated with Alzheimer's disease pathology and memory performance, but its implications for memory may depend on fibrillar tau topography. We examined whether tau-PET subtype modified the association between plasma p-tau217 and memory.

METHODS: We analyzed 396 amyloid-positive, tau-positive participants spanning cognitively unimpaired, mild cognitive impairment, and dementia stages from six cohorts with tau-PET and plasma p-tau217; 301 had harmonized memory data. Tau-PET subtypes were derived using data-driven disease progression modelling. Primary cross-sectional models tested subtype×p-tau217 interactions for memory, adjusting for age, sex, education, APOE ε 4 status, and cohort. Secondary and exploratory analyses examined latent global cognition, non-memory measures, and longitudinal cognitive change.

RESULTS: Three tau-PET subtypes were retained: limbic-predominant, medial temporal lobe (MTL)-sparing, and posterior-predominant. Cross-sectionally, MTL-sparing participants had lower plasma p-tau217 than the other subtypes. The association between higher plasma p-tau217 and worse memory differed by subtype (interaction p =0.002) and was stronger in MTL-sparing (B =-0.191, p <0.001) than in limbic-predominant (B =-0.07, p =0.002) and posterior-predominant participants (B =-0.07, p <0.001). The interaction remained significant after additional adjustment for diagnostic group (p =0.015). This pattern also persisted after additional adjustment for PET tau burden, amyloid Centiloids, or plasma Aβ42/40; none of these biomarkers showed comparable subtype modification. Subtype modification was also observed for a global cognitive composite (interaction p =0.004) and subsequent memory decline in an exploratory analysis conditioned on baseline memory (interaction p =0.016).

DISCUSSION: Tau-PET subtype modified the p-tau217-memory association, suggesting that the cognitive implications of plasma p-tau217 may vary with tau topography.},
}

@article {pmid42856599,
year = {2026},
author = {Krishingner, T and Fausett, SR},
title = {A New Soaking Protocol to Live Stain C. elegans with Proteostat Dye Reveals Global Patterns of Stress-Induced Protein Aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755777},
pmid = {42856599},
issn = {2692-8205},
abstract = {Protein aggregates are a diverse array of intra- and extracellular structures containing misfolded proteins with limited macromolecular movement. Protein aggregation is induced by aging and cellular stress and is a hallmark of neurodegenerative diseases including Huntington's, Alzheimer's, and Parkinson's. Fluorescent tools to visualize global protein aggregation in whole organisms are, therefore, important for screening genes and compounds that may reduce or alter protein aggregation in connection with improved health outcomes. Fluorescent probes that report low fluidity structures in cells, such as molecular rotor dyes, are gaining popularity and overcome certain limitations of targeted markers such as tagged proteins or antibodies. However, permeability has been a key barrier preventing widespread use of such probes in whole organisms, including in C. elegans . To achieve visualization of non-specific protein aggregates in whole C. elegans nematodes without the need for strain engineering, we have developed a simple soaking protocol. Our protocol overcomes the permeability limitations of the commercially available molecular rotor dye, Proteostat, enabling widespread labeling of protein aggregates in live and post-fixed worms. Here, we present our novel approach and demonstrate quantification of protein aggregates in multiple tissues to detect differences in protein aggregation due to both genotype and treatment effects. We also outline anticipated future applications for this protocol, including its adaptation for other dyes, as well as limitations and special considerations for its use.},
}

@article {pmid42856607,
year = {2026},
author = {Onken, MD and Cooper, JA},
title = {The Alzheimer's Disease-associated gene CD2AP regulates permeability of endothelial cells and transendothelial migration of immune cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.01.755982},
pmid = {42856607},
issn = {2692-8205},
abstract = {Variants at the CD2AP locus, which encodes a branched-actin regulator, are associated with late-onset Alzheimer's disease (AD), and CD2AP-deficient mice show increased blood-brain barrier (BBB) permeability. CD2AP is enriched in endothelial cells, but its function there is poorly understood. In endothelium, branched actin networks maintain cell-cell junctions and are also required for immune cells to cross through individual endothelial cells (transcellular transendothelial migration, TEM). We previously showed that the Arp2/3 activators N-WASP and WAVE2 contribute to these processes, but the capping protein (CP)-interacting proteins involved are unknown. Here we tested whether CD2AP, a CP-interacting protein recruited to cell-cell contacts, regulates both junction integrity and TEM. In primary human microvascular endothelial cells, shRNA knockdown of CD2AP increased TNFα-induced monolayer permeability, measured by transendothelial electrical resistance, and altered VE-cadherin junction morphology. Unexpectedly, on soft hydrogels the same knockdown reduced TEM of NK-92 MI cells, lowering the proportion of transcellular events. Thus, loss of CD2AP weakens the endothelial barrier yet impairs a distinct, actin-dependent route of immune-cell passage. These findings suggest that CD2AP risk variants may affect the BBB through more than permeability, and they identify endothelial immune-cell trafficking as a testable link between CD2AP and AD.},
}

@article {pmid42856764,
year = {2026},
author = {Krokidis, MG and Sagar, R and Mustapic, M and Papatheodorou, MC and Exarchos, TP and Lyketsos, CG and Vlamos, P and Kapogiannis, D and Mahairaki, V},
title = {APOE4 differentially alters lipid composition in extracellular vesicles from hiPSC-derived neurons of Alzheimer's disease patients.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1917428},
pmid = {42856764},
issn = {1663-9812},
abstract = {BACKGROUND: The Apolipoprotein E4 (APOE4) is the most significant genetic risk factor for late-onset Alzheimer's disease (AD), but the cellular mechanisms by which it increases vulnerability remain poorly understood. Lipids play a crucial role in membrane organization, vesicle trafficking, and inflammatory signaling in the brain. Increasing evidence suggests that changes in lipid metabolism might serve as a connection between genetic risk and neurodegeneration. Extracellular vesicles (EVs) reflect the lipidomic composition of their parent cell offering a window into lipidomic alterations that may be tracked in living humans over time. Given high variability in human samples, we sought to define APOE4-related lipidomic EV signatures in a controlled human cellular system.

METHODS: We studied EVs secreted by four replicates of human-induced pluripotent stem cell (iPSC)-derived glutamatergic neurons from two healthy individuals (APOE2/E3 and APOE4/4) and two patients with AD (APOE3/3 and APOE4/4). Targeted lipidomics enabled quantitative profiling of hundreds of individual lipid species across major lipid classes. Univariate and multivariate analyses were applied to identify lipid alterations associated with APOE genotype and AD status.

RESULTS: APOE4 was associated with differences in lipid composition in neuronal EVs from both healthy and AD donors, suggesting that APOE4 influences EV lipid composition regardless of AD. Additionally, APOE4/4 carriers with AD exhibited clear, species-specific lipid imbalances. Lower levels of ganglioside GM3 and higher of phosphatidylserine emerged as consistent contributors to the APOE4-associated AD lipid signature, alongside alterations in dihydrosphingomyelin and phosphatidylinositol species linked to membrane integrity, endolysosomal function, and inflammatory pathways. These lipid species were among the strongest variables distinguishing healthy and AD APOE4/4 samples in multivariate analyses.

CONCLUSION: These findings specify lipidomic changes in AD related to the APOE4 genotype, and support a model by which APOE4 creates a lipid profile that becomes selectively dysregulated in AD. By identifying specific lipid species associated with APOE4 and AD, this work provides further evidence that distinct lipidomic signatures are associated with both APOE4 and AD. These findings may contribute to the identification of lipid-based biomarkers and support future investigations into genotype-informed therapeutic strategies, although validation in larger, independent cohorts is required.},
}

@article {pmid42856767,
year = {2026},
author = {Farzana, S and Arian, A and , and , and Ahsan, H},
title = {Evaluating Patient Representation Strategies for Early Prediction of Alzheimer's Disease and Related Dementias from Longitudinal EHRs.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10988118/v1},
pmid = {42856767},
issn = {2693-5015},
abstract = {The neurodegenerative processes underlying Alzheimer's disease and related dementias (ADRD) begin years before clinical diagnosis, motivating scalable approaches for earlier identification. Electronic health records (EHRs) provide longitudinal clinical information for early ADRD prediction but are sparse, temporal, and hierarchical, and alternative EHR representations encode these characteristics differently. We systematically evaluated how EHR representation and temporal distance from diagnosis influence ADRD prediction and whether representation-specific performance generalizes across health systems. Using All of Us EHRs, we compared interpretable count-based representations with pretrained clinical foundation-model representations at clinically meaningful lead times across multiple ADRD case definitions. Count-based models achieved the strongest overall discrimination and calibration. Performance generally declined with increasing prediction horizons, while differences between representations narrowed; at 36 months, pretrained representations achieved comparable AUROC (0.719 versus 0.738) with higher sensitivity and F1 at a fixed operating threshold. Temporal feature attribution showed greater model reliance on healthcare-utilization indicators at longer horizons and increasing importance of cognitive phenotypes, including amnesia and mild cognitive impairment, nearer diagnosis. Zero-shot evaluation on independent UChicago Medicine EHRs showed substantial performance degradation across representations, demonstrating challenges in cross-institutional transportability. These findings characterize representation-dependent tradeoffs in early ADRD prediction across temporal horizons and healthcare systems.},
}

@article {pmid42856786,
year = {2026},
author = {Li, X and Qi, H and Zhang, X and Jin, X and Xu, J and Ma, J},
title = {Comparative effects of six exercise modalities on global cognitive function in Alzheimer's disease, Parkinson's disease, and mild cognitive impairment: a systematic review and network meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1877537},
pmid = {42856786},
issn = {1664-2295},
mesh = {Humans ; *Cognitive Dysfunction/therapy/psychology/rehabilitation ; *Parkinson Disease/therapy/psychology/rehabilitation ; *Alzheimer Disease/therapy/psychology/rehabilitation ; *Exercise Therapy/methods ; *Cognition/physiology ; Cognitive Enhancement ; *Exercise ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) are commonly accompanied by cognitive decline. Although exercise is recommended as a non-pharmacological strategy, the comparative effects of different exercise modalities on global cognition remain uncertain.

OBJECTIVE: To compare six exercise modalities-aerobic exercise (AE), mind-body exercise (MBE), resistance training (RT), multi-component exercise (MCE), flexibility training (FT), and functional training (FTr)-for global cognitive function in people with AD, PD, or MCI, and to explore dose-related associations.

METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to January 26, 2026. Randomized controlled trials (RCTs) were synthesized using a frequentist random-effects network meta-analysis (NMA) with standardized mean differences (SMDs) and 95% confidence intervals (CIs). Treatment rankings were summarized using SUCRA. Subgroup analyses, meta-regression, diagnosis-related sensitivity analyses, and CINeMA certainty assessments were also performed.

RESULTS: Twenty-eight trials involving 1,993 participants were included. Compared with control group (CG), AE [SMD = 0.47, 95% CI (0.18, 0.77)], MBE [SMD = 0.79, 95% CI (0.46, 1.11)], RT [SMD = 1.50, 95% CI (0.77, 2.23)], MCE [SMD = 0.83, 95% CI (0.26, 1.40)], and FTr [SMD = 0.83, 95% CI (0.13, 1.53)] improved global cognition, whereas FT showed no clear effect [SMD = -0.20, 95% CI (-1.27,0.87)]. RT ranked first, followed by MCE, FTr, MBE, AE, and FT. Heterogeneity was substantial (τ[2] = 0.23; I[2] = 80%), although no statistically significant global incoherence was detected. RT remained first after the exclusion of AD, PD, or MCI studies. Studies lasting more than 12 weeks, delivered 3-5 times per week, and using sessions of 31-60 min showed favorable pooled effects, but subgroup interaction tests and meta-regression were not significant. Certainty of evidence ranged from low to very low.

CONCLUSION: AE, MBE, RT, MCE, and FTr may improve global cognition in people with AD, PD, or MCI. RT showed the largest effect estimate and the most favorable ranking. However, substantial heterogeneity and sparse evidence for several modalities limit firm conclusions. Exercise selection should be individualized, and dose-related findings require confirmation in adequately powered comparative trials.},
}

Humans
*Cognitive Dysfunction/therapy/psychology/rehabilitation
*Parkinson Disease/therapy/psychology/rehabilitation
*Alzheimer Disease/therapy/psychology/rehabilitation
*Exercise Therapy/methods
*Cognition/physiology
Cognitive Enhancement
*Exercise

@article {pmid42856930,
year = {2026},
author = {Shaw, S and Warren, SL and Teng, C and Huynh, J and Ahmed, R and Piguet, O and Whitton, AE and Irish, M},
title = {Early anhedonia distinguishes behavioral variant frontotemporal dementia from Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70501},
pmid = {42856930},
issn = {2352-8729},
abstract = {INTRODUCTION: Differentiating behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD) remains challenging due to overlapping early behavioral and cognitive features. Anhedonia has emerged as a promising clinical marker, yet its multidimensional nature and temporal emergence across dementia syndromes remain unclear.

METHODS: Anticipatory and consummatory components of anhedonia were assessed in bvFTD and AD using the Temporal Experience of Pleasure Scale. Event-based modeling was applied in each group to stage the probabilistic emergence of anticipatory and consummatory anhedonia dimensions relative to apathy and cognitive symptoms.

RESULTS: Relative to controls, bvFTD showed marked loss of pleasure across anticipatory and consummatory components, whereas AD showed selective anticipatory anhedonia in the context of preserved consummatory pleasure. Event-based modeling placed consummatory and anticipatory anhedonia dimensions as early features of bvFTD occurring prior to overt cognitive changes. In contrast, for AD, anhedonia was probabilistically more likely to arise at later stages of the disease sequence, subsequent to cognitive decline.

DISCUSSION: These findings highlight consummatory anhedonia as an early, clinically informative marker of bvFTD and support the value of multidimensional hedonic assessment for improving dementia differentiation.},
}

@article {pmid42856984,
year = {2026},
author = {Ferreira, NV and Bertola, L and Paradela, RS and Ciciliati, AM and Silva, CM and Grinberg, LT and Pasqualucci, CA and Paes, VR and Ferriolli, E and Naslavsky, M and Leite, RP and Suemoto, CK},
title = {Social determinants of health modify the association of Alzheimer's disease pathology with cognitive abilities but not of apolipoprotein E-ε4 with Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70462},
pmid = {42856984},
issn = {2352-8729},
abstract = {INTRODUCTION: Apolipoprotein E (APOE) -ε4 and social determinants of health (SDoH) are major Alzheimer's disease (AD) risk factors, yet whether SDoH modify the relationship between APOE-ε4, AD pathology, and cognition remains unclear.

METHODS: Using Biobank for Aging Studies (BAS) data, we assessed APOE-ε4 using polymerase chain reaction (PCR), AD pathology using immunohistochemistry, and cognitive abilities using Clinical Dementia Rating - Sum of Boxes (CDR-SB).

RESULTS: In 1,193 individuals (mean [SD] age 73.4 [13.0] years; 50.1% women; 65.4% White), APOE-ε4 carriers had higher odds of AD pathology (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 2.85; 5.51; p < 0.001), and AD pathology was associated with poorer cognition (β = 8.07, 95% CI: 7.47; 8.67; p < 0.001). SDoH modified this pathology-cognition association (p = 0·002), which was stronger in the unfavorable (β = 9.09, 95% CI: 8.00; 10.19, p < 0.001) versus the favorable SDoH profile (β = 6.39, 95% CI: 5.42; 7.37; p < 0.001). SDoH did not modify the APOE-ε4-pathology association (p = 0.806), and no race effect modification was observed.

DISCUSSION: AD pathology was more strongly associated with poorer cognition in unfavorable SDoH profiles, highlighting SDoH as targets for AD prevention.},
}

@article {pmid42857015,
year = {2026},
author = {Zheng, Y and Hong, L and Wu, L and Chen, X and Hu, Q and Chen, L and Ni, X and Zhuang, X and Yin, L},
title = {Effects of 12-week 24-form Tai Chi on cognitive function, cerebral perfusion, and vascular function in postmenopausal women with mild cognitive impairment: an exploratory randomized controlled trial.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1880915},
pmid = {42857015},
issn = {1663-4365},
abstract = {BACKGROUND: Postmenopausal women are at increased risk of mild cognitive impairment (MCI). Vascular and cerebrovascular dysfunction may contribute to this increased vulnerability. Tai Chi has been shown to benefit cognitive function, but its effects on cerebrovascular health in this high-risk population remain poorly defined. This study aimed to evaluate the impact of a 12-week Tai Chi intervention on cognitive performance, cerebral perfusion, and circulating vasomotor and Alzheimer's disease (AD)-related biomarkers in postmenopausal women with MCI.

METHODS: This single-center, parallel-group, open-label exploratory randomized controlled trial was conducted from June 2023 to September 2024 in Fuzhou, China. Forty postmenopausal women with MCI were randomized in a 1:1 ratio using block randomization to either a 12-week supervised 24-form Tai Chi program or a health education control group. Primary and secondary outcomes included Montreal Cognitive Assessment (MoCA) total and domain-specific scores, cerebral blood flow in cognition-related brain regions, circulating vasomotor factors, and serum AD-related biomarkers.

RESULTS: Compared with the health education control group, the Tai Chi group showed greater improvement in MoCA total score (β = 4.95, p < 0.001) and in delayed recall (β = 1.50), visuospatial/executive function (β = 1.10), and attention (β = 1.05) (all p < 0.001). Tai Chi was also associated with greater increases in global and regional CBF, including a significant group-by-time interaction for global CBF (β = 15.29, p < 0.001), as well as increased plasma NO (β = 10.41, p < 0.001), a lower ET-1/NO ratio (β = -0.97, p = 0.004), and greater reductions in circulating T-tau (β = -255.45, p < 0.001), P-tau (β = -135.67, p < 0.001), and Aβ1-42 (β = -169.41, p < 0.001). No intervention-related adverse events occurred.

CONCLUSION: A 12-week program of standardized 24-form Tai Chi was associated with improvements in overall cognitive performance as assessed by the MoCA in postmenopausal women with MCI. These cognitive changes were accompanied by increased cerebral perfusion, a more favorable vasomotor profile, and reductions in circulating AD-related biomarkers. Tai Chi appears to be a feasible and well-tolerated non-pharmacological intervention for this vulnerable population.

CLINICAL TRIAL REGISTRATION: ChiCTR2300068871.},
}

@article {pmid42857127,
year = {2026},
author = {Green, ZD and O'Bryant, SE and Johnson, LA and Burns, JM and Vidoni, ED and Morris, JK},
title = {Metabolic dysfunction associates with neuroimaging measures of brain structure and connectivity.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1889255},
pmid = {42857127},
issn = {1662-4548},
abstract = {INTRODUCTION: Metabolic syndrome (MetS) and insulin resistance are established risk factors for Alzheimer's disease (AD) and have been linked to alterations in brain structure and function, including within the Default Mode Network (DMN).

METHODS: Here, we examined associations between metabolic dysfunction, brain structure, and DMN functional connectivity using data from the Health and Aging Brain Study: Health Disparities (HABS-HD) cohort. Participants were classified as being cognitively unimpaired (CU; n = 1,045; mean age = 66.1 years; 65% female), or having mild cognitive impairment (MCI; n = 186; mean age = 66.5 years; 52% female) or dementia (n = 76; mean age = 69.0 years; 47% female).

RESULTS: Across diagnostic groups, cortical thickness in AD-vulnerable regions varied by both cognitive status and HbA1c grouping, with the strongest effects observed in the CU cohort. HbA1c grouping was also associated with white matter microstructure, including stepwise reduc tions in fractional anisotropy of the anterior corona radiata across glycemic cat egories (normoglycemia > prediabetes > diabetes) in CU individuals. Functional connectivity of the posterior DMN (pDMN) showed main effects of both cognitive status and HbA1c grouping. Using a continuous index of cardiometabolic risk (MetS-Z), pDMN connectivity decreased linearly with increasing cardiometabolic burden in the CU cohort, whereas other DMN subnetworks exhibited positive associations with MetS-Z.

DISCUSSION: These findings suggest network-specific associations between cardiometabolic risk and DMN organization that are detectable in indi viduals with MCI, a clinical state preceding dementia, as well as in some degree within cognitively unimpaired individuals. Longitudinal analyses are needed to determine whether metabolic dysfunction predicts divergent trajectories of DMN connectivity over time.},
}

@article {pmid42857161,
year = {2026},
author = {Torrigiani, EG and Cianca, D and Gaetani, L and Nardi, G and Paolini Paoletti, F and Chiasserini, D and Parnetti, L and Gammaitoni, L and Neri, I and Bellomo, G},
title = {Application of unsupervised and supervised machine learning approaches to blood-based biomarkers of Alzheimer's disease in a memory clinic cohort.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1922577},
pmid = {42857161},
issn = {1663-4365},
abstract = {INTRODUCTION: Blood-based biomarkers (BBMs) are promising tools to facilitate biological diagnosis of Alzheimer's Disease (AD). Establishing reliable cutoffs for BBMs represents a major issue for real-world implementation and the investigation of combined BBM approaches is limited. Our aim is to test different machine learning (ML) models for BBMs interpretation with respect to established gold-standard in vivo biomarkers, i.e., cerebrospinal fluid (CSF) biomarkers, to enhance their standalone and combined diagnostic value for AD.

METHODS: We selected 434 patients who referred to Perugia University Hospital for perceived cognitive decline with available CSF A β 42/40, pTau181 and tTau and plasma Aβ42, Aβ40, pTau217, pTau181 and NfL. Multiple unsupervised clustering algorithms for cutoff determination and supervised classification models were compared for the prediction of AD defined by a CSF A[+]/T [+] profile.

RESULTS: Different unsupervised clustering models obtained cutoffs with high performances in predicting an AD CSF profile (accuracy > 0.85). Each combination of cutoffs was tested, the best ones achieving A[+]/T[+] CSF profile prevalences > 0.9 in BBM-positive subgroups. The best supervised ML models achieved accuracies up to 0.88 in 10-fold cross-validation.

DISCUSSION: Our results prove that clustering approaches can help in identifying reliable BBMs cutoffs for AD diagnosis even in the absence of CSF gold standard reference and that ML approaches combining multiple BBMs can strongly enhance their diagnostic accuracy.},
}

@article {pmid42857391,
year = {2026},
author = {Shankar, A and Kryza-Lacombe, M and Insel, PS and Harris, E and Kassel, MT and Goldstein, L and Krystal, AD and Landau, SM and Tosun, D and Butters, MA and Aisen, P and Raman, R and Toga, AW and Jack, CR and Nelson, JC and Mackin, RS},
title = {Depression severity and sleep efficiency's associations with amyloid burden are additive but dependent on underlying genetic risk in late life depression.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70478},
pmid = {42857391},
issn = {2352-8729},
abstract = {INTRODUCTION: Evidence linking late-life depression (LLD) to amyloid beta (Aβ) burden remains mixed, possibly in part due to limited examinations of the confounding role of comorbid sleep disturbance and the moderating role of the apolipoprotein E (APOE) ɛ4 gene.

METHODS: We analyzed 110 older adults (ages 65-88, 66% female) with LLD to jointly model depression severity and sleep disturbance's relationship with Aβ, and to examine the moderating role of APOE ɛ4 genotype.

RESULTS: Depression severity, sleep efficiency, and sleep duration did not demonstrate a direct relationship with Aβ; however, a significant APOE ɛ4 moderation effect occurred for depression severity and sleep efficiency. In APOE ɛ4 carriers only, higher depression severity and lower sleep efficiency were associated with greater total Aβ burden and indicated greater likelihood of reaching clinical cutoffs for amyloid positivity. The effects of depressive symptoms and sleep efficiency were statistically unique and additive. Exploratory analyses demonstrated APOE ɛ4 also moderated the effect of lifetime duration of untreated depression on increased Aβ.

DISCUSSION: Depression severity and sleep efficiency's relationship with Aβ may be dependent on the presence of the APOE ɛ4 allele. This, among other individual differences, may partially explain mixed findings examining LLD as a risk factor for Alzheimer's disease. Furthermore, these findings do not suggest that the relationship between depression severity and amyloid is explained by the confounding role of sleep duration or sleep efficiency.},
}

@article {pmid42857403,
year = {2026},
author = {Agosta, F and Cecchetti, G and Ghirelli, A and Spinelli, EG and Rugarli, G and Pisano, S and Coraglia, F and Gajate, AMS and Vezzulli, P and Calloni, S and Canu, E and Castelnovo, V and Gilioli, A and Tripodi, C and Freri, F and Bianchi, A and Panzacchi, A and Pepe, G and Falini, A and Chiti, A and Filippi, M},
title = {Residualized occipital amyloid burden and plasma biomarker profiles in relation to ARIA-E during anti-amyloid treatment.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70401},
pmid = {42857403},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid-related imaging abnormalities with edema (ARIA-E) represent the main safety concern of anti-amyloid monoclonal antibodies. Whether regional amyloid topology refines ARIA-E risk in real-world practice remains unclear.

METHODS: We analyzed 31 treatment courses in early Alzheimer's disease under European Medicines Agency labeling. Residualized occipital amyloid burden was defined as observed occipital standardized uptake value ratio (SUVR) minus occipital SUVR predicted from global composite SUVR in an expanded baseline positron emission tomography derivation sample (n = 53). Associations with ARIA-E and baseline plasma biomarkers were assessed.

RESULTS: ARIA-E occurred only in the elevated occipital amyloid group: 4/13 treatment courses, versus 0/18 low or comparable courses (Fisher exact p = 0.055). All ARIA-E events involved posterior regions. The elevated pattern showed higher baseline glial fibrillary acidic protein (GFAP), phosphorylated tau (p-tau)181, and p-tau217 levels, whereas amyloid beta 42/40 did not differ between groups. A GFAP + p-tau217 model showed exploratory discrimination of the elevated phenotype (area under the curve: 0.76).

DISCUSSION: Disproportionate occipital amyloid burden may identify a biologically vulnerable subgroup requiring validation in larger cohorts.},
}

@article {pmid42857419,
year = {2026},
author = {Ghirelli, A and Cecchetti, G and Spinelli, EG and Samanes Gajate, AM and Rugarli, G and Pisano, S and Zamboni, IAL and Canu, E and Castelnovo, V and Sibilla, E and Gilioli, A and Tripodi, C and Freri, F and Panzacchi, A and Pepe, G and Chiti, A and Filippi, M and Agosta, F},
title = {Regional amyloid-PET clearance dynamics and anti-Aβ monoclonal antibody therapy: a preliminary real-world study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70448},
pmid = {42857419},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) is the reference biomarker for treatment target engagement in anti-amyloid beta (Aβ) therapies in early symptomatic Alzheimer's disease (AD), yet global metrics may mask a regional heterogeneity of amyloid clearance.

METHODS: We report real-world longitudinal amyloid-PET data from 26 patients treated with lecanemab or donanemab for 6 months. Global Centiloids and regional standardized uptake value ratios (SUVRs) were quantified at baseline and 6 months and examined according to treatment, clinical diagnosis, and clinical stage.

RESULTS: Amyloid removal was regionally heterogeneous. Patients with mild cognitive impairment showed greater cortical amyloid reduction than those with mild dementia, while early- and late-onset AD exhibited comparable clearance. Frontal, anterior cingulate, and parietal regions showed the largest SUVR reductions, whereas the occipital cortex and temporal mesial cortex were consistently spared, including in patients reaching global amyloid-PET negativity.

DISCUSSION: Early amyloid clearance following anti-amyloid treatment is regionally heterogeneous and incompletely captured by global PET measures.},
}

@article {pmid42857445,
year = {2026},
author = {Ledesma-Aparicio, J and Caro-Gómez, LA and Padilla-Godínez, FJ and Hernández-González, O and Soto-Rojas, LO and Reyes-Grajeda, JP and Arias-Carrión, O and Palomero-Rivero, M and Bertrand, B and Munoz-Garay, C and Guerra-Crespo, M},
title = {Tau protein in Parkinson's disease: advances in phosphoproteomics and molecular dynamics simulations.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1841131},
pmid = {42857445},
issn = {1663-4365},
abstract = {Tau dysregulation, particularly abnormal phosphorylation, is increasingly implicated in Parkinson's disease (PD) and in the pathogenic interaction between Tau and α-synuclein. This review proposes an integrated PD-focused workflow connecting phosphoproteomic discovery, structural modeling, computational drug discovery, and experimental validation. Phosphoproteomic analyses of post-mortem brain tissue, biofluids, and patient-derived dopaminergic neuronal models can identify candidate Tau phosphosignatures associated with vulnerable brain regions, α-synuclein pathology, genetic background, or clinical progression. Molecular dynamics simulations can then evaluate how these signatures alter Tau conformation, microtubule binding, aggregation-prone motifs, membrane association, and pathogenic protein interactions. The resulting structural information can guide ensemble docking, chemoinformatics, and artificial intelligence approaches to prioritize conformer-selective ligands and regulatory targets. Candidate biomarkers should subsequently be validated in independent and longitudinal PD cohorts, whereas therapeutic candidates require mechanistic and functional validation in PD-relevant experimental models before clinical translation. This iterative framework may help distinguish mechanistically relevant Tau phosphoconformers from nonspecific phosphorylation changes, support biomarker-based patient stratification, and focus therapeutic development on structurally defined pathological states. Because much of the available structural evidence derives from Alzheimer's disease and other tauopathies, direct validation in PD remains essential. By linking PD-derived and disease-relevant molecular evidence with atomistic mechanisms and therapeutic prioritization, this workflow may support biomarker-informed strategies aimed at restoring Tau homeostasis and disrupting pathogenic Tau-α-synuclein interactions.},
}

@article {pmid42857586,
year = {2027},
author = {Zhang, Y and Li, H and Fan, Y},
title = {Discovering Heterogeneous Neurodegenerative Disease Patterns From MRI Data for Improved Prediction.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {16894},
number = {},
pages = {160-170},
pmid = {42857586},
abstract = {Neurodegenerative diseases exhibit substantial heterogeneity, complicating both diagnosis and prognosis. Identifying clinically meaningful subtypes is crucial for understanding disease mechanisms and improving diagnostic precision and prognostic accuracy. Existing subtyping approaches primarily rely on unsupervised learning of patient data for capturing inter-individual variability, but they may fail to uncover subtypes that are directly informative for diagnosis or prognosis. To address this limitation, we propose a novel mixture-of-experts (MoE) framework that integrates predictive modeling with subtype discovery. Unlike traditional subtyping methods, our approach learns a router to assign individuals to specialized expert networks, each corresponding to a distinct subtype, for improving predictive accuracy. By coupling subtype identification with prediction, the proposed MoE framework encourages the discovery of subtypes that are not only statistically distinct but also clinically informative. We evaluate the framework on a real-world dataset of mild cognitive impairment (MCI) subjects and a semi-simulated dataset, demonstrating superior performance in predicting progression from MCI to Alzheimer's disease while revealing distinct, clinically meaningful MCI subtypes. Code is available at https://github.com/Kateridge/MoESubtyping.},
}

@article {pmid42853241,
year = {2026},
author = {Mugikura, S and Mori, N and Satake, M and Chiba, I and Taira, M and Koyama, T and Onuma, T and Saito, T and Takase, M and N Motoike, I and Hidaka, T and Otsuki, A and Orui, M and Obara, T and Nagami, F and Nakaya, N and Ogishima, S and Kumada, K and Katsuoka, F and Koshiba, S and Taki, Y and Shimizu, R and Kuriyama, S and Ohneda, K and Izumi, Y and Fuse, N and Hozawa, A and Kinoshita, K and Yamamoto, M},
title = {Accelerated hippocampal atrophy in APOE ε4 homozygotes and females: Longitudinal findings from the Tohoku Medical Megabank MRI study.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42853241},
issn = {1432-1920},
support = {JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; 24K06543, 25K10609//JSPS KAKENHI/ ; 24K06543, 25K10609//JSPS KAKENHI/ ; JP 25tm0524003h0003//Medical Research and Development (AMED)/ ; JP23dm0307003h0006//Medical Research and Development (AMED)/ ; },
abstract = {PURPOSE: The apolipoprotein E ε4 allele is a major genetic risk factor for Alzheimer's disease, but its longitudinal effect on hippocampal atrophy is unclear. Selective hippocampal atrophy, defined as greater hippocampal volume (HpV) loss relative to total brain volume (TBV), is an early marker of preclinical Alzheimer's disease. We examined age-related effects of APOE ε4 on longitudinal hippocampal atrophy in a large population-based cohort.

METHODS: We analyzed MRI data from 9,453 adults in the Tohoku Medical Megabank MRI Study, including 5,774 participants with follow-up MRI after a mean interval of 4.7 years. Cross-sectional analyses used linear regression to assess HpV and TBV, adjusting for age, sex, APOE genotype, and intracranial volume. Longitudinal analyses assessed HpV-Ratio and TBV-Ratio, defined as the second MRI volume divided by the first volume, using regression models including age, sex, APOE genotype, MRI interval, and interaction terms between age and APOE genotype and between age and sex. Montreal Cognitive Assessment (MoCA) scores obtained at the second MRI were included to assess effects independent of cognition.

RESULTS: No significant APOE genotype effects were observed in cross-sectional analyses. Longitudinally, ε4/ε4 carriers showed greater decline in HpV-Ratio than ε3/ε3 and ε3/ε4 carriers, and females showed lower HpV-Ratio than males. No APOE genotype or sex main effects were observed for TBV-Ratio. Interactions between age and APOE genotype and between age and sex demonstrated age-related acceleration of HpV-Ratio decline in ε4/ε4 carriers and females, and these effects persisted after adjustment for MoCA scores.

CONCLUSION: APOE ε4 homozygosity and female sex accelerate selective hippocampal atrophy in population-based cohorts.},
}

@article {pmid42853245,
year = {2026},
author = {Wang, D and Weedor, JG and Weah, NM and Koda, S and Quayon, CM and Pan, W and Yu, Y},
title = {The ACOD1-itaconate axis in anti-neuroinflammation and protection against neurodegenerative diseases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261495587},
doi = {10.1177/13872877261495587},
pmid = {42853245},
issn = {1875-8908},
abstract = {Chronic neuroinflammation mediated by activated microglia constitutes a central pathogenic mechanism underlying neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Despite substantial progress in elucidating disease mechanisms, effective disease-modifying therapies remain elusive. Recent investigations have identified the aconitate decarboxylase 1 (ACOD1)-itaconate axis, a mitochondrial enzyme-metabolite pathway, as a critical immunometabolic checkpoint that regulates inflammation across diverse pathological contexts. This pathway exerts immunomodulatory effects through multiple mechanisms, including succinate dehydrogenase inhibition, nuclear factor erythroid 2-related factor 2 activation via Kelch-like ECH-associated protein 1 alkylation, and suppression of the NOD-like receptor protein 3 inflammasome. Emerging evidence has demonstrated that ACOD1-derived itaconate and its cell-permeable derivatives modulate neuroinflammation, preserve synaptic integrity, and ameliorate cognitive deficits in preclinical models of neurodegenerative diseases. This review critically synthesizes current evidence on the ACOD1-itaconate axis in central nervous system pathology, with particular emphasis on its roles in AD, PD, MS, and metabolic cognitive dysfunction. We further summarize the mechanistic insights and therapeutic potential of targeting this pathway in neuroinflammation-driven cognitive impairment. Additionally, this review uniquely integrates infection-induced and diet-induced cognitive impairment models and provides a critical perspective on translating this pathway from the bench to the bedside.},
}

@article {pmid42853248,
year = {2026},
author = {Low, S and Zheng, H and Moh, A and Liu, JJ and Liu, S and Ang, K and Lim, Z and Tang, WE and Sum, CF and Subramaniam, T and Lim, SC},
title = {Association between urinary metabolomics and cognitive performance in Asians with type 2 diabetes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493174},
doi = {10.1177/13872877261493174},
pmid = {42853248},
issn = {1875-8908},
abstract = {BackgroundThere is an ongoing quest for novel biomarkers which may serve as therapeutic targets in cognitive impairment, alongside a growing appreciation of urinary metabolomics as a promising non-invasive approach to identify metabolic signature of Alzheimer's disease and other causes of dementia.ObjectiveWe studied whether urine metabolomics were associated with mild cognitive impairment (MCI) and cognitive performance in a diabetic milieu.MethodsWe implemented a cross-sectional study on 1053 patients who had Type 2 diabetes (T2D). Urinary metabolites were quantitated by nuclear magnetic resonance (NMR). We evaluated cognitive performance by administering Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Criteria for mild cognitive impairment (MCI) were met if patients scored > 1.5 standard deviations (SDs) less than the mean RBANS score for total index or any of the cognitive domains.ResultsThe average age was 65.1 ± 7.9. Four metabolites were associated with RBANS total score after multiple testing correction by Benjamini-Hochberg (BH) procedure in the adjusted analyses: sucrose (β = -1.17 (95%CI -1.71, -0.62)), 4-hydroxyhippurate (β = -0.92 (-1.42, -0.42)), trans-aconitate (β = -0.93 (-1.46, -0.40)), and tryptophan (β = -0.82 (-1.33, -0.32)). Sucrose was associated with MCI (OR = 2.19 (1.44, 3.32). Sucrose, trans-aconitate, 4-hydroxyhippurate, and 4-deoxythreonate were associated with delayed memory. Hypoxanthine, sucrose and tryptophan were related to visuo-spatial/constructional function.ConclusionsOur study identified several urinary metabolites which were differentially linked to cognitive performance in T2D. Future investigations are warranted to confirm the findings.},
}

@article {pmid42853249,
year = {2026},
author = {Kim, H and Kim, J and Choi, H and Kim, YS},
title = {Benzodiazepine use, incident dementia and Alzheimer's disease, and progression to severe dementia: A nationwide Korean cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261492672},
doi = {10.1177/13872877261492672},
pmid = {42853249},
issn = {1875-8908},
abstract = {BackgroundThe association between benzodiazepine (BZD) use and dementia risk remains controversial owing to conflicting observational findings and incomplete adjustment for confounders.ObjectiveTo examine the association between BZD use and incident dementia, including Alzheimer's disease (AD), and to determine whether BZD use accelerates progression to severe dementia, using nationwide claims data with detailed comorbidity adjustment.MethodsWe conducted a matched cohort study using Korean National Health Insurance Service data, comparing 132,805 BZD users with 132,805 age- and sex-matched controls. Incident dementia (AD [F00], vascular dementia [F01], and other subtypes) was defined by ≥3 diagnostic claims within one year, and severe cases by national special-registration codes. Hazard ratios (HRs) were estimated using Cox models adjusted for the Charlson Comorbidity Index (CCI) and clinical covariates.ResultsDementia incidence was 382.4/100,000 person-years in BZD users versus 280.7 in controls. BZD users had higher multimorbidity (CCI ≥7: 42.5% versus 26.5%) and psychiatric comorbidity (e.g., anxiety disorders: 42.6% versus 2.7%). After full adjustment, the HR for overall dementia attenuated from 1.43 to 1.15 (95% CI, 1.09-1.22), with similar attenuation for AD and severe dementia. The risk of progression from dementia to severe dementia was not increased among BZD users (adjusted HR, 0.98; 95% CI, 0.84-1.14), with no dose- or duration-response observed.ConclusionsBZD use showed only a modest association with incident dementia, largely attributable to the higher multimorbidity burden among users, and was not associated with accelerated progression to severe dementia.},
}