@article {pmid42602204,
year = {2026},
author = {Wang, H and Zhang, X},
title = {Bridging the islands of innovation: A machine-assisted Semantic-Bibliometric review and conceptual roadmap for closed-loop digital dementia care.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261479403},
pmid = {42602204},
issn = {2055-2076},
abstract = {BACKGROUND: Artificial intelligence (AI), extended reality (XR), and socially assistive robotics (SAR) are each advancing Alzheimer's disease (AD) research and care at a rapid pace. Yet despite substantial progress within each domain, clinical implementation remains weakly integrated across diagnostic, therapeutic, and care functions, producing islands of innovation rather than coordinated care systems.

METHODS: We conducted a machine-assisted semantic-bibliometric synthesis of 2,636 publications on AI-, immersive technology/VR-, and SAR-enabled approaches to AD diagnosis, intervention, and care published between 2021 and 2025. Available title-abstract metadata were encoded using SBERT embeddings, projected via UMAP, and clustered using K-Means to characterize the functional topology of the field. From this mapped corpus, we selected a semantically central subset of 50 studies for high-fidelity full-text synthesis, preserving cross-domain representativeness while maintaining interpretive tractability.

RESULTS: The mapped landscape suggests a three-part pattern of architectural separation. Precision neuroimaging (Cluster C4, 22%) functions primarily as a state-oriented diagnostic domain. Immersive therapeutics (Cluster C2, 48%), the largest cluster, increasingly incorporate adaptive personalization but remain weakly connected to biomarker-based stratification. Embodied robotic care (Cluster C5, 10%) addresses behavioral stabilization with little longitudinal coupling to upstream sensing. Across all three domains, high component-level sophistication coexists with limited evidence of cross-layer coordination.

CONCLUSION: Contemporary digital solutions for AD remain predominantly siloed and state-oriented rather than longitudinally integrated. We synthesize these observations into a conceptual Closed-Loop Architecture, proposed as a roadmap for future integrated digital dementia care. Advancing this agenda will depend on interoperable infrastructure, longitudinal modeling, and prospective cross-layer evaluation-not solely on further isolated gains in classification accuracy.},
}

@article {pmid42602264,
year = {2026},
author = {Tarbiat, S and Kantarci-Carsibasi, N},
title = {Dual inhibitory potential of N-methylcytisine against GSK-3β and AChE: implications for Alzheimer's disease treatment.},
journal = {Open life sciences},
volume = {21},
number = {1},
pages = {20251363},
pmid = {42602264},
issn = {2391-5412},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and irreversible cognitive decline. Glycogen synthase kinase 3β (GSK-3β) is significant in tau hyperphosphorylation and neurodegeneration. The cholinergic hypothesis of AD links cognitive impairment to reduced synaptic acetylcholine (ACh). Increased acetylcholinesterase (AChE) activity exacerbates this issue. To search for a potential dual GSK-3β/AChE inhibitor, we focused on N-methylcytisine. This natural cytisine-derived alkaloid has not been studied for its various biological effects on the prevention of AD. The in vitro results indicated that N-methylcytisine displayed promising activity against GSK-3β and AChE with IC50 values of 11 and 22.7 µM, respectively. GSK-3β kinetic study according to the varying substrate or ATP concentrations at different N-methylcytisine levels revealed mixed-type inhibition. The results of the integrated in silico workflow indicate that N-methylcytisine exhibited favorable binding to AChE (docking score -9.6 kcal/mol; MM-GBSA -70.2 kcal/mol), comparable to the reference inhibitor galantamine (-10.8 kcal/mol; -70.6 kcal/mol). In contrast, its interaction with GSK-3β was more moderate (-5.3 kcal/mol; -50.3 kcal/mol) relative to staurosporine (-8.5 kcal/mol; -82.6 kcal/mol), consistent with its smaller scaffold. Overall, the results support a flexible, mixed-type interaction profile and highlight N-methylcytisine as a promising dual-acting candidate for Alzheimer's disease.},
}

@article {pmid42602282,
year = {2026},
author = {Gu, J and Chen, Z and He, Z},
title = {Refining genetic discoveries of group knockoffs via a feature-level filter.},
journal = {Journal of the Royal Statistical Society. Series C, Applied statistics},
volume = {75},
number = {4},
pages = {1067-1090},
pmid = {42602282},
issn = {0035-9254},
abstract = {Identifying variants that carry substantial information on the trait of interest remains a core topic in genetic studies. In analysing the EADB-UKBB dataset to identify genetic variants associated with Alzheimer's disease (AD), however, we recognize that both existing marginal association tests and conditional independence tests using existing knockoff filters suffer either power loss or lack of informativeness, especially when strong correlations exist among variants. To address these limitations, we propose a new feature-versus-group (FVG) filter that seeks balance between the power and precision in identifying important features from a set of strongly correlated features using group knockoffs. In extensive simulation studies, the FVG filter controls the expected proportion of false discoveries and identifies important features in smaller catching sets without large power loss. Applying the proposed method to the EADB-UKBB dataset, we discover important variants from 89 loci (similar to the most powerful group knockoff filter) with catching sets of substantially smaller size and higher purity and verify the biological informativeness of our discoveries.},
}

@article {pmid42602355,
year = {2026},
author = {Yang, G and Xu, X and Xu, Y},
title = {TREM2 as a central immunometabolic hub in Alzheimer's disease: linking microglial states, lipid stress, and disease-stage-specific intervention.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1893545},
pmid = {42602355},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/pathology ; *Receptors, Immunologic/metabolism/genetics/immunology ; *Microglia/metabolism/immunology ; *Membrane Glycoproteins/metabolism/genetics/immunology ; Animals ; *Lipid Metabolism ; Signal Transduction ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial function in Alzheimer's disease (AD) and other neurodegenerative disorders. Genetic studies have identified rare coding variants in TREM2 as significant risk factors for late-onset AD (LOAD), highlighting the importance of disrupted microglial signaling in disease pathogenesis. Biochemically, TREM2 acts as a receptor for lipid- and damage-associated molecular patterns, recognizing anionic phospholipids, myelin-derived lipids, apolipoproteins, and aggregated amyloid-β (Aβ). It engages with adaptors like DAP12 and DAP10, activating key signaling pathways, including SYK, PI3K-AKT-mTOR, and PLCγ2, leading to microglial transcriptional and metabolic reprogramming. These processes are essential for the transition of microglia to disease-associated microglia (DAM), influencing amyloid plaque compaction and tau pathology propagation. This review aims to synthesize the latest insights into TREM2 biology, focusing on the role of TREM2 in microglial state transitions, lipid metabolism, and myelin turnover. It also examines the pathophysiological relevance of soluble TREM2 (sTREM2) and AD-associated TREM2 variants. Furthermore, the review explores the therapeutic potential of targeting TREM2, including strategies based on agonistic antibodies and modulation of receptor shedding. Beyond prior descriptive summaries, we organize these findings within a stage-resolved immunometabolic framework that links disease timing, lipid-stress context, and microglial state transitions. This framework is intended to explain why similar TREM2-directed interventions may yield different outcomes across disease stages and pathology compositions. We further highlight stage-specific translational logic, including biomarker-informed (e.g., sTREM2-guided) stratification and monitoring, to support testable and clinically actionable trial designs.},
}

Humans
*Alzheimer Disease/metabolism/immunology/pathology
*Receptors, Immunologic/metabolism/genetics/immunology
*Microglia/metabolism/immunology
*Membrane Glycoproteins/metabolism/genetics/immunology
Animals
*Lipid Metabolism
Signal Transduction

@article {pmid42602413,
year = {2026},
author = {Kim, JW and Yeldesbay, A and Kehm, C and Fassbender, RV and Onur, OA and Rosjat, N and Fink, GR and Daun, S},
title = {Microstates and connectivity states reveal task-related network reorganization in Alzheimer's disease patients.},
journal = {Clinical neurophysiology practice},
volume = {11},
number = {},
pages = {664-676},
pmid = {42602413},
issn = {2467-981X},
abstract = {OBJECTIVE: Microstates derived from EEG amplitude and connectivity states from EEG phase examine distinct aspects of the brain's dynamic organization. However, it is unclear how sensitive they are to changes in functional connectivity in Alzheimer's disease (AD). We examined pre- and post-task alterations of brain activity in AD patients to compare the ability of microstates and connectivity states to capture disease-related network dysfunction.

METHODS: Resting-state EEG (RS-EEG) was recorded before and after a memory task in fifteen patients with AD and fifteen healthy controls. During the memory task, either low-intensity repetitive transcranial magnetic stimulation (rTMS) over the parieto-occipital region or sham stimulation was applied. We quantified microstates and phase-based connectivity states in the alpha frequency range from the RS-EEG.

RESULTS: While microstates showed task-related alterations in healthy controls only, connectivity states were more sensitive to alterations in the AD group. rTMS appeared to reduce these task-related alterations in connectivity states. Connectivity states indicated a shift towards lower, more diffuse connectivity in AD patients. Connectivity states were correlated with memory task performance and amyloid-beta levels in the AD group.

CONCLUSIONS: Connectivity states indicated decreased task-related network stability in AD patients, which correlated with memory task performance. The findings support the neural efficiency hypothesis, which states that more efficient brain network optimization during tasks is linked to better performance.

SIGNIFICANCE: Given the progressive decline of alpha power in AD patients, phase-based connectivity states provide valuable complementary information to microstates and may serve as a biomarker for assessing large-scale network alterations in relation to disease progression.},
}

@article {pmid42602524,
year = {2026},
author = {Dwivedi, AK and Imbimbo, BP and Abanto, J and Espay, AJ},
title = {Comparison of double-blind and open-label decline rates in lecanemab and donanemab trials in Alzheimer's disease.},
journal = {BMJ neurology open},
volume = {8},
number = {2},
pages = {e001649},
pmid = {42602524},
issn = {2632-6140},
abstract = {BACKGROUND: Phase 3 trials of the anti-amyloid monoclonal antibodies lecanemab and donanemab in Alzheimer's disease demonstrated modest slowing of cognitive decline over 18 months. Subsequent open-label extensions (OLE) suggested greater long-term benefit based on comparisons with historical untreated cohorts, which are vulnerable to selection and attrition bias.

METHODS: We simulated longitudinal Clinical Dementia Rating-Sum of Boxes trajectories using mixed-effects models calibrated to reproduce published means, variances and attrition patterns from the Clarity-AD and TRAILBLAZER-ALZ 2 trials, separately for early- and delayed-start cohorts and in combined analyses. Observed annualised slopes were also directly compared between double-blind (DB) and OLE phases. Placebo effects were estimated by comparing DB placebo arms with matched untreated historical cohorts derived from published natural history data.

RESULTS: Simulations closely reproduced reported trajectories. In both trials, the early-start cohorts showed significantly faster annualised decline during OLE than during DB treatment (lecanemab ∆=0.53; 95% CI 0.40 to 0.66; donanemab ∆=0.66; 95% CI 0.41 to 0.91), whereas delayed-start cohorts showed no meaningful phase-related differences. OLE decline rates approximated those observed in DB placebo groups. In the lecanemab trial, DB placebo participants declined more slowly than matched untreated controls; decline in the donanemab trial varied by baseline severity.

CONCLUSIONS: Despite selective retention favouring slower progressors, both lecanemab and donanemab accelerated cognitive decline during OLE phases and paralleled placebo-level declines.},
}

@article {pmid42602880,
year = {2026},
author = {Murugadoss, K and Venkatakrishnan, AJ and Soundararajan, V},
title = {GLP-1-based incretin therapy is associated with lower incident Alzheimer's disease and cardiorenal events in adults with documented neuropsychiatric, cognitive, or sensory risk.},
journal = {Biology methods & protocols},
volume = {11},
number = {1},
pages = {bpag043},
pmid = {42602880},
issn = {2396-8923},
abstract = {Alzheimer's disease (AD) develops over years, creating an opportunity for interventions that target modifiable risk factors before the onset of clinical dementia. Here we applied a federated electronic health record (EHR) system encompassing over 29 million de-identified patients toward a target-trial emulation framework involving 153,412 adults aged 50 years or older with at least one documented AD risk factor. New users of glucagon-like peptide-1 (GLP-1)-based incretin therapy were compared with new users of non-GLP-1 antidiabetic medications after a 12-month washout, with 1:1 propensity-score matching on 30 baseline variables and additional exact matching on index year of therapy initiation and 5-year age band. In the primary matched cohort, 28,901 patients per arm, incretin initiation was associated with lower first recorded AD diagnosis (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.29-0.73, q = 0.003), all-cause dementia (HR 0.66 [0.55-0.79], q < 0.001), and all-cause mortality (HR 0.46 [0.37-0.58], q < 0.001), with directionally-lower Mild Cognitive Impairment (HR 0.76 [0.61-0.94], q = 0.135) and Alzheimer's-related medication initiation (HR 0.82 [0.65-1.03], q = 0.217). The AD diagnosis mitigation signal was independently reproduced for semaglutide (HR 0.56; N = 23,675 per arm; q = 0.02), with the directionally consistent tirzepatide point estimate (HR 0.60) not reaching significance. GLP-1 RA initiation was also associated with substantially lower (all q < 0.001) incidence of heart failure (HR 0.50 [0.45-0.55]), cardiomyopathy (HR 0.38 [0.31-0.47]), major adverse cardiovascular events (HR 0.74 [0.67-0.82]), acute kidney injury (HR 0.67 [0.67-0.74]), and chronic kidney disease (HR 0.68 [0.62-0.75]). Negative-control outcomes showed no significant separation (all q > 0.45), including allergic rhinitis (HR 0.96 [0.87-1.07]), hemorrhoids (HR 1.07 [0.95-1.21]), and inguinal hernia (HR 1.39 [0.89-2.18]). Stricter two-code ICD definitions supported lower first recorded AD diagnosis in the incretin arm (HR 0.51 [0.29-0.89], q = 0.018) and lower first recorded all-cause dementia diagnosis (HR 0.68 [0.54-0.85], q = 0.003). In 12-month landmark analyses among semaglutide initiators, ≥5% weight-loss responders had lower 3-year AD cumulative incidence than non-responders after matching (0.07% vs. 0.40%; incidence ratio 5.76; P = .036), although this was not significant in the hazard-ratio model (HR 0.54, P = .39). Sustained-dose stratification showed no comparable gradient (high-dose vs. low-dose 0.30% vs. 0.14%; HR 2.77; P = .38), with ≤12 AD events per group. The weight-loss-specific pattern did not extend to all-cause dementia: weight-loss responders and non-responders had similar 3-year cumulative incidence (1.54% vs. 1.70%; HR 0.87, P = .53). Initiation of GLP-1 receptor agonist therapy in adults with documented AD risk factors was associated with lower recorded incidence of AD, dementia, mortality, and multiple cardiovascular and renal outcomes in this observational target-trial emulation. These findings support the hypothesis that earlier incretin therapy may contribute to AD risk modification through upstream cardiometabolic pathways, while prospective randomized prevention studies will be required to determine causality, underlying biological mechanisms, and optimal treatment timing.},
}

@article {pmid42602999,
year = {2026},
author = {Rauhala, E and Johansson, J and Karrasch, M and Eskola, O and Tolvanen, T and Rajander, J and Rinne, JO},
title = {Change in brain glucose metabolism and cognition in amnestic MCI patients in relation to amyloid accumulation: A 3-year follow-up study.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100165},
pmid = {42602999},
issn = {2589-9589},
abstract = {Our aim was to investigate the change in brain glucose metabolism with [[18]F]fluorodeoxyglucose positron emission tomography ([[18]F]FDG PET) in amyloid beta positive and negative amnestic mild cognitive impairment (aMCI) patients. We investigated associations between change in [[18]F]FDG uptake and cognitive functioning in aMCI patients over up to 3 years. Twenty patients underwent [[18]F]FDG PET (15 men and 5 women, mean age 73.0 years, SD 6.3 at baseline) within a short time interval from [[18]F]Flutemetamol PET. The patients were classified as amyloid positive vs. negative based on the amyloid PET marker [[18]F]Flutemetamol uptake. Patients were examined with brain MRI and cognitive tests at baseline and after 3-year follow-up or earlier if the patient had converted to probable Alzheimer's disease. [[18]F]FDG data was analysed with automated region-of-interest analysis and voxel-based statistical parametric mapping (SPM). [[18]F]FDG uptake nor change of [[18]F]FDG uptake over time differed between amyloid positive and negative groups. However, the amyloid positive patients exhibited significant decline in MMSE scores over three years while the amyloid negative patients maintained stable MMSE level over time. The amyloid positive group had poorer episodic memory scores at baseline and follow-up, and significantly slower processing speed at follow-up as well as significantly more negative change over time in language functions compared to amyloid negative patients. Moreover, we found that [[18]F]FDG uptake was positively associated with cognition in the whole aMCI patient group. Together, our results suggest that brain glucose metabolism in aMCI is independent of amyloid pathology, and probably reflects other brain degenerative processes.},
}

@article {pmid42603243,
year = {2026},
author = {Anwer, T and Verma, A and Asiri, A and Alaklobie, M and Albaqami, A and Alshahrani, F and Aly, K and Sharma, M and Siddiqui, S and Alam, N and Alam, MF},
title = {Restoration of Neuronal Metabolism and Memory in Alzheimer's Disease by Reprogramming the Exosomal microRNA Network.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42603243},
issn = {1559-1166},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; *Exosomes/metabolism/genetics ; Animals ; *Neurons/metabolism ; Neuronal Plasticity ; *Memory ; },
abstract = {Historically the development of amyloid-β plaques and tau neurofibrillary tangles have been used as the hallmarks of Alzheimer's disease (AD). However, there is increasing evidence suggests that these pathological hallmarks are secondary to deeper metabolic defect in the brain. AD is progressively being recognized as a metabolic synaptic disorder characterized by insulin resistance, impaired cellular energy homeostasis, mitochondrial dysfunction, and synaptic degeneration. Synaptic plasticity is closely linked to the insulin-sensitive system of glucose utilization, mitochondrial activity, and local protein synthesis that render the synapses highly sensitive to the malfunction of the metabolic system. Recent discoveries highlight the important role of exosomes in mediating communication between neural cells by transferring regulatory miRNAs across neuronal networks. Exosomal miRNAs regulate insulin signaling, synaptic gene expression, mitochondrial function, and neuroinflammation. In AD, exosomal miRNA profiles are significantly altered, with enrichment of miR-29, miR-34a, miR-146a, and miR-21, alongside depletion of synapse-supporting miR-132. These changes contribute to insulin resistance, impaired glucose transporter trafficking, dendritic spine destabilization, and reduced expression of synaptic proteins such as PSD-95 and synaptophysin, ultimately leading to cognitive decline. Importantly, neuron-derived exosomes can cross the blood-brain barrier, making their miRNA cargo promising biomarkers and therapeutic targets for early AD diagnosis and precision treatment.},
}

Humans
*Alzheimer Disease/metabolism/genetics
*MicroRNAs/metabolism/genetics
*Exosomes/metabolism/genetics
Animals
*Neurons/metabolism
Neuronal Plasticity
*Memory

@article {pmid42603367,
year = {2026},
author = {Besser, LM and Mitsova, D and Carmichael, O and Bateman, JR and Lovasi, GS and Tourelle, M and Galvin, JE and Chang, LC and DeCarli, C and Morris, JC and Meyer, OL},
title = {Neighborhood greenspace and brain imaging outcomes in older adults without dementia from three US Alzheimer's Disease Research Centers.},
journal = {Health & place},
volume = {101},
number = {},
pages = {103731},
doi = {10.1016/j.healthplace.2026.103731},
pmid = {42603367},
issn = {1873-2054},
abstract = {Although mounting evidence supports that neighborhood greenspaces (e.g., trees and parks) may benefit cognitive health in older age, fewer studies have investigated benefits to brain health measured via magnetic resonance imaging (MRI). We used data on 892 older adults without dementia from three Alzheimer's Disease Research Centers, examining whether neighborhood greenspace (i.e., greenness and percentage park space) is associated with white matter hyperintensity (WMH) and hippocampal volumes from MRI. We also examined whether associations varied by sex, racial group, urbanicity, or apolipoprotein E genotype (genetic risk factor for Alzheimer's disease). Linear regression models that accounted for neighborhood clustering controlled for demographics, research center, cognitive function, neighborhood deprivation, and comorbidities (e.g., hypertension, diabetes, obesity). Interaction terms (e.g., greenness×sex) were added to the models to evaluate potential effect modification. Living in greener neighborhoods was associated with fewer WMH and greater hippocampal volume in the overall sample. In stratified analyses, the beneficial greenness-WMH association was restricted to Black (not White) participants (i.e., significant interaction). In contrast, an adverse association between park space and lower hippocampal volumes was detected among Black (not White) participants (i.e., significant interaction). Overall, this study suggests associations between living in neighborhoods with more greenspace and MRI biomarkers of lower cerebrovascular and dementia risk, although results were mixed for Black individuals. Our findings need replication in other cohorts that are ethnoracially diverse and that represent different geographic regions, and future studies are needed explain the counterintuitive associations between park space and hippocampal volume among Black older adults.},
}

@article {pmid42603521,
year = {2026},
author = {Ma, J and Hua, Z and Zhao, B and Xu, J and Bao, K and Guo, R},
title = {Generation of a human induced pluripotent stem cell line (HEBHMUi019-A) from a 67-year-old male Alzheimer's patient with APOE-ε4/ε4 genotype.},
journal = {Stem cell research},
volume = {95},
number = {},
pages = {104082},
doi = {10.1016/j.scr.2026.104082},
pmid = {42603521},
issn = {1876-7753},
abstract = {Apolipoprotein E (apoE), encoded by the polymorphic APOE gene, plays a key role in lipid transport and metabolism. The three major APOE alleles are ε2, ε3, and ε4, with ε4 being the strongest genetic risk factor for late-onset Alzheimer's disease. We generated human induced pluripotent stem cells from peripheral blood mononuclear cells of a 67-year-old male patient with Alzheimer's disease carrying the APOE ε4/ε4 genotype. The generated cell line displayed typical iPSC morphology, a normal karyotype, trilineage differentiation potential, and pluripotency-marker expression, providing a resource for investigating APOE ε4-associated disease mechanisms and preclinical therapeutic screening.},
}

@article {pmid42603526,
year = {2026},
author = {Wang, M and Guo, M and Li, S and Song, L and Wu, M and Zhao, J and Xu, T and Zhou, Y},
title = {Kaempferol attenuates microglial activation in Alzheimer's disease via inhibiting the cytosolic HK2-mediated NF-κB signaling pathway.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {160},
number = {},
pages = {158708},
doi = {10.1016/j.phymed.2026.158708},
pmid = {42603526},
issn = {1618-095X},
abstract = {INTRODUCTION: Kaempferol (KAE), a natural flavonoid with substantial anti-inflammatory activity, has demonstrated efficacy against Alzheimer's disease (AD). However, the fundamental mechanisms are not yet fully understood.

OBJECTIVES: The objective of this study was to elucidate the role of KAE in alleviating microglia-mediated neuroinflammation in AD and its underlying mechanisms.

METHODS: The 3 × Tg-AD mice and LPS-stimulated BV2 microglial cells were employed as in vivo and in vitro model respectively. The HK-TAT peptide was utilized to induce mitochondrial dissociation of HK2, and 3-BP was applied as a HK2 inhibitor. Transcriptomic and metabolomic analyses were performed to discover the inhibitory effect of KAE on HK2. Immunofluorescence and Western blotting were employed to explore the suppressive role of KAE in cytosolic HK2-mediated NF-κB signaling. Additionally, the interaction between KAE and HK2 was investigated through molecular docking, validated by SPR, and confirmed via CETSA.

RESULTS: Our findings demonstrated that KAE significantly attenuated LPS-induced microglial activation, along with the release of pro-inflammatory factors and enhanced glycolytic activity. In vivo, KAE partially rescued cognitive impairment and neuronal damage in 3 × Tg-AD mice. Microglial activation was also markedly suppressed. Mechanistically, we revealed that dissociation of HK2 from mitochondria to the cytosol was sufficient to induce microglial activation, and this process was consequently constrained by the suppression of HK2 level and activity using 3-BP. By reducing HK2 levels, KAE suppressed cytosolic HK2-mediated IκBα phosphorylation and subsequent nuclear translocation of NF-κB. Furthermore, KAE not only downregulated HK2 transcription but also bound to HK2, promoting its ubiquitination-mediated degradation.

CONCLUSION: Our data indicate that KAE alleviates microglia-mediated neuroinflammation in AD, which correlates with the suppression of HK2 and the modulation of cytosolic HK2-dependent NF-κB activation.},
}

@article {pmid42603539,
year = {2026},
author = {Dişli, A and Tan, B and Adem, Ş and Akdoğan, N and Rawat, R and Eyüpoğlu, V},
title = {Phenothiazine-tetrazole hybrids as potent cholinesterase inhibitors: Integrated experimental and computational insights for Alzheimer's therapy.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110350},
doi = {10.1016/j.bioorg.2026.110350},
pmid = {42603539},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal loss and cognitive decline. A key pathological feature of AD is the reduction of acetylcholine (ACh) levels resulting from the enzymatic activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Therefore, inhibition of these enzymes remains a well-established therapeutic strategy for AD management. In this study, a novel series of phenothiazine-tetrazole hybrids was designed and synthesized as potential cholinesterase inhibitors. Their inhibitory activities against AChE and BChE were evaluated in vitro, and IC50 values were determined in the micromolar range. Among the tested derivatives, Compound E3a (IC50 = 10.664 μM) and Compound E5b (IC50 = 10.315 μM) exhibited the strongest AChE inhibition, whereas Compound D5b showed the highest activity toward BChE (IC50 = 18.734 μM). Enzyme kinetic analysis revealed that E5b and E3a act as competitive AChE inhibitors, with Ki values of 1.313 ± 0.032 μM and 1.520 ± 0.033 μM, respectively. To elucidate the molecular basis of inhibition, molecular docking studies were performed, followed by 500 ns molecular dynamics simulations, MM-PBSA binding free energy calculations, and free energy landscape analyses. The computational results revealed that Compound E3a forms a more dynamically and thermodynamically stabilized complex with AChE, primarily driven by favorable van der Waals interactions. ADMETlab 3.0 predictions further indicated acceptable preliminary drug-like features, although lipophilicity, solubility, CYP liability, and toxicity-related endpoints require further optimization and experimental validation. Collectively, these findings highlight phenothiazine-tetrazole hybrids as promising scaffolds for the rational development of next-generation cholinesterase inhibitors for Alzheimer's therapy.},
}

@article {pmid42603633,
year = {2026},
author = {Choi, HS and Jeon, SH and Liu, H and Kim, M and Yu, JS and Yoo, SS and Son, DJ and Han, SB and Yeo, IJ and Lim, SC and Hong, JT},
title = {p53 deficiency increases vulnerability to chronic stress-induced anxiety- and depression-like behaviors: Role of calcium dysregulation and BDNF signaling.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116437},
doi = {10.1016/j.bbr.2026.116437},
pmid = {42603633},
issn = {1872-7549},
abstract = {The tumor suppressor protein p53 is a known modulator of neurodegenerative disease (ND) processes. Although p53 expression is increased in the brains of patients with Alzheimer's disease, Parkinson's disease, and ischemic stroke, its role in mood disorders such as anxiety and depression remains unclear. To investigate the role of p53 in behavioral responses to chronic stress, we examined behavioral and molecular alterations in p53 knockout (p53[-/-]) mice and wild type mice. In p53[-/-] mice, increased vulnerability to chronic unpredictable mild stress (CUMS)-induced anxiety- and depression-like behaviors was observed following CUMS exposure. In parallel with these behavioral changes, BDNF expression was reduced, whereas glutamate levels were elevated in the prefrontal cortex of p53[-/-] mice. Increased calcium-associated staining and NMDAR2B expression were observed together with increased neuronal injury- and cell death-related markers. In primary cortical neurons derived from p53[-/-] mice, corticosterone treatment resulted in greater increases in glutamate levels, NMDAR2B expression compared to wild-type controls. Cell death markers (cleaved caspase-3, p-p38, p-JNK) were upregulated, while neuroprotective signals (BDNF, p-Akt, p-ERK, p-CREB) were suppressed in p53[-/-] mice, and corticosterone-treated primary neuronal cells from p53[-/-] mice. These findings indicate that p53 deficiency is associated with enhanced vulnerability to CUMS-induced anxiety- and depression-like behaviors and is accompanied by alterations in calcium handling, glutamate homeostasis, neuronal injury-related markers, and BDNF-associated neuroprotective signaling.},
}

@article {pmid42603674,
year = {2026},
author = {Motoyoshi, M and Nagai, J},
title = {Astrocyte engineering.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105103},
doi = {10.1016/j.neures.2026.105103},
pmid = {42603674},
issn = {1872-8111},
abstract = {Tiling across the central nervous system, astrocytes contact synapses, blood vessels and other glial cells through highly specialised processes, allowing them to regulate local brain environments across multiple spatial and temporal scales. These anatomical and signalling features make astrocytes attractive substrates for modulating brain function and repair. Here, we frame "astrocyte engineering" as the intentional design of molecular access, sensing and effector modules in astrocytes to interrogate or modify local brain states. This Review focuses on how astrocyte interface biology can be converted into engineering logic, from genetic access and signalling perturbation to emerging sensor-effector designs. We first outline how astrocyte morphology, diversity and intercellular interactions shape the logic of cell-specific targeting. We then summarise tools for astrocyte-specific gene delivery and signalling control, including adeno-associated virus (AAV)-based strategies and G-protein coupled receptor (GPCR) signalling modulation approaches that can alter disease-relevant phenotypes. Further, we discuss recent proof-of-concept studies that equip astrocytes with new recognition or effector functions, including chimeric antigen receptor (CAR) astrocytes, synNotch-based systems, and trophic-factor delivery. We propose that future astrocyte engineering should be guided by omics-based design principles that link cell state, molecular access, input recognition, and effector selection.},
}

@article {pmid42603776,
year = {2026},
author = {Tang, FL and Huang, LJ and Wang, YX and Wang, SM and Ji, WS and Gao, F and Sun, L and Xu, JB},
title = {Novel C3-Aminated Galantamine Derivatives as Selective Butyrylcholinesterase Inhibitors With Neuroprotective Effects.},
journal = {ChemMedChem},
volume = {21},
number = {16},
pages = {e70431},
pmid = {42603776},
issn = {1860-7187},
support = {82404470//National Natural Science Foundation of China/ ; 2025ZNSFSC1731//Natural Science Foundation of Sichuan Province/ ; 2682026CX101//Fundamental Research Funds for the Central Universities/ ; },
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Galantamine/pharmacology/chemistry/chemical synthesis/analogs & derivatives ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Butyrylcholinesterase/metabolism ; Humans ; Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Structure ; Hydrogen Peroxide/pharmacology/antagonists & inhibitors ; Apoptosis/drug effects ; Dose-Response Relationship, Drug ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Molecular Dynamics Simulation ; },
abstract = {To explore natural-inspired novel anti-AD bioactive molecules, a series of galantamine derivatives 6a-6u were synthesized via Pd-catalyzed Buchwald-Hartwig cross-coupling, with various nitrogen-containing functional groups installed at the C3 position of galantamine. Compared with galantamine, these compounds showed greatly enhanced selective BChE inhibition activity, suggesting that the C3 position of galantamine might be a key modifiable site for developing new selective BChE inhibitors. Among them, the derivative 6l which contained a 3,5-difluoroaniline structure moiety exhibited promising selective inhibitory activity against eqBChE, with an IC50 of 0.88 μM and a selectivity index of 26.2. Molecular docking and molecular dynamics simulations were performed to elucidate the interaction model between compound 6l and BChE. Moreover, 6l also showed favorable neuroprotection potency against H2O2 injured SH-SY5Y cells. Preliminary mechanistic study revealed that compound 6l could mitigate oxidative stress and suppress cellular apoptosis. This work not only offers a novel galantamine analog with promising in vitro cholinesterase inhibitory and neuroprotective effects for further anti-AD study, but also provides new insights into the structure optimization of natural drug galantamine.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Galantamine/pharmacology/chemistry/chemical synthesis/analogs & derivatives
*Neuroprotective Agents/pharmacology/chemistry/chemical synthesis
*Butyrylcholinesterase/metabolism
Humans
Structure-Activity Relationship
Molecular Docking Simulation
Molecular Structure
Hydrogen Peroxide/pharmacology/antagonists & inhibitors
Apoptosis/drug effects
Dose-Response Relationship, Drug
Cell Line, Tumor
Oxidative Stress/drug effects
Molecular Dynamics Simulation

@article {pmid42603781,
year = {2026},
author = {Kaleem, M and Raza, A and Kalpina, FNU and Fatima, M and Batool, SJ and Haider, B and Rashid, H and Jamal, M and Turkmani, M and Khan, U},
title = {Rising Comorbid Alzheimer's and Hypertension Mortality in Older Adults in the United States: Trends and Disparities From a 21-Year CDC WONDER Analysis (1999-2019).},
journal = {Journal of clinical hypertension (Greenwich, Conn.)},
volume = {28},
number = {8},
pages = {e70348},
pmid = {42603781},
issn = {1751-7176},
mesh = {Humans ; United States/epidemiology ; *Alzheimer Disease/mortality/epidemiology ; Female ; Aged ; *Hypertension/mortality/epidemiology/complications ; Male ; Aged, 80 and over ; Risk Factors ; Comorbidity/trends ; },
abstract = {Hypertension, affecting nearly half of US adults, is a significant modifiable risk factor for Alzheimer's disease (AD), the fifth leading cause of death among Americans aged 65 and older. Hypertension contributes to AD through microvascular damage, reduced cerebral perfusion and neuroinflammation, leading to cognitive decline and dementia. This study examines US national trends and disparities in mortality due to comorbid AD and hypertension in older adults (≥65 years) using CDC WONDER data from 1999-2019. Age-adjusted mortality rates (AAMRs) per 100 000 individuals and crude rates (CRs) were determined. Joinpoint regression was used to calculate Annual Percentage Changes (APCs) and Average Annual Percentage Changes (AAPCs). A total of 372 839 deaths occurred, increasing from 4948 to 27 257 annually (1999-2019). AAMRs rose from 14.51 to 53.13, with an AAPC of 6.16%. Females (47.09) had higher AAMRs than males (33.80). Non-Hispanic Blacks experienced the highest mortality rates (54.82), while NH Asians had the lowest (28.14); Hispanics experienced the highest AAPC (6.81). The 85+ age group bore the greatest mortality burden (AAPC: 6.84%). Most deaths (60.05%) occurred in hospice/nursing facilities. Mortality was highest in the West (AAMR: 50.28) and lowest in the Northeast (27.00). Mississippi had the highest, Massachusetts the lowest state-level mortality burden. Non-metropolitan areas exceeded metropolitan AAMRs (47.89 vs. 41.28). Targeted interventions are needed to counter observed trends, addressing hypertension as a key manageable risk factor for AD prevention.},
}

Humans
United States/epidemiology
*Alzheimer Disease/mortality/epidemiology
Female
Aged
*Hypertension/mortality/epidemiology/complications
Male
Aged, 80 and over
Risk Factors
Comorbidity/trends

@article {pmid42604096,
year = {2026},
author = {Bayly, H and Salvati, L and Lenio, S and Mez, J and Alosco, ML and Tripodis, Y},
title = {Evaluating inclusion of continuous multivariable cognitive scores for operational enrichment of preclinical Alzheimer's disease trials: a retrospective emulation study.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100081},
pmid = {42604096},
issn = {2534-773X},
abstract = {BACKGROUND: Prevention trials for Alzheimer's Disease face significant challenges due to the slow and uncertain rate of cognitive decline in asymptomatic, amyloid-positive individuals. Biomarker positivity alone does not guarantee clinically meaningful progression, often leaving studies underpowered.

OBJECTIVES: Evaluate model-based operational trial enrichment within an amyloid-positive, cognitively normal subgroup.

METHODS: Trained on a small cohort from the National Alzheimer's Coordinating Center (N = 113), with external validation using baseline data of a similar small cohort from the Alzheimer's Disease Neuroimaging Initiative (N = 161). Gradient-boosted decision trees estimated progression risk and projected power under alternative enrollment strategies. Predictors included neuropsychological scores, demographics, medical history, and ApoE ε4 genotype. The primary outcome was clinical progression to cognitive impairment within 1- and 3-year follow-up windows.

RESULTS: In the independent testing set, the model successfully increased the effective prevalence of the outcome. The Positive Predictive Value for the 1-year window was 0.27 (a 35% relative increase over the 0.20 baseline prevalence) and 0.43 for the 3-year window (a 23% relative increase over the 0.35 baseline). Power simulations for an emulated trial (N = 500) demonstrated that this enrichment strategy consistently increased statistical power, potentially reducing the required sample size to achieve 80% power by up to 32% for small treatment effect sizes.

CONCLUSIONS: This operational methodology functions as a screening filter to optimize event rates within a highly specific, preselected trial population.},
}

@article {pmid42604767,
year = {2026},
author = {Furuta, M and Ohara, T and Sakata, S and Shibata, M and Oishi, E and Furuta, Y and Kageyama, S and Asakawa, M and Shimazaki, Y and Takeshita, T and Ninomiya, T},
title = {Periodontal Status and the Risk of All-Cause Dementia, Alzheimer's Disease and Vascular Dementia in a Community: The Hisayama Study.},
journal = {Journal of clinical periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jcpe.70185},
pmid = {42604767},
issn = {1600-051X},
support = {24K13242//Japan Society for the Promotion of Science/ ; 23FA1022//Health and Labor Sciences Research Grants of the Ministry of Health, Labor and Welfare of Japan/ ; },
abstract = {AIM: This study examined the associations of periodontal status with incident dementia and its subtypes in a Japanese community.

MATERIALS AND METHODS: The 1396 participants aged ≥ 60 years without dementia were followed for 10 years. Periodontal status at baseline and 5 years was assessed using mean probing pocket depth (PPD), clinical attachment level (CAL) and percentage of bleeding on probing (%BOP), categorized into quartiles. Cox proportional hazards and time-varying Cox models were used.

RESULTS: During follow-up, 267 participants developed dementia; 194 and 51 had Alzheimer's disease (AD) and vascular dementia (VaD), respectively. Compared with the lowest quartile, the highest quartiles of PPD, CAL and %BOP at baseline were associated with increased dementia risk (hazard ratio 1.72 [95% confidence interval 1.18-2.46], 1.59 [1.07-2.38] and 1.56 [1.09-2.22], respectively, all p for trend < 0.05). Elevated %BOP was associated with AD risk (p for trend = 0.023). Higher PPD tended to be associated with VaD (p for trend = 0.076). Similar associations for all-cause dementia were observed in time-varying Cox analyses.

CONCLUSIONS: Poor periodontal status was associated with dementia in older Japanese adults. These findings highlight the potential public health importance of preventing periodontitis to reduce the risk of dementia.},
}

@article {pmid42604943,
year = {2026},
author = {Molnar, FJ},
title = {Those Debating Alzheimer Disease Modifying Therapies Should Review the Seminal JAGS Dementia Minimal Clinically Important Difference Article.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70657},
pmid = {42604943},
issn = {1532-5415},
}

@article {pmid42604981,
year = {2026},
author = {Falcone, C and Arckens, L and Baiula, M and Bedini, A and Bocchi, R and Broadhead, MJ and Caprini, M and Cavaliere, F and Cesca, F and Chowdhury, HH and Ciuba, K and Civiero, L and Escartin, C and Ferroni, S and Formaggio, F and Frasca, A and Gratton, R and Holt, M and Iraci, N and Kreft, M and Leggio, L and Lia, A and Malik, AR and Min, R and Müller, FE and Murat, C and Pereira, MJ and Pekowska, A and Petrelli, F and Ramos-Gonzalez, P and Sanchez-Mico, MV and Smole, Z and Sokolova, D and Solas, M and Soldano, A and Szewczyk, LM and Torazza, C and Severino, FPU and Urrestizala-Arenaza, N and Zeug, A and Zhou, J and Zonta, M and Zorec, R and Verkhratsky, A and Gunhanlar, N},
title = {Written in the Stars: Astrocyte Biology From Evolution to Disease.},
journal = {Acta physiologica (Oxford, England)},
volume = {242},
number = {9},
pages = {e70289},
doi = {10.1111/apha.70289},
pmid = {42604981},
issn = {1748-1716},
support = {CNS2025-166813//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; RYC2021-033202-I//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; PID2023-146385NA-I00//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; PID2024-160537OB-I00//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; 951923//European Commission (H2020)/ ; //European Union - NextGenerationEU/PRTR/ ; 2023.17564.ICDT//FCT (Fundação para a Ciência e a Tecnologia, Portugal)/ ; UMO-2018/01/H/NZ4/00001//National Science Centre (NCN, Poland)/ ; UMO-2021/43/B/NZ2/02934//National Science Centre (NCN, Poland)/ ; UMO-2021/42/E/NZ2/00392//National Science Centre (NCN, Poland)/ ; UMO-2023/51/D/NZ3/02998//National Science Centre (NCN, Poland)/ ; 2024/54/E/NZ4/00134//National Science Centre (NCN, Poland)/ ; 2024/53/B/NZ4/03058//National Science Centre (NCN, Poland)/ ; A2023021F//BrightFocus Foundation/ ; 2023.00418.BD//Fundação para a Ciência e a Tecnologia (FCT) doctoral fellowship/ ; G0C9922N//KU Leuven Research Council (C14/20/071) and the Research Foundation Flanders (FWO), Belgium/ ; },
mesh = {Humans ; *Astrocytes/physiology/pathology ; Animals ; *Biological Evolution ; *Brain ; *Neurodegenerative Diseases/metabolism/pathology ; *Nervous System Diseases ; },
abstract = {In the 21st century, neuroglial research has entered a period of Renaissance, extending the views of prominent neuroanatomists and neurologists of the 19th and early 20th centuries, who assigned to glial cells numerous physiological functions and highlighted their fundamental role in the pathophysiology of nervous system diseases. Astrocytes are highly diversified in structure and function; they control brain homeostasis, support synaptic connectivity, and enable information processing in neural networks. Evolutionary diversification of astrocytes, initially emerging as supportive cells of primitive sensory organs, drove a continuous expansion of astroglial complexity and functional versatility, ultimately making them indispensable neuroprotectors and homeostatic regulators. The large, morphologically elaborate astrocytes of the human brain arguably reflect an evolutionary response to increased neuronal homeostatic demands. Astrocytes are indispensable for synaptic function, serving as the principal regulators of neurotransmitter turnover and neuronal excitability. Astrocytes also govern brain energy metabolism, mitochondrial dynamics, and calcium signaling, thereby actively shaping cortical plasticity and circuits. Astrocytes are fundamental elements of the pathophysiology of neurological, neuropsychiatric, and neurodegenerative diseases, including Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Rett syndrome, genetic astrocytopathies, and neurotrauma, where they demonstrate complex reactive changes directed at tissue preservation and regeneration, but which can also contribute to disease progression. Advances in single-cell transcriptomics, calcium imaging, chemogenetics, and iPSC-based models have transformed our understanding of astrocyte diversity and disease-specific dysfunction, opening new avenues of investigation. Given that no CNS disorder is known to occur without astrocyte involvement, multiple astrocyte-specific molecules represent compelling targets for cell-directed therapeutic strategies.},
}

Humans
*Astrocytes/physiology/pathology
Animals
*Biological Evolution
*Brain
*Neurodegenerative Diseases/metabolism/pathology
*Nervous System Diseases

@article {pmid42605027,
year = {2026},
author = {Duijkers, S and Ter Huurne, DBG and Blom, M and Bodde, HE and Dobbe, JHM and Van der Flier, W and Jansen, WJ and Olde Rikkert, M and Papma, JM and Verhey, FRJ and Ramakers, IHGB},
title = {Current Practice and Long-Term Developments in Multidisciplinary Dutch Memory Clinics.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261478290},
doi = {10.1177/08919887261478290},
pmid = {42605027},
issn = {1552-5708},
abstract = {ObjectivesMemory Clinics (MCs) have a central role in multidisciplinary diagnostics and care of cognitive disorders and dementia. This study describes current clinical practice and developments of Dutch MCs since their start in 1986.MethodsA survey was sent to all Dutch hospital-based MCs in 1998, 2004, 2009, 2017 and 2023. Topics included: organization, patient characteristics, scales and questionnaires, neuropsychological assessment, additional assessments, novel biomarkers, disclosure of diagnosis and treatment. 74 out of the total of 89 MCs completely or partially filled out the questionnaire.ResultsThe number of MCs increased to 89. The number of patients seen increased substantially (per MC/year: 1998: 130; 2023: 324; total: 1998: 1560; 2023: 28,848). The proportion of patients diagnosed with dementia decreased from 80% in 1998 to 47% in 2023. Most commonly available assessments were neuroimaging (100%), routine laboratory testing of blood (98%) and neuropsychological assessment (NPA; 98%). Thirty-one percent indicated infrastructure needed to be changed before prescribing monoclonal antibody treatments for Alzheimer's disease.ConclusionsMCs showed substantial development in number, number of patients and geographical distribution within the country. Nowadays, MCs are central care facilities for the timely and multidisciplinary diagnosis and treatment of people with cognitive disorders and dementia.},
}

@article {pmid42605139,
year = {2026},
author = {Javed, MN and Khan, SM and Mustafa, S and Mujtaba, A and Amin, H and Azhar, N and Hameed, A and Zayed, A and Khalid, M and Hussain, JM},
title = {Gantenerumab for Early Alzheimer's Disease: An Updated Systematic Review and Meta-Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71643},
doi = {10.1002/brb3.71643},
pmid = {42605139},
issn = {2162-3279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Randomized Controlled Trials as Topic ; Amyloid beta-Peptides ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Gantenerumab, a β-amyloid-targeting monoclonal antibody, has shown mixed clinical results. With new trial data available, this updated systematic review and meta-analysis re-evaluates its efficacy and safety in early AD.

METHODS: Registered on PROSPERO (CRD420251082463) under PRISMA guidelines, we searched PubMed, Cochrane Library, and Google Scholar from inception to October 2025 for randomized trials in early AD comparing gantenerumab with placebo. A random-effects model assessed pooled outcomes with heterogeneity (I[2]) and sensitivity analyses. Additionally, meta-regression and certainty of evidence using Gradepro were performed. Risk of bias was evaluated using the Cochrane tool. An Institutional Review Committee (IRC) and its Ethical Review Board (ERB) approval was not required.

RESULTS: Six trials (3103 participants: 1718 gantenerumab; 1385 placebo) were included. Gantenerumab showed no significant effect on CDR-SB (MD = -0.07; 95% CI: -0.34-0.20; p = 0.62; I[2] = 16%) but produced small improvements in FAQ (MD = -0.73; 95% CI: -1.30 to -0.17; p = 0.01; I[2] = 0%) and Amyloid-PET score (MD = -45.67; 95% CI: -88.09 to -3.24; p = 0.03; I[2] = 99%). While significant statistical improvement was seen in the ADAS-Cog13 score (MD = -0.95; 95% CI: -1.76 to -0.13; p = 0.02; I[2] = 0%), the effect sizes for both FAQ and ADAS-Cog13 fell below established MCID thresholds. MMSE and ADCS-ADL showed no significant differences. Safety analysis revealed higher risks of ARIA-E (RR = 5.51), ARIA-H (RR = 1.73), and injection site reactions (RR = 2.15), with no differences in other adverse events.

CONCLUSION: Gantenerumab significantly reduces amyloid and statistically improves select functional (FAQ) and cognitive (ADAS-Cog13) measures in early AD; however, these changes remain below accepted MCID thresholds, indicating a lack of true clinical meaningfulness. Combined with its failure to enhance global cognition and an increased ARIA risk, routine clinical use is not supported.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Randomized Controlled Trials as Topic
Amyloid beta-Peptides

@article {pmid42605141,
year = {2026},
author = {Wang, J},
title = {Comment on 'Predicting cognitive function in Alzheimer's clinical trials via amyloid β-protein biomarkers'.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70790},
pmid = {42605141},
issn = {1365-2125},
support = {//Zhejiang Chinese Medical University/ ; },
}

@article {pmid42605248,
year = {2026},
author = {Demura, M and Gregory, P and Fukuda, N and Lo, EH and Arai, K},
title = {Exercise and Circadian Rhythm Regulation: Mechanisms, Resilience, and Therapeutic Potential for Neurological Diseases.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {8},
pages = {e71035},
doi = {10.1002/cns.71035},
pmid = {42605248},
issn = {1755-5949},
support = {R01NS113556/NH/NIH HHS/United States ; //Takeda Science Foundation/ ; },
mesh = {Humans ; *Circadian Rhythm/physiology ; Animals ; *Nervous System Diseases/therapy/physiopathology ; *Exercise/physiology ; Alzheimer Disease/physiopathology/therapy ; },
abstract = {BACKGROUND: Circadian rhythms regulate sleep-wake cycles, hormonal secretion, metabolism, and immune responses. Disruption of these rhythms is linked to the onset and progression of various neurological diseases. Emerging evidence suggests that exercise, a non-photic zeitgeber, can modulate circadian function at both central and peripheral levels by regulating core clock gene expression, synchronizing hormonal and metabolic rhythms, and reducing neuroinflammation. Through these mechanisms, exercise enhances the amplitude, stability, and phase alignment of circadian rhythms and may promote physiological resilience.

REVIEW: This review summarizes the molecular and systemic mechanisms through which exercise supports circadian homeostasis and discusses their relevance to stroke and Alzheimer's disease. In both conditions, circadian misalignment contributes to pathological processes including oxidative stress, neuroinflammation, and impaired neurovascular repair. By restoring circadian alignment, appropriately timed exercise may improve neurological outcomes through effects on neuroplasticity, immune regulation, and metabolic synchronization.

SUMMARY: Taken together, current evidence may suggest that exercise can be a promising non-pharmacological strategy to enhance circadian resilience, reduce disease vulnerability, and support neurological recovery.},
}

Humans
*Circadian Rhythm/physiology
Animals
*Nervous System Diseases/therapy/physiopathology
*Exercise/physiology
Alzheimer Disease/physiopathology/therapy

@article {pmid42602062,
year = {2026},
author = {Bréchet, L and Bouhour, C and Rochas, V and Mekrom, VA and Eshmawey, M and Unschuld, PG},
title = {Personalized, home-based transcranial alternating current stimulation for memory improvement in mild cognitive impairment: randomized, sham-controlled clinical trial protocol.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1882406},
pmid = {42602062},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD) and represents a critical window for interventions aimed at slowing neurodegenerative progression. Disruptions in neural oscillatory activity are key contributors to memory dysfunction in MCI and AD. Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulation technique that entrains neural oscillations at specific frequencies, potentially restoring network dynamics underlying memory.

METHODS: The MemStim study is a randomized, sham-controlled, parallel-arm, double-blind clinical trial evaluating the efficacy of personalized, home-based gamma-frequency tACS over the left angular gyrus, delivered 5 days a week for 4 weeks, in individuals with MCI. Safety and tolerability are monitored throughout the intervention. Forty participants aged ≥55 years with clinically diagnosed MCI will be recruited at the Geneva University Hospitals and randomized to active or sham stimulation. All participants undergo baseline and post-stimulation assessments, including cognitive testing, structural MRI, and high-density EEG (hdEEG). Individual MRI-based electric-field modeling personalizes stimulation montages targeting the left angular gyrus, a key node of the memory network.

OUTCOMES: The primary outcome is the change in global cognitive function measured by the Montreal Cognitive Assessment (MoCA) from baseline to post-intervention. Secondary outcomes include changes in gamma-band oscillatory power measured with hdEEG. Exploratory EEG analyses will examine spectral, temporal, and spatial brain dynamics. Cognitive assessments are repeated 3 months post-intervention to evaluate persistence of effects.

DISCUSSION: This trial investigates whether personalized gamma-frequency tACS can modulate hdEEG measures of resting-state brain activity and improve memory function in MCI. By integrating individualized stimulation targeting, electrophysiological biomarkers, and remotely supervised home-based delivery, the MemStim study aims to advance personalized neuromodulation as a scalable therapeutic strategy for early intervention in cognitive decline.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT05708001.},
}

@article {pmid42602177,
year = {2026},
author = {Azimzadeh, M and Ababzadeh, S and Kahaki, AG and Babaei, SMH and Seyedebrahimi, R and Farsani, ME},
title = {The Gut-Brain Axis in Neurodegeneration: Mechanistic Links Between Dysbiosis and Neuropathology.},
journal = {Iranian journal of pathology},
volume = {21},
number = {4},
pages = {507-522},
pmid = {42602177},
issn = {1735-5303},
abstract = {BACKGROUND & OBJECTIVE: The gut-brain axis is essentially a two-way communication system that physically connects the brain and the intestinal tract. The connection is mediated through a series of pathways, including neural, endocrine, and immune pathways. Gut dysbiosis, which is explained as an imbalance in the microbial community, has been linked to the causation of various neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the pathological mechanisms in the brain are only partially known. The present review outlines the process of gut dysbiosis and neurodegeneration, detailing the roles of protein aggregation, neuroinflammation, barrier disruption, and neuroglial dysfunction. Then, extending the comparison to a range of neurodegenerative diseases, we discuss the possibility of common pathway therapeutics and actual microbiome-based treatment options planning from the standpoint of microbiome-directed interventions.

CONTENT/FINDINGS: Gut dysbiosis triggers a definable cascade, starting with the disruption of the intestinal barrier and increased permeability (leaky gut), which allows bacterial products (lipopolysaccharides, bacterial amyloids) and pro-inflammatory cytokines to enter systemic circulation. Such peripheral changes weaken the blood-brain barrier and thus allow these factors to access the CNS, where they lead to neuroglial dysfunction (microglial priming, astrocytic reactivity, and oligodendrocyte injury) by disruption of glial homeostasis. CNS glial cell malfunction leads to the development of proteinopathies characteristic of each disease: amyloid and tau hyperphosphorylation in Alzheimer's disease through BACE1 upregulation and kinase activation; synuclein in Parkinson's disease via molecular mimicry, oxidative stress, and impaired clearance; and demyelination in multiple sclerosis through oligodendrocyte apoptosis. Oral bacteria such as Porphyromonas gingivalis aggravate this inflammatory loop through the direct invasion of the CNS and proteolytic cleavage of amyloid and tau. The vagus nerve is yet another pathway through which gut-derived inflammatory signals and pathological synuclein can be transmitted to the brain.

CONCLUSION: The gut microbiome is more than just a correlate of neurodegeneration; it actively promotes neurodegenerative diseases through pathways that can be mechanistically defined. Microbiome-targeted interventions such as dietary changes, precision probiotics, fecal microbiota transplantation, and anti-inflammatory agents offer a measure of hope for changing these pathological processes. Future studies need to be directed at determining the time sequence of cause and effect, finding dependable microbiota-based biomarkers, and formulating tailored strategies that can account for individual microbial composition variability, genetic susceptibility, and environmental exposures. A deeper understanding of the gut-brain axis from this mechanistic perspective could eventually lead to the prevention or postponement of neurodegeneration.},
}

@article {pmid42598783,
year = {2026},
author = {Liu, M and Gong, K and Chen, Y and Heo, G and Xu, Y and Timsina, J and Western, D and Budde, J and Morris, JC and Marco, G and Holtzman, DM and Hinson, J and Levin, S and Ashton, N and Denkinger, M and Schindler, SE and Das, K and Ali, M and Cruchaga, C},
title = {A plasma-based protein signature combining NPTXR, ACHE, and p-tau217 predicts progression to symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71748},
pmid = {42598783},
issn = {1552-5279},
support = {R01-AG058501/NH/NIH HHS/United States ; //Cure Alzheimer's Fund/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; Disease Progression ; *tau Proteins/blood ; Biomarkers/blood ; Female ; Male ; *Acetylcholinesterase/blood ; *Nerve Tissue Proteins/blood ; Aged ; Longitudinal Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We recently identified a plasma-based seven-protein model with strong performance for Alzheimer's disease (AD) classification. Here, we evaluated whether these proteins, alone or combined with plasma phosphorylated tau 217 (p-tau217), predict progression from cognitively unimpaired to symptomatic AD.

METHODS: Using longitudinal data from Knight-ADRC (Alzheimer's Disease Research Center) with replication in Alzheimer's Disease Neuroimaging Initiative (ADNI), we modeled time to progression using Cox regression. Models included p-tau217, the seven-protein panel, and their combination.

RESULTS: The p-tau217 alone showed similar progression prediction (hazard ratio [HR] = 4.08) than the seven-protein model (HR = 4.85). Integrating the seven-protein model with ptau217 significantly improved risk, identifying a high-risk group (HR = 11.15) with two intermediate-risk groups. Simplified models retained prognostic value, with top-performing ratios, Complexin-2/Synaptic vesicle membrane protein VAT-1 homolog (CPLX2/VAT1) and Acetylcholinesterase/Neuronal pentraxin receptor (ACHE/NPTXR) also lead to a significantly better risk stratification than p-tau217 alone.

DISCUSSION: Integrating p-tau217 with targeted plasma proteins enables graded risk stratification and identifies individuals at highest risk of progression, supporting clinically scalable approaches for early risk assessment.},
}

Humans
*Alzheimer Disease/blood/diagnosis
Disease Progression
*tau Proteins/blood
Biomarkers/blood
Female
Male
*Acetylcholinesterase/blood
*Nerve Tissue Proteins/blood
Aged
Longitudinal Studies
Aged, 80 and over

@article {pmid42599498,
year = {2026},
author = {Zhang, P and Guo, X and Yang, M and Cai, Y and Wang, L and Gao, Y},
title = {Photo/Copper-Catalyzed Oxidative Direct Diphosphorothiolation of Indolin-2-ones with P(O)SH Compounds.},
journal = {The Journal of organic chemistry},
volume = {91},
number = {32},
pages = {11141-11147},
doi = {10.1021/acs.joc.6c01443},
pmid = {42599498},
issn = {1520-6904},
support = {22201242//National Natural Science Foundation of China/ ; 22271285//National Natural Science Foundation of China/ ; 2025J09053//Natural Science Foundation of Fujian Province/ ; XYBSKYZZ201926//Xinxiang Medical University/ ; 505527//Research Foundation for Distinguished Professor?s Team of Xinxiang Medical University/ ; },
abstract = {A visible-light-promoted cross-dehydrogenative coupling (CDC) of indolin-2-ones with S-hydrogen phosphorothioates via 4H elimination has been developed, providing 3,3-diphosphorothiolated oxindoles in good yields with broad functional group tolerance. The protocol was also extended to monophosphorothiolation and late-stage diversification of drug-derived substrates. Notably, the products displayed potent and selective butyrylcholinesterase (BuChE) inhibitory activity, suggesting potential as leads for Alzheimer's disease.},
}

@article {pmid42599532,
year = {2026},
author = {Raj, SN and Natnan, ME and Lou, WP and Mediani, A and Tencomnao, T and Baharum, SN},
title = {Unravelling the phytochemical complexity of neuroprotective plants: a metabolomics approach to Alzheimer's disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42599532},
issn = {1573-4978},
support = {GGP-2020-043//Universiti Kebangsaan Malaysia/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy ; *Metabolomics/methods ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; *Phytochemicals/metabolism/therapeutic use/pharmacology ; *Plants, Medicinal/metabolism/chemistry ; Animals ; Metabolome ; Drug Discovery/methods ; },
abstract = {Metabolomics is a comprehensive study of organisms at the metabolite level. The emergence of metabolomics as one of the 'omics' in systems biology perspectives has gained significance in relation to disease research. The use of metabolomics pipeline to unravel the potential of bioactive compounds in medicinal plants for benefiting mankind has become a powerful strategy for drug discovery. While traditional metabolite profiling has mainly classified medicinal plants according to broad biological activities, such as anti-inflammatory, anticancer, anti-diabetic and atherosclerosis effects, the non-targeted and targeted metabolomics offer a comprehensive approach for characterizing novel or previously unknown secondary metabolites providing a far more detailed approach. These advanced methodologies allow researchers to expand current research by providing deeper insight into how these compounds work and their underlying mechanisms at the molecular level. To investigate these metabolic shifts particularly in neurodegenerative diseases model, studies frequently use advanced analytical platform, such as nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS) to analyze metabolites in biofluids like blood, urine, and cerebrospinal fluid (CSF). This review will highlight recent metabolomics discoveries on unravelling the complex phytochemical composition of selected medicinal plants in producing neuroprotective bioactive compounds and therapeutic potential to combat neurodegenerative related disease especially Alzheimer's disease (AD).},
}

*Alzheimer Disease/metabolism/drug therapy
*Metabolomics/methods
Humans
*Neuroprotective Agents/pharmacology/therapeutic use/metabolism
*Phytochemicals/metabolism/therapeutic use/pharmacology
*Plants, Medicinal/metabolism/chemistry
Animals
Metabolome
Drug Discovery/methods

@article {pmid42599667,
year = {2026},
author = {Wang, Y and Gu, Z and Zhang, H and Bi, X and Chen, L and Lu, J},
title = {Multimodal MRI insights into hippocampal pathological changes across the Alzheimer's disease continuum: advances and challenges.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42599667},
issn = {1867-108X},
support = {82371495//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with early and progressive hippocampal pathology serving as a hallmark across the AD continuum, including subjective cognitive decline, mild cognitive impairment, and AD dementia. Single-modal MRI fails to fully capture multilevel hippocampal neuropathology, hindering accurate early diagnosis and prognostic prediction of AD. This narrative review summarizes recent advances in structural MRI, diffusion tensor imaging, magnetic resonance spectroscopy, quantitative susceptibility mapping, arterial spin labeling, and functional MRI for evaluating hippocampal and medial temporal lobe abnormalities in AD. These techniques provide a multifaceted characterization of AD-associated hippocampal alterations, including macroscopic atrophy, microstructural degeneration, metabolic dysregulation, aberrant iron deposition, hemodynamic dysfunction, and abnormal neuronal activity. Hippocampal damage in AD exhibits distinct subfield specificity, hemispheric asymmetry, and stage-dependent progression, modulated by Aβ/tau pathology, neuroinflammation, and apolipoprotein E ε4 genotype. Notably, multimodal imaging fusion integrated with machine learning outperforms single-modal biomarkers, significantly improving the accuracy of AD early screening, differential diagnosis, and prognostic prediction. Nevertheless, existing studies are hampered by inadequate pathological validation, limited sample sizes, unsatisfactory reproducibility, and multicenter technical heterogeneity. Multimodal MRI offers robust non-invasive evidence for exploring AD hippocampal pathophysiology. Future large-scale multicenter longitudinal studies combining artificial intelligence will advance precision diagnosis and targeted therapy for AD by clarifying the interplay among AD pathology, genetics, and heterogeneous hippocampal injury.},
}

@article {pmid42599691,
year = {2026},
author = {Wang, S and Zou, S and , },
title = {Cerebrospinal fluid glial cell line-derived neurotrophic factor levels interact with APOE ε4 genotype to influence cognitive decline in older adults without dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477047},
doi = {10.1177/13872877261477047},
pmid = {42599691},
issn = {1875-8908},
abstract = {BackgroundAlthough both apolipoprotein E (APOE) ε4 and glial cell line-derived neurotrophic factor (GDNF) are implicated in the pathogenesis of Alzheimer's disease (AD), it remains unclear whether they interact to affect cognitive decline among older adults without dementia.ObjectiveThis study aimed to examine the interactive effects of APOE ε4 and GDNF on longitudinal cognitive decline.MethodsA total of 543 individuals (mean age 73 [±7] years; 43% female) with cognitively unimpaired (CU) or mild cognitive impairment (MCI) were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear mixed-effects models were used to examine the contributions of cerebrospinal fluid (CSF) GDNF levels and APOE ε4 status to longitudinal changes in cognitive measures, including the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating - Sum of Boxes (CDR-SB), the 13-item Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog-13), and the Rey Auditory Verbal Learning Test (RAVLT) total score.ResultsWe found that the 3-way interaction (APOE ε4 × GDNF × time) was significant for MMSE, CDR-SB, and ADAS-Cog-13, and of marginal significance for RAVLT total score, after adjusting for age, sex, and education. Specifically, individuals who were APOE ε4 carriers with low CSF GDNF levels showed the fastest rate of cognitive decline among the four groups (Low/APOE4-, High/APOE4-, Low/APOE4+, and High/APOE4+).ConclusionsAPOE ε4 appears to interact with CSF GDNF levels to affect longitudinal cognitive decline among older adults without dementia.},
}

@article {pmid42599695,
year = {2026},
author = {Alavi, A and Gujral, J and Gandhi, OH and Amanullah, AA and Ayubcha, C and Patil, S and Werner, TJ and Høilund-Carlsen, PF},
title = {The case for FDG-PET and NaF-PET in risk stratification of mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477750},
doi = {10.1177/13872877261477750},
pmid = {42599695},
issn = {1875-8908},
abstract = {According to a recent study, integrating amyloid-PET, structural MRI, carotid Doppler ultrasound, cognitive testing, and APOE genotyping improves estimation of dementia progression in patients with mild cognitive impairment, with carotid plaque burden emerging as a dominant predictor in amyloid-β-negative cases. We agree that vascular pathology is crucial but suggest that future models consider supplementing amyloid-PET with FDG-PET, a well-validated functional marker of neuronal injury, and carotid Doppler with [18]F-sodium fluoride (NaF)-PET which can detect and quantify early, active microcalcification. This could further improve risk stratification while facilitating detection of potentially modifiable disease processes.},
}

@article {pmid42599799,
year = {2026},
author = {Liu, R and Zhang, Y and Lai, M and Davydzenka, V and Moffitt, C and England, N and Barbera, G and Chen, R and Lin, DT and Li, Y},
title = {Graph theory identifies altered prefrontal microcircuit organization in Shank3 mice, a mouse Model of autism.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117852},
doi = {10.1016/j.celrep.2026.117852},
pmid = {42599799},
issn = {2211-1247},
abstract = {Graph theory provides unique tools to assess complex networks. It has been previously used with functional magnetic resonance imaging (fMRI) datasets to quantify macroscopic-scale connections among different brain regions, readily capturing brain network changes in subjects with Alzheimer's disease. Here, we apply graph theory to miniscope calcium imaging data recorded from the prefrontal cortex of freely behaving wild-type (WT) and Shank3[fx] mice (a mouse model of autism) during social behavior tasks to compare microscopic-scale functional connections among individual neurons. We demonstrate that Shank3[fx] mice display reduced population-level neural activity and a less-integrated and rigid prefrontal microcircuit. Furthermore, we employ machine learning to predict genotypes and behavioral differences between WT and Shank3[fx] mice using graph-theoretic metrics extracted from prefrontal microcircuits. Our results indicate strong links between altered prefrontal microcircuits and social behavior deficits in the Shank3[fx] mice, highlighting prefrontal microcircuitry as a potential diagnostic and therapeutic target for autism.},
}

@article {pmid42599802,
year = {2026},
author = {Bhatta, S and Grzybowski, A and Ortiz, G and DiStasio, M},
title = {TTN[+] macrophages are enriched in the human choroid plexus in Alzheimer's disease.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117859},
doi = {10.1016/j.celrep.2026.117859},
pmid = {42599802},
issn = {2211-1247},
abstract = {The choroid plexus (ChP) regulates cerebrospinal fluid homeostasis and immune surveillance, but its cellular organization and response to Alzheimer's disease (AD) remain incompletely defined. Here, we integrate single-nucleus RNA sequencing with spatial transcriptomics to generate a high-resolution atlas of the adult human ChP. We identify all major epithelial, stromal, and immune populations and resolve heterogeneity within macrophages, including a distinct subset expressing the giant protein TTN. These TTN[+] macrophages exhibit coordinated cytoskeletal, stress-response, and phagocytic gene programs and localize to perivascular and stromal niches. In AD, we observe broad, cell type-specific transcriptional remodeling across epithelial, endothelial, mesenchymal, and immune compartments, with expansion of TTN[+] macrophages and increased senescence signatures. Spatial and ligand-receptor analyses reveal altered tissue organization and macrophage interaction patterns with neighboring cells. Combined with in situ validations, these findings provide evidence of TTN expression by macrophages, and reveal a broader AD-associated contextual shift in human ChP immune function in which TTN[+] macrophages are enriched.},
}

@article {pmid42599805,
year = {2026},
author = {Zou, ZM and Wang, D and Tang, WJ and Chen, XL and Li, HJ and Li, GL and Xiao, R and Xu, LH and Si, WK and Chen, ZY},
title = {GLUT4 plasma translocation in lateral septum GABAergic neurons supports neuronal activation and social familiarity.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117854},
doi = {10.1016/j.celrep.2026.117854},
pmid = {42599805},
issn = {2211-1247},
abstract = {Social interaction regulates neuronal excitability and behavior, and the lateral septum (LS) plays an important role in social behavior. However, the molecular mechanisms that support LS-dependent social responses remain unclear. Here, we show that neuronal activity-driven glucose transporter 4 (GLUT4) plasma translocation in LS GABAergic neurons supports social familiarity. Neuronal activation triggers CaMKIIα-mediated phosphorylation of GLUT4 at Ser243 and Ser254, which enhances Rab10 binding, GLUT4 surface insertion, and glucose uptake. A cell-permeable TAT-GLUT4(2D) peptide disrupts GLUT4-Rab10 binding, blocks activity-dependent GLUT4 translocation, and impairs social familiarity. LS GLUT4 knockdown disrupts social novelty preference, and this deficit is rescued by wild-type GLUT4 but not trafficking- or transport-deficient mutants. In 5xFAD mice, GLUT4 plasma translocation is reduced during social novelty preference. Selective expression of plasma-localized GLUT4 in LS GABAergic neurons restores neuronal activation and social familiarity impairments, identifying GLUT4 trafficking as a potential target for Alzheimer's disease-related social impairments.},
}

@article {pmid42600000,
year = {2026},
author = {Chae, H and Park, Y and Kim, Y and Yoon, E and Kim, KW and Yoo, S},
title = {Wearable transparent OLED glasses for cognitive stimulation: Enhancing brain connectivity through gamma entrainment.},
journal = {Science advances},
volume = {12},
number = {33},
pages = {eaee5504},
pmid = {42600000},
issn = {2375-2548},
mesh = {Humans ; *Wearable Electronic Devices ; *Cognition/physiology ; *Brain/physiology ; *Gamma Rhythm/physiology ; Cognitive Enhancement ; },
abstract = {Gamma wave entrainment is a promising approach for improving cognitive function, particularly in the early stages of Alzheimer's disease. However, for everyday treatment, a light source system that maintains visibility while delivering effective stimulation is essential for patient comfort and practicality. To address this need, we developed organic light-emitting diode (OLED) glasses with optimized large-area transparent OLEDs for gamma wave entrainment. The optimization involved all layers of the device, including encapsulation, to achieve high luminous transmittance (75%), uniformity (over 90%), and electrical performance, ensuring suitability for wearable applications. Under real-world conditions (see-through visibility and ambient light present), the transparent OLED glasses successfully induced gamma rhythm entrainment, enhancing brain connectivity between the occipital and frontal regions. They also notably reduced visual discomfort and showed a trend of enhanced connectivity compared to nontransparent OLEDs. These results highlight the potential of this noninvasive wearable technology for early cognitive intervention, providing comfortable therapeutic light stimulation.},
}

Humans
*Wearable Electronic Devices
*Cognition/physiology
*Brain/physiology
*Gamma Rhythm/physiology
Cognitive Enhancement

@article {pmid42600372,
year = {2026},
author = {Rudroff, T},
title = {Sex composition as an unaddressed confound in FDG-PET predictive models of Alzheimer's disease conversion.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {10},
pages = {100955},
doi = {10.1016/j.jnha.2026.100955},
pmid = {42600372},
issn = {1760-4788},
}

@article {pmid42600466,
year = {2026},
author = {Kumar, N and Khan, I and Singh, J and Kumar, K and Kushwaha, VK and Ojha, S and Raman, SK and Shankar, G},
title = {Recent developments in donepezil-based hybrid molecules as multi-target therapeutics for Alzheimer's disease: A paradigm shift beyond symptomatic treatment.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110361},
doi = {10.1016/j.bioorg.2026.110361},
pmid = {42600466},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder characterized by the gradual loss of cholinergic neurons, leading to cognitive impairment, synaptic dysfunction, and irreversible neuronal degeneration. The multifactorial nature of AD, involving cholinergic deficits, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and metal dyshomeostasis, has limited the clinical success of single-target therapeutic strategies. Although donepezil (DPZ), a clinically approved acetylcholinesterase (AChE) inhibitor, remains one of the most widely prescribed agents for symptomatic management, it does not alter the underlying neurodegenerative processes. Consequently, DPZ has emerged as an attractive medicinal chemistry scaffold for the development of multi-target-directed ligands (MTDLs) that simultaneously modulate multiple interconnected pathological pathways implicated in AD. This review provides a comprehensive and critically organized overview of recent advances in DPZ-based hybrid molecules, emphasizing rational design strategies, hybridization approaches, structure-activity relationships (SAR), molecular mechanisms, and pharmacological profiles. To facilitate a mechanistic understanding, the reported hybrids are systematically classified according to structural modifications of the indanone moiety, the benzylpiperidine moiety, or simultaneous modification of both pharmacophoric regions. Comparative analysis reveals how scaffold engineering, linker optimization, and strategic incorporation of complementary pharmacophores influence cholinesterase inhibition, anti-amyloid activity, antioxidant capacity, neuroprotection, metal chelation, monoamine oxidase inhibition, and blood-brain barrier permeability. Importantly, this review critically examines the current translational landscape, highlighting that despite encouraging in vitro and in vivo findings, no DPZ-based hybrid has yet advanced to clinical evaluation. Key challenges, including pharmacokinetic optimization, metabolic stability, safety, target engagement, and clinical translatability, are discussed together with future medicinal chemistry directions. Rather than presenting DPZ-based hybrids as established disease-modifying therapies, the available evidence supports their role as promising multifunctional lead compounds and valuable molecular platforms for the rational design of next-generation anti-Alzheimer agents. By integrating emerging SAR trends with critical translational perspectives, this review provides a contemporary framework to guide future development of clinically relevant multifunctional therapeutics for AD.},
}

@article {pmid42600613,
year = {2026},
author = {Brioschi, S and Belk, JA and Storck, SE and Wu, Y and Wang, Z and Feng, Z and van Olst, L and Emery, JL and Sudan, R and Wu, J and Du, S and Genua, M and La Terza, F and Edwards, AJ and Nguyen, KM and Sanford, J and Lee, DD and Bugatti, M and Federico, AJ and Chen, Y and Wang, Z and Penati, S and Rodrigues, PF and Antonova, AU and Loo, HQ and Smirnov, I and Gilfillan, S and Halabi, CM and Ponce, J and Yan, J and Chang, HY and Randolph, GJ and Vermi, W and Cella, M and Meers, M and Ostuni, R and Gate, D and Nguyen, AT and Cruchaga, C and Hu, S and Kipnis, J and Colonna, M},
title = {Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.07.043},
pmid = {42600613},
issn = {1097-4172},
abstract = {Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.},
}

@article {pmid42600734,
year = {2026},
author = {Sharma, T and Sharma, P and Bashir, B and Singh, SK and Vishwas, S},
title = {Small nucleolar RNAs: Emerging therapeutic and diagnostic frontiers in Alzheimer's disease.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104771},
doi = {10.1016/j.drudis.2026.104771},
pmid = {42600734},
issn = {1878-5832},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which effective therapeutic interventions remain scarce, highlighting the urgent need for new molecular approaches. Small nucleolar RNAs (snoRNAs), classically known for directing ribosomal modifications, have recently emerged as multifunctional regulators of gene expression, stress responses and neuronal homeostasis. Emerging evidence shows snoRNA dysregulation in the biofluids and brain tissue of patients with AD, positioning them as promising diagnostic biomarkers and therapeutic targets. This review outlines the structural, functional and translational potential of snoRNAs, with a particular focus on their ability to modulate AD pathology while also addressing key challenges in their clinical translation, including delivery barriers, biological stability and target specificity.},
}

@article {pmid42600807,
year = {2026},
author = {Fereidouni, A and Nematollahi, S and Mathew, KT and Favennec, V and Liceran, L and Aldenhoff-Kelly, C and Valdivieso, MA and Trent, S and Moradikor, N},
title = {Allosteric modulation of ionotropic and G protein-coupled receptors in Alzheimer's disease: A neuroprotective strategy and therapeutic implications.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154063},
doi = {10.1016/j.ijbiomac.2026.154063},
pmid = {42600807},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and still lacks an effective treatment that can slow or stop disease progression. In addition to amyloid-β and tau pathology, AD involves major disturbances in calcium balance, neurotransmission, and synaptic plasticity. Conventional orthosteric drugs provide limited symptomatic benefit and often interfere with physiological receptor function, underscoring the need for more selective therapeutic strategies. This review explores allosteric modulation of neurotransmitter receptors as a potential neuroprotective strategy in AD, with an emphasis on mechanisms that restore synaptic integrity, regulate calcium homeostasis, and engage disease-relevant intracellular signaling pathways. The review synthesizes preclinical and clinical evidence on allosteric modulators targeting key ionotropic receptors, including NMDA, AMPA, GABA-A, nicotinic acetylcholine, and P2X7 receptors, and G protein-coupled receptors (GPCRs) such as M1 muscarinic receptors, metabotropic glutamate receptors, and the calcium-sensing receptor. Particular attention is given to receptor selectivity, signaling bias, and translational relevance. Allosteric modulation of ionotropic receptors can influence excitability and synaptic plasticity and may preserve endogenous neurotransmission, with circuit-stabilizing effects reported mainly in preclinical studies. GPCR-directed allosteric modulators can affect AD-related processes, including amyloid- and tau-associated toxicity, excitotoxicity, and neuroinflammation, although evidence for these effects is largely preclinical and clinical translation remains challenging. Convergent pathways, such as Ca[2+]-dependent signaling, ERK/CREB, PI3K/Akt, and cAMP/PKA, may represent shared mediators of disease-relevant effects. Allosteric modulation may offer a more refined, receptor-specific framework for therapeutic investigation in AD. Ionotropic and GPCR-targeted agents may each produce symptomatic or preclinical disease-relevant effects, but their capacity to slow disease progression in patients remains unproven and will require current pharmacological and translational challenges to be addressed.},
}

@article {pmid42600874,
year = {2026},
author = {Xiao, J and Lan, Z and Zhang, R and Zhang, J and Hu, Z and Jia, B and Tang, H and Xu, T and Bao, X and Xu, Y and Yu, L and Ji, SL and Zhu, X},
title = {Novel natural inhibitor Rubimaillin targets NLRP3 R167/Y381 to ameliorate inflammatory and neurodegenerative diseases.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122293},
doi = {10.1016/j.jep.2026.122293},
pmid = {42600874},
issn = {1872-7573},
abstract = {Rubia cordifolia L. is traditionally used in Chinese medicine for treating arthritic and inflammatory conditions by cooling blood and activating circulation. Gouty arthritis, one of the disease models investigated in this study, falls within this traditional anti-arthritic application. This study investigates whether rubimaillin (Rub), a naphthoquinone from Rubia cordifolia, selectively inhibits NLRP3 inflammasome activation and exerts therapeutic effects in relevant disease models. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a key driver of various inflammatory, metabolic, and neurodegenerative disorders; yet, no clinically approved inhibitor is currently available. Rubia cordifolia L. is a traditional medicinal herb, and Rubimaillin (Rub), a naphthoquinone isolated from this herb, has potential anti-inflammatory properties, but its role and mechanism in regulating NLRP3 activation remain unclear.

AIM OF STUDY: This study aimed to determine whether Rubimaillin (Rub), a naphthoquinone isolated from Rubia cordifolia L., can selectively inhibit NLRP3 inflammasome activation and yield therapeutic effects in relevant NLRP3-driven disease models.

MATERIALS AND METHODS: Mouse primary microglia, bone marrow-derived macrophages (BMDMs), and the human macrophage cell line THP-1 were primed with lipopolysaccharide (LPS) for 3 h, then stimulated with Nigericin or ATP to induce NLRP3 inflammasome assembly and pyroptosis. Caspase-1 activation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, interleukin-1β (IL-1β) release, and lactate dehydrogenase (LDH) secretion were quantified. Mutagenesis studies were conducted to identify critical residues required for Rub's binding to NLRP3. The in vivo therapeutic potential of Rub was assessed in three murine models of NLRP3-driven inflammation: LPS-induced sepsis, monosodium urate crystal (MSU)-induced gouty arthritis, and the APP/PS1 double-transgenic Alzheimer's disease (AD) mouse model. Mice received intraperitoneal Rub or vehicle, and disease severity was evaluated by histopathology, cytokine profiling, and behavioral tests.

RESULTS: Rub significantly reduced pyroptosis and IL-1β release in mouse primary microglia, BMDMs, and THP-1 cells in a dose-dependent manner, without affecting Absent in melanoma 2(AIM2) or NLR family CARD domain containing 4 (NLRC4) pathways. Mechanistically, Rub directly bound to NLRP3, thereby blocking the oligomerization of both NLRP3 and ASC, as well as preventing caspase-1 activation and gasdermin D (GSDMD) cleavage. Furthermore, mutagenesis studies identified arginine 167 and tyrosine 381 as critical residues for Rub's binding to NLRP3. In vivo, Rub treatment significantly prolonged survival and attenuated lung injury in the sepsis model, reduced paw swelling and bone erosion in the gout model, and ameliorated cognitive deficits and neuroinflammation in the AD model, respectively.

CONCLUSION: Collectively, these findings demonstrate that Rub selectively targets the NLRP3 inflammasome and exerts therapeutic effects on NLRP3-driven diseases including sepsis, gout, and AD. This study provides a molecular basis for the traditional application of Rubia cordifolia L. and highlights Rub as a promising natural lead compound for the treatment of NLRP3-driven disorders.},
}

@article {pmid42600903,
year = {2026},
author = {Wu, X and Ye, Q and Zi, M and Jiang, H and Meng, S and Zheng, J and Zeng, S and Ma, C and Hu, X and Zhao, B and Li, H},
title = {Pyroptosis in Alzheimer's disease: Mechanisms and neuroinflammatory networks.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104113},
doi = {10.1016/j.mcn.2026.104113},
pmid = {42600903},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuronal loss, and sustained neuroinflammation. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory programmed cell death, has been recognized as a potential mechanism linking innate immune activation to neurodegenerative injury. This review summarizes the major molecular pathways of pyroptosis, including the canonical inflammasome-caspase-1-GSDMD pathway, the noncanonical caspase-4/5/11-GSDMD pathway, and alternative pathways involving caspase-3/GSDME and caspase-8, with a focus on their roles in the initiation, amplification, and propagation of neuroinflammation in AD. Current evidence suggests that AD-related stimuli, including Aβ aggregation, tau pathology, mitochondrial dysfunction, oxidative stress, and lysosomal damage, can induce inflammasome activation, gasdermin cleavage, and inflammatory mediator release, thereby sustaining chronic neuroinflammation. Concurrently, microglia, neurons, astrocytes, and oligodendrocytes may exhibit varying degrees of pyroptosis-related responses, contributing to impaired Aβ clearance, neuronal injury, glial dysfunction, and myelin pathology, respectively. This review further summarizes potential therapeutic strategies targeting the NLRP3 inflammasome, caspases, gasdermins, natural bioactive compounds, and the gut-brain axis. Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.},
}

@article {pmid42601004,
year = {2026},
author = {Shanehbandpour-Tabari, F and Golchoobian, R and Pourabdolhossein, F},
title = {Hippocampal Klotho Expression Is Associated with the Neuroprotective Effects of Metformin Against ICV-STZ-Induced Cognitive Deficits.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179245},
doi = {10.1016/j.ejphar.2026.179245},
pmid = {42601004},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and neuroinflammation. Increasing evidence links metabolic dysfunction to AD, suggesting that antidiabetic drugs such as metformin may exert neuroprotective effects. This study investigated the effects of long-term metformin pretreatment on cognitive function, hippocampal pathology, and neuroprotective gene expression in an intracerebroventricular streptozotocin (ICV-STZ) rat model of AD. Adult male Sprague-Dawley rats were assigned to Sham, STZ, Metformin, and STZ+Metformin groups. Metformin (2 g/L in drinking water) was administered for 12 weeks before ICV-STZ injection. Spatial learning and memory were assessed using the Morris water maze. Hippocampal pathology was evaluated by H&E, Nissl, and Congo red staining, and gene expression was analyzed by quantitative PCR. ICV-STZ induced cognitive impairment, hippocampal Aβ deposition, neuronal loss, and increased expression of pro-inflammatory and oxidative stress markers. Metformin pretreatment significantly improved spatial learning and memory, reduced amyloid burden, and preserved neuronal integrity in the CA1 and CA3 regions. Metformin increased hippocampal Klotho mRNA expression, enhanced antioxidant defenses (Nrf2 and HO-1), suppressed TNF-α, IL-1β, and iNOS expression, and increased IL-10 levels. Although BDNF mRNA expression showed an upward trend, the change was not statistically significant. No significant changes in blood glucose levels were observed. In conclusion, long-term metformin pretreatment attenuated STZ-induced AD-like pathology and cognitive deficits. Its neuroprotective effects were associated with increased hippocampal Klotho expression and reduced oxidative stress and neuroinflammation, supporting further investigation of metformin and the Klotho pathway as potential preventive strategies for AD.},
}

@article {pmid42601176,
year = {2026},
author = {Koh, H and Choi, S and Sung, JE},
title = {Verb-Semantic Feature Analysis for Alzheimer's Dementia in a verb-final language: evidence from Korean.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/09602011.2026.2715712},
pmid = {42601176},
issn = {1464-0694},
abstract = {This study examined the effects of Verb-Semantic Feature Analysis (Verb-SFA) on verb naming, noun retrieval, sentence comprehension, and discourse production in individuals with Dementia of the Alzheimer's Type (DAT). Given the lexical-semantic degradation characteristic of DAT and the central role of verbs in Korean, a verb-final language, this study evaluated whether Verb-SFA facilitates treatment, near-transfer, and far-transfer effects. Three male participants, aged 60 or older with 16 years of education, completed 17 sessions: pre-treatment (4 sessions), treatment (10 sessions), and post-treatment (3 sessions). Treatment effects were assessed using 45-item probe sets derived from the Korean Item Selection Naming Test. Results showed significant improvement in naming accuracy for treated verbs, with a robust interaction between treatment sessions and treated items. No significant near-transfer effects were found for untreated verbs in the probe set or on the Action Naming Test. However, significant near-transfer effects were observed for noun retrieval on the Korean-Boston Naming Test, although verbal fluency tasks showed no improvement. Far-transfer effects emerged in sentence comprehension, suggesting strengthened verb-semantic processing supports higher-level linguistic abilities. No measurable gains were observed in discourse production. Overall, Verb-SFA treatment enhanced verb naming and sentence comprehension in individuals with DAT.},
}

@article {pmid42601455,
year = {2026},
author = {Coulon, A and Rabiller, F and Takalo, M and Roy, A and Pelletier, A and Martiskainen, H and Siedlecki-Wullich, D and Lannette-Weimann, N and Majerníková, N and Grenon, A and Gao, V and Erhardt, A and Pernodet, A and Lemaire, M and Limoge, F and Walle, P and Mendes, T and Guyot, K and Lemeu, C and Carvalho, LI and Melo de Farias, AR and Hulsman, M and Najdek, C and Freire-Regatillo, A and Saha, O and Amouyel, P and Charbonnier, C and Deleuze, JF and Dols-Icardo, O and Jeskanen, H and Willman, RM and Kuulasmaa, T and Kurki, M and Hardy, J and Heikkinen, S and Holstege, H and Mäkinen, P and Nicolas, G and Mead, S and Wagner, M and Ramirez, A and Rauramaa, T and Palotie, A and Sims, R and Soininen, H and van Swieten, J and Williams, J and Bellenguez, C and Gelle, C and Lambert, E and Costa, MR and Tcw, J and Glaab, E and Ayral, AM and Demiautte, F and Grenier-Boley, B and Muntaner, M and Eberlé, D and Deforges, S and Haas, JT and Kilinc, D and Mulle, C and Chapuis, J and Hiltunen, M and Dumont, J and Lambert, JC},
title = {PLCG2 downregulation impairs synaptic function and increases Alzheimer's disease hallmarks in neuronal cultures.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42601455},
issn = {1546-1718},
abstract = {We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.},
}

@article {pmid42601488,
year = {2026},
author = {Abila, E and Buljan, I and Zheng, Y and Kleissl, L and Klotz, S and Veres, T and Weng, Z and Nackenhorst, M and Kamies, R and Michl, A and Kadri, S and Moustafa, S and Hulla, W and Perkonigg, M and Drach, M and Tschandl, P and Sterniczky, B and Heinig, M and De Sadeleer, LJ and Wuyts, W and Vanaudenaerde, B and Ceulemans, LJ and Buchanan, DD and Fennell, LJ and Stary, G and Tolkach, Y and Wöhrer, A and Schiller, HB and Rendeiro, AF},
title = {Histological aging signatures for monitoring tissue-specific aging and disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42601488},
issn = {1546-170X},
support = {101220825//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; 70116893//Deutsche Krebshilfe (German Cancer Aid)/ ; 70116893//Deutsche Krebshilfe (German Cancer Aid)/ ; 1316/1-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 18E2B24N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; PAT 8019123//Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)/ ; LF-OC-24-001518//LEO Pharma Research Foundation/ ; GNT1194896//Department of Health | National Health and Medical Research Council (NHMRC)/ ; Dame Kate Campbell Fellowship//University of Melbourne (Melbourne University)/ ; CCAF-2024 Fennell//Cure Cancer Australia Foundation (CCAF)/ ; },
abstract = {Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies and comorbidities. Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.},
}

@article {pmid42601641,
year = {2026},
author = {Almela, F and Belondrade, M and Caillierez, R and Leclercq, S and Bouillet, T and Bégard, S and Oosterlynck, M and Eddarkaoui, S and Boluda, S and Buée, L and Nicot, S and Colin, M and Bougard, D},
title = {Amplification of seeding-competent tau aggregates by PMCA in human and experimental tauopathies.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42601641},
issn = {2051-5960},
support = {ANR-21-CE18-0046//Agence Nationale de la Recherche/ ; AmpliTAU//Association France Alzheimer/ ; },
mesh = {Animals ; Humans ; *tau Proteins/metabolism/genetics ; *Tauopathies/metabolism/pathology ; Mice, Transgenic ; *Brain/metabolism/pathology ; Mice ; Disease Models, Animal ; Protein Folding ; Alzheimer Disease/metabolism/pathology ; Female ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; Male ; },
abstract = {Tau assemblies, associated with tauopathies, are believed to self-propagate through prion-like mechanisms in the central nervous system, driving neurodegeneration. Recently, protein seed amplification assays have emerged as highly sensitive methods for detecting trace amounts of misfolded protein assemblies across various neurodegenerative diseases. In this study, we utilized protein misfolding cyclic amplification (PMCA) to demonstrate that tau assemblies from the brains of transgenic mice or human patients with tauopathies can be efficiently amplified. Amplification was achieved using complex matrix substrates, such as brain homogenates or cell lysates expressing aggregation-prone mutant tau proteins, with heparin as a cofactor. This assay enabled the highly sensitive detection of tau assemblies, even at 1-million-fold dilutions of brain homogenate from aged and symptomatic THY-Tau30 transgenic mice (a model of tauopathy) and human cases of frontotemporal lobar degeneration (FTLD-P301L). Tau assemblies from Alzheimer's disease (AD) patients were also successfully amplified, albeit with lower sensitivity compared to other tauopathies. Critically, the PMCA-generated tau assemblies retained seeding competence, inducing further tau aggregation in reporter tau "biosensor" cells and in young THY-Tau30 mice following intracerebral injection. Together, our findings establish PMCA as an in vitro model for studying the seeded aggregation of tau assemblies, providing a powerful tool to advance research into tau aggregation mechanisms and the development of therapeutic interventions.},
}

Animals
Humans
*tau Proteins/metabolism/genetics
*Tauopathies/metabolism/pathology
Mice, Transgenic
*Brain/metabolism/pathology
Mice
Disease Models, Animal
Protein Folding
Alzheimer Disease/metabolism/pathology
Female
*Protein Aggregation, Pathological/metabolism
Protein Aggregates
Male

@article {pmid42601653,
year = {2026},
author = {Jiang, M and Lan, G and Zhu, J and Zhang, L and Li, A and He, Z and Zhu, Y and Zhou, X and Liang, L and Gao, N and Sun, P and Cai, Y and Fan, X and Chen, X and Shi, D and Liu, Z and Wang, Q and Cheng, G and Wang, L and , and Dong, M and Wang, YJ and Guo, T},
title = {Cross-Sectional and Longitudinal Diagnostic Performance of Plasma p-tau217 and p-tau217/Aβ42 in Alzheimer's Disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78322},
pmid = {42601653},
issn = {1531-8249},
abstract = {OBJECTIVE: Recent studies suggest that combining plasma phosphorylated tau (p-tau) with β-amyloid (Aβ) may improve diagnosis accuracy for Alzheimer's disease (AD). However, the cross-sectional and longitudinal concordance of these markers with Aβ positron emission tomography (PET) positivity remains incompletely understood. This study aimed to evaluate the diagnostic performance of plasma p-tau, alone and in combination with plasma Aβ, in AD.

METHODS: We included 326 participants from the Alzheimer's Disease Neuroimaging Initiative and 357 Chinese older adults from the Greater-Bay-Area Healthy Aging Brain Study who underwent Aβ-PET imaging. Longitudinal data were available for 285 Alzheimer's Disease Neuroimaging Initiative participants. Plasma p-tau181, p-tau217, Aβ42, and Aβ40 were measured on different analytical platforms. Diagnostic performance for Aβ-PET positivity was assessed using a two-cutoff approach.

RESULTS: Combining plasma p-tau with Aβ42 or the Aβ42/40 ratio reduced the intermediate zone. Notably, p-tau217/Aβ42 showed stronger agreement with Aβ-PET positivity than p-tau217 alone. Among individuals classified as p-tau217/Aβ42 positive but p-tau217 intermediate, 57.1 to 83.3% were Aβ-PET positive. Longitudinally, most Stable Positive (88.0-96.1%) and Stable Negative (89.4-90.9%) cases defined by p-tau217 or p-tau217/Aβ42 were Aβ-PET positive and Aβ-PET negative, respectively. Critically, 69.7 to 75.8% of Non-positive to Positive cases defined by p-tau217/Aβ42 were Aβ-PET positive.

INTERPRETATION: These findings provide novel insights into the cross-sectional and longitudinal diagnostic performance of plasma p-tau217/Aβ42 in AD. To be specific, plasma p-tau217/Aβ42 can reduce the intermediate zone and improve agreement with Aβ-PET positivity, and longitudinal p-tau217/Aβ42 monitoring is particularly informative for identifying Aβ-PET-positive patients who were p-tau217/Aβ42 negative or intermediate at baseline and were misclassified as low risk of AD. ANN NEUROL 2026.},
}

@article {pmid42601701,
year = {2026},
author = {Yang, G and Hou, W and Wu, J and Yang, X and Yang, Y and Chen, Q and Liu, Y},
title = {Association between habitual sleep duration and Alzheimer's disease: A cross-sectional study based on NHANES 2007-2018.},
journal = {Medicine},
volume = {105},
number = {33},
pages = {e50086},
doi = {10.1097/MD.0000000000050086},
pmid = {42601701},
issn = {1536-5964},
support = {KS2325//the Kunshan Key Research and Development Program (Social Development) Project Fund/ ; SYWD2024196//Suzhou City Applied Basic Research and Science and Technology Innovation Project/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/mortality ; *Sleep Duration ; Cross-Sectional Studies ; Female ; Nutrition Surveys ; United States/epidemiology ; Male ; Aged ; Middle Aged ; Risk Factors ; *Sleep Wake Disorders/epidemiology ; Prevalence ; },
abstract = {Given the potential importance of sleep disturbances in the pathophysiology of Alzheimer's disease (AD), as well as the fact that habitual sleep duration - an observable and modifiable lifestyle factor - has become a significant potential target for early risk warning of neurodegenerative diseases, this study utilizes data from the National Health and Nutrition Examination Survey to thoroughly examine the association between AD and habitual sleep patterns among adults in the United States. It aims to determine the correlations among sleep duration, Alzheimer's disease, and all-cause mortality, thereby providing population-based evidence for the early prevention and public health intervention of AD. Using a cross-sectional design, 29,692 participants were selected. A multiple logistic regression model was used to assess the association between sleep duration and Alzheimer's disease. Additionally, all-cause mortality status was derived from matched records obtained from the United States National Death Index. The Cox regression model was used to calculate the hazard ratios and 95% confidence intervals of all-cause mortality associated with the relationship between sleep duration and AD. Our analysis revealed a significant positive correlation between increased sleep time and AD prevalence, a relationship that persisted in the adjusted model. Subgroup analysis showed that this association remained consistent across different populations. This study clarifies the effectiveness of sleep time as a predictive tool for AD and underscores its importance in AD assessment. Based on the predictive value of sleep time, our study advocates incorporating body composition factors into AD risk assessment, thus expanding the scope of Alzheimer's disease prevention strategies.},
}

Humans
*Alzheimer Disease/epidemiology/mortality
*Sleep Duration
Cross-Sectional Studies
Female
Nutrition Surveys
United States/epidemiology
Male
Aged
Middle Aged
Risk Factors
*Sleep Wake Disorders/epidemiology
Prevalence

@article {pmid42601718,
year = {2026},
author = {Huang, KY and Wei, YY and Zhang, ST and He, LC and Zhou, J and Zhou, LS and Su, HB and Lu, GD},
title = {Gut microbiota alterations and their correlation with constipation in older adults with Alzheimer's disease or mild cognitive impairment: A cross-sectional study.},
journal = {Medicine},
volume = {105},
number = {33},
pages = {e50227},
doi = {10.1097/MD.0000000000050227},
pmid = {42601718},
issn = {1536-5964},
support = {2023GXNSFAA026155//Natural Science Foundation of Guangxi/ ; RTFY202502//Key Laboratory of Human Development and Disease Research (Guangxi Medical University), Education Department of Guangxi Zhuang Autonomous Region/ ; 32160160//Natural Science Foundation of China/ ; 202410598018//College Students’ Innovative Entrepreneurial Training Plan Program/ ; S202410598106//College Students’ Innovative Entrepreneurial Training Plan Program/ ; },
mesh = {Humans ; *Constipation/microbiology ; *Alzheimer Disease/microbiology/complications ; *Cognitive Dysfunction/microbiology/complications ; Aged ; *Gastrointestinal Microbiome/physiology ; Female ; Cross-Sectional Studies ; Male ; Feces/microbiology ; Aged, 80 and over ; },
abstract = {Previous studies have suggested a link between gut microbiota, constipation and Alzheimer's disease (AD) as well as mild cognitive impairment (MCI). In this study, we aimed to investigate the changes in the gut microbiota and their relationship with constipation in patients with AD and MCI. A total of 90 participants (30 with AD, 30 with MCI, and 30 normal controls) were recruited from the community-based Nanning Community Elderly Population cohort. We collected fresh fecal samples for analysis and compared the differences in the gut microbiota among the groups. We also categorized these 90 participants into a constipation group and a non-constipation (normal) group using the Rome IV diagnostic criteria, allowing for a comparison of gut microbiota between these 2 groups. There were significant differences in alpha and beta diversity of the gut microbiota among the AD, MCI, and control groups, as well as between the constipation and non-constipation groups. At the genus level, the relative abundance of Lachnospira was decreased in both the AD group and the constipation group, while the relative abundance of Paeniclostridium was increased in both the MCI group and the constipation group. Our findings suggest that changes in the gut microbiota in patients with AD or MCI are partially consistent with those observed in older adults with constipation and may be involved in the pathogenesis of AD.},
}

Humans
*Constipation/microbiology
*Alzheimer Disease/microbiology/complications
*Cognitive Dysfunction/microbiology/complications
Aged
*Gastrointestinal Microbiome/physiology
Female
Cross-Sectional Studies
Male
Feces/microbiology
Aged, 80 and over

@article {pmid42601743,
year = {2026},
author = {Chen, IW and Chang, LC and Lai, YC and Ho, CN and Wu, JY and Hung, KC},
title = {Vitamin D deficiency and dementia risk in patients with chronic kidney disease: A multi-institutional 10-year retrospective cohort study.},
journal = {Medicine},
volume = {105},
number = {33},
pages = {e50267},
doi = {10.1097/MD.0000000000050267},
pmid = {42601743},
issn = {1536-5964},
mesh = {Humans ; *Vitamin D Deficiency/complications/epidemiology ; *Renal Insufficiency, Chronic/complications/epidemiology ; Retrospective Studies ; Female ; Male ; *Dementia/epidemiology/etiology ; Aged ; Risk Factors ; Vitamin D/blood/analogs & derivatives ; Middle Aged ; Alzheimer Disease/epidemiology ; },
abstract = {Patients with chronic kidney disease (CKD) face elevated dementia risk, and vitamin D deficiency (VDD) has emerged as a potential contributor to cognitive decline. This study investigated the association between VDD and dementia development in patients with CKD using real-world data. We conducted a retrospective cohort study using the TriNetX database, analyzing patients with CKD aged ≥50 years from January 2010 to December 2022. Patients were stratified by serum 25-hydroxyvitamin D levels as follows: VDD group (<20 ng/mL) vs control group (≥30 ng/mL). The primary outcome was new-onset dementia occurring 1 to 10 years post-index, with the risk of Alzheimer's disease (AD) as a secondary outcome. During the 10-year follow-up, patients with VDD were associated with a significantly higher dementia risk (hazard ratios [HR] 1.45, 95% confidence intervals [CIs]: 1.37-1.54, P < .001). The association emerged early, with a 5-year HR of 1.52 (1.41-1.64, P < .001). The risk of AD was similarly elevated (10-year HR 1.37, 95% CI: 1.21-1.56, P < .001). Dose-response analysis revealed an increased risk even with mild insufficiency (20-30 ng/mL), while severe deficiency (<10 ng/mL) showed the highest risk. Subgroup analysis identified hypertension as a significant effect modifier, with VDD conferring an elevated risk in hypertensive patients (HR 1.43, 95% CI: 1.35-1.52) but not normotensive individuals. VDD was significantly associated with increased risks of dementia and AD in patients with CKD, following a clear dose-response pattern. The association is particularly pronounced among hypertensive patients, suggesting that VDD represents a potentially modifiable risk factor warranting clinical attention in CKD management.},
}

Humans
*Vitamin D Deficiency/complications/epidemiology
*Renal Insufficiency, Chronic/complications/epidemiology
Retrospective Studies
Female
Male
*Dementia/epidemiology/etiology
Aged
Risk Factors
Vitamin D/blood/analogs & derivatives
Middle Aged
Alzheimer Disease/epidemiology

@article {pmid42601919,
year = {2026},
author = {Wei, H and Zhang, T and Liang, Z and Li, M and Kong, M and Ba, M},
title = {Amyloid-β modulates APOE ε4 effects on cognition but not on targeted structural or functional connectivity measures over 2 years in pre-dementia adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1889743},
pmid = {42601919},
issn = {1663-4365},
abstract = {BACKGROUND: The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet emerging evidence suggests its cognitive effects may be age- and pathology-dependent. Whether and how amyloid-β (Aβ) pathology modifies the longitudinal cognitive trajectory associated with APOE ε4 in the pre-dementia stage remains unclear.

METHODS: We conducted a 2-year longitudinal study in 70 pre-dementia adults from the Alzheimer's disease Neuroimaging Initiative (ADNI), assessing APOE genotype, Aβ status via positron emission tomography (PET), multi-domain cognition, structural magnetic resonance imaging (MRI) volumes, and resting-state functional connectivity of a predefined hippocampus-auditory network. Linear mixed-effects models evaluated the three-way interaction of time, APOE ε4 carrier status, and Aβ status on longitudinal trajectories. Sensitivity and exploratory mediation analyses were performed.

RESULTS: A significant three-way interaction (Time × APOE ε4 × Aβ status) was observed for global cognitive decline (ADAS13: β = -4.54, p = 0.001, P_FDR = 0.003), indicating that Aβ pathology moderates the effect of APOE ε4 on cognitive trajectories. Post-hoc analyses revealed that among Aβ-positive individuals, APOE ε4 carriers exhibited a slower rate of cognitive decline compared to non-carriers, whereas no such difference was evident in Aβ-negative individuals. This moderating effect was robust to sensitivity analyses and was consistently observed across multiple cognitive domains (MMSE, CDRSB, FAQ, MoCA; all P_FDR < 0.01). However, no significant three-way interactions survived multiple comparison correction for regional brain volumes or hippocampus-auditory functional connectivity, though nominally significant trends were observed in middle temporal gyrus volume and specific temporal lobe connections. Longitudinal hippocampal atrophy did not mediate the observed association.

CONCLUSION: Aβ pathology modifies the longitudinal cognitive trajectory associated with APOE ε4 in pre-dementia adults over a 2-year period. While consistent with the antagonistic pleiotropy framework, this observation requires independent replication, and alternative explanations including cognitive reserve and survivor bias warrant careful consideration.},
}

@article {pmid42601937,
year = {2026},
author = {Guo, Y and Niu, X and Xia, Y and Yang, Y and Fu, X and Li, T and Zhang, Y and Ji, Y and Ni, H},
title = {Microstructural white matter alterations in dementia with lewy bodies and Alzheimer's disease: a diffusion tensor imaging and neurite orientation dispersion and density imaging study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1830477},
pmid = {42601937},
issn = {1663-4365},
abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are common types of dementia, however, diagnosis is challenging. An innovative MR method called neurite orientation dispersion and density imaging (NODDI) is used to assess different microstructural alterations between the conditions.

OBJECTIVE: To assess microstructural white matter (WM) changes in DLB and AD using NODDI.

METHODS: Diffusion images were acquired from 26 DLB patients, 36 AD patients, and 37 normal controls (NCs). The diffusion tensor imaging (DTI) was used to generate fractional anisotropy (FA), mean diffusivity (MD), and NODDI was used to generate neurite density index (NDI), orientation dispersion index (ODI), and volume fraction of isotropic water molecules (Viso), these parameters were compared among groups applying Tract-based spatial statistics (TBSS). We also analyzed the correlations between altered parameters and cognitive scores and investigated the diagnostic efficacy of different parameters using k-nearest neighbor (KNN).

RESULTS: Compared with NC, FA, ODI, and NDI significantly decreased, while MD and Viso significantly increased in both DLB and AD. Compared with DLB, ODI and NDI significantly decreased in AD. The diffusion parameters of multiple fibers were strongly correlated with cognition. NDI exhibited a relatively larger AUC value in differentiating between groups.

CONCLUSION: Widespread disruption of white matter microstructure is evident in both DLB and AD, with differences in these alterations between the two conditions. NDI holds promise as a neuroimaging biomarker for distinguishing DLB from AD.},
}

@article {pmid42601984,
year = {2026},
author = {Lai, A and Issa, M and Ali, A and Pereira, A and Ali, AA and Chhablani, J and Yan, P},
title = {Aging-Related Choroidal Heterogeneity and Loss: An Investigative Global Human Choroidal Thickness Review (ARCHLIGHT Study).},
journal = {Journal of vitreoretinal diseases},
volume = {},
number = {},
pages = {24741264261457969},
pmid = {42601984},
issn = {2474-1272},
abstract = {PURPOSE: To synthesize current evidence on the pathophysiology, clinical relevance, and implications for age-related choroidal thinning.

METHODS: A systematic literature search of relevant publications was conducted across MEDLINE, Embase, and Cochrane Library, up to and including May 2024. Identified studies reported choroidal thickness changes with aging. Data on subfoveal choroidal thickness, choroidal vascularity index, and associated factors (ethnicity, systemic disease, axial length) were analyzed (PROSPERO ID: CRD420251041101).

RESULTS: Choroidal thickness declines with age, with ethnicity-specific rates ranging from -0.93 µm/year in Spanish cohorts to -4.00 µm/year in Chinese populations. Age-related choroidal thinning correlates with retinal and neurodegenerative pathologies, including glaucoma (nasal choroidal thinning >250 µm in older adult patients), myopic maculopathy (subfoveal choroidal thickness <100 µm in high myopia), and Alzheimer disease (subfoveal choroidal thickness 169 µm vs 253 µm in control patients). Enhanced depth imaging optical coherence tomography (OCT) and swept-source OCT reveal preferential vascular loss (choroidal vascularity index <30%) and stromal atrophy. Systemic risks, such as hypertension or smoking, accelerate choroidal thinning.

CONCLUSIONS: Age-related choroidal thinning exists on a continuum between physiologic aging and pathology, with implications for retinal and systemic health. Future prospective studies will help determine diagnostic thresholds (subfoveal choroidal thickness <200 µm in nonmyopic adults >60 years or rapid thinning beyond ethnic normative values), management recommendations for high-risk cohorts (glaucoma, age-related macular degeneration, high myopia), and therapeutic considerations for monitoring of choroidal thickness changes from moderate- to low-certainty evidence.},
}

@article {pmid42533617,
year = {2026},
author = {Rasmussen, LK and Gomes Moreira, D and Okarmus, J and Simonsen, A and Meyer, M},
title = {Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/15548627.2026.2711596},
pmid = {42533617},
issn = {1554-8635},
abstract = {Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMFR/GP78: autocrine motility factor receptor; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATG: autophagy related; Aβ: amyloid beta; BCL2L13: BCL2 like 13; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAMc: core autophagy machinery components; CSNK2/CK2: casein kinase 2; DUB: deubiquitinase; DNM1L/DRP1: dynamin 1 like; FKBP8: FKBP prolyl isomerase 8; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; GLP-1: glucagon-like peptide 1; HD: Huntington disease; HUWE1: HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; IMM: inner mitochondrial membrane; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARCHF5: membrane associated ring-CH-type finger 5; MCL1: MCL1 apoptosis regulator, BCL2 family member; MDV: mitochondria-derived vesicle; MFN1: mitofusin 1; MFN2: mitofusin 2; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; OMM: outer mitochondrial membrane; OMMAD: outer mitochondrial membrane-associated degradation; OPA1: OPA1 mitochondrial dynamin like GTPase; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PARL: presenilin associated rhomboid like; PD: Parkinson disease; PE: phosphatidylethanolamine; PG: phagophore; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PINK1: PTEN induced kinase 1; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RHOT1/Miro1: ras homolog family member T1; ROS: reactive oxygen species; SIAH1: siah E3 ubiquitin protein ligase 1; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TCA: tricarboxylic acid cycle; TFAM: transcription factor A, mitochondrial; TIMM: translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UPRmt: mitochondrial unfolded protein response; UPS: ubiquitin-proteasome system; USP30: ubiquitin specific peptidase 30; VCP: valosin containing protein; VDAC: voltage dependent anion channel; WIPI: WD repeat domain, phosphoinositide interacting.},
}

@article {pmid42594034,
year = {2026},
author = {Stancu, P and Goodheart, AE and Hentsch, L and Hertler, C and Allali, G and Assal, F},
title = {When Walking Outlasts Cognition: Rethinking the Late-Stage of Lewy Body Dementia.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ndd/aduag001},
pmid = {42594034},
issn = {1660-2862},
abstract = {BACKGROUND: Lewy body dementia (LBD) is characterized by pervasive cognitive, motor, and neuropsychiatric symptoms. Although cognitive decline has traditionally shaped staging and prognosis, accumulating evidence indicates that gait and postural disturbances follow partially independent trajectories and may remain preserved even as cognition deteriorates. These observations challenge conventional assumptions about late-stage decline and suggest that locomotor function may complement cognitive measures when assessing late-stage transition in LBD.

SUMMARY: This review synthesizes current evidence on gait disturbances across the LBD spectrum and their neural substrates, in comparison with Alzheimer's disease (AD) and Parkinson's disease (PD). Gait impairment in LBD arises from distributed network dysfunction involving dopaminergic and cholinergic pathways, fronto-striatal, parietal, and cerebellar contributions, resulting in greater gait variability, reduced automaticity, and heightened dual-task costs relative to AD and PD. Despite this vulnerability, preserved procedural memory, brainstem locomotor circuits, and cerebellar-cortical compensation may allow walking to persist longer than cognition in some individuals. In advanced disease, rapid gait deterioration has been described near the end of life, suggesting that gait trajectories may capture aspects of late-stage decline that cognitive measures, affected by fluctuations and attentional instability, may not reliably reflect.

KEY MESSAGES: -Gait and cognition do not decline in parallel in LBD; in some individuals, walking may outlast cognitive abilities.-Gait disturbances reflect distributed network dysfunction rather than isolated motor system degeneration.-In late stages, gait performance may offer a clinically useful indicator of disease transition when cognitive testing becomes less reliable. -Integrating gait assessment into clinical evaluation may enhance prognostication and support palliative care planning in LBD.},
}

@article {pmid42594145,
year = {2026},
author = {Zhang, H and Chen, W and Yuan, S and Ding, S and Bao, H and Cai, B and Sun, J and Lu, W and Zhu, H and Shi, G},
title = {Unraveling the molecular Nexus of Alzheimer's Disease and HIV encephalitis: The role of cellular senescence and transcriptional regulation.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0355548},
pmid = {42594145},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/diagnosis/pathology ; Forkhead Box Protein O3/genetics/metabolism ; *Cellular Senescence/genetics ; Biomarkers/metabolism ; Gene Expression Regulation ; Female ; Male ; Transcription, Genetic ; STAT3 Transcription Factor/metabolism/genetics ; Gene Expression Profiling ; },
abstract = {Alzheimer's disease (AD) and HIV-associated neurocognitive disorder (HAND) share progressive cognitive decline. Their common molecular mechanisms remain poorly understood. Current therapeutic approaches lack effective biomarkers for early diagnosis and intervention. We integrated transcriptomic profiles from multiple independent cohorts across brain tissues and blood. We systematically evaluated diagnostic performance using machine learning algorithms including Random Forest, Support Vector Machine, and XGBoost. Notably, FOXO3 emerged as the top cross-disease biomarker. FOXO3 achieved diagnostic accuracy in AD temporal cortex (area under the curve [AUC] = 0.922, 95% CI: 0.885-0.959). FOXO3 showed diagnostic performance in HAND frontal cortex (AUC = 0.771, 95% CI: 0.724-0.818). FOXO3 expression positively correlated with APP (R = 0.558). FOXO3 expression negatively correlated with MAPT (R = -0.690) and SORL1 (R = -0.856). ACE showed strong positive correlation with FOXO3 (R = 0.685), suggesting vascular involvement. STAT3 and ZNF341 were identified from 21 transcription factor candidates. STAT3 ranked first in HAND integrated cohort (n = 107, AUC = 0.759). STAT3 may function as an inflammatory mediator through JAK-STAT signaling. ZNF341 showed strongest transcriptional association with disease status (β = 5.09 in AD, β = 4.85 in HAND). The two-gene panel (FOXO3-ZNF341) achieved diagnostic accuracy in blood samples (AUC = 0.764, n = 329). This performance approaches clinical utility thresholds. Blood-based detection offers non-invasive diagnostic potential. Saturation analysis identified three molecules as optimal panel size. Marginal AUC gains declined below 0.02 beyond this threshold. FOXO3, STAT3, and ZNF341 showed stable selection frequency (97%, 65%, and 100%, respectively). PI3K-Akt and FoxO signaling pathways were enriched, which are known to regulate apoptosis and cell survival. Taken together, these computational findings indicate FOXO3 transcriptional regulatory activity in neurodegeneration. The three-molecule panel represents candidate blood-based diagnostic biomarkers. These candidate biomarkers warrant further investigation in independent clinical cohorts.},
}

Humans
*Alzheimer Disease/genetics/metabolism/diagnosis/pathology
Forkhead Box Protein O3/genetics/metabolism
*Cellular Senescence/genetics
Biomarkers/metabolism
Gene Expression Regulation
Female
Male
Transcription, Genetic
STAT3 Transcription Factor/metabolism/genetics
Gene Expression Profiling

@article {pmid42594195,
year = {2026},
author = {Piller, C and Smith, JE},
title = {Magic or realism?.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6812},
pages = {652-659},
doi = {10.1126/science.ael4184},
pmid = {42594195},
issn = {1095-9203},
abstract = {Recently discovered genetic variants seem to protect against Alzheimer's disease, suggesting a path toward a cure. But are their powers believable?},
}

@article {pmid42594210,
year = {2026},
author = {Reardon, S},
title = {Tau can wreak havoc in brain cells' energy factories.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6812},
pages = {651},
doi = {10.1126/science.ael4194},
pmid = {42594210},
issn = {1095-9203},
mesh = {*Mitochondria/metabolism ; Humans ; *tau Proteins/metabolism ; *Brain/metabolism/cytology ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Energy Metabolism ; *Neurons/metabolism ; },
abstract = {Study of mitochondria suggests new treatment strategy for Alzheimer's and other diseases.},
}

*Mitochondria/metabolism
Humans
*tau Proteins/metabolism
*Brain/metabolism/cytology
*Alzheimer Disease/metabolism/drug therapy
Animals
*Energy Metabolism
*Neurons/metabolism

@article {pmid42594414,
year = {2026},
author = {Dinnerstein, E},
title = {The missing improvers: Tau pathology, neuroplasticity, and the case for tau-informed patient selection before amyloid immunotherapy.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100653},
doi = {10.1016/j.tjpad.2026.100653},
pmid = {42594414},
issn = {2426-0266},
abstract = {Amyloid immunotherapy with lecanemab and donanemab has been approved on the basis of statistically significant slowing of cognitive and functional decline in early Alzheimer's disease (1,2). Yet clinicians treating individual patients face the everyday challenge of estimating whether a given patient is declining at the rate that would be expected for them, and whether their trajectory reflects a response to treatment. I argue that this difficulty arises in large part because the field cannot yet routinely stratify patients by tau pathology before treatment, even though tau burden is among the strongest available predictors of both the rate of progression and the magnitude of response to amyloid-targeting therapy. Post-hoc and open-label analyses of the Clarity AD and TRAILBLAZER-ALZ 2 programmes suggest that patients with absent, low, or medium tau burden may constitute a biologically distinct group in whom amyloid clearance is most likely to permit clinical stabilization or measurable functional gain. These observations remain hypotheses, generated largely from subgroup, open-label, and biomarker data rather than from prospective trials designed to test them I propose that tau status should be given strong consideration in patient selection, that tau-guided selection should be evaluated prospectively, and that the access, reimbursement, and standardization barriers to tau positron emission tomography (PET) - together with the promise of scalable plasma tau biomarkers - be addressed deliberately as the field moves toward tau-informed treatment. One tau PET tracer is currently approved by the US Food and Drug Administration, and a regulatory decision on a second is anticipated in 2026.},
}

@article {pmid42594416,
year = {2026},
author = {Calm, B and Hinojosa-Calleja, A and García-Gutiérrez, F and Blazquez-Folch, J and Alegret, M and Fernández, MV and De Rojas, I and García-González, P and Olivé, C and Valenzuela-Seba, A and Bayón-Buján, P and Cano, A and Puerta, R and Capdevila-Bayo, M and Muñoz-Morales, Á and Miguel, A and Solivar, A and Montrreal, L and Sanz-Cartagena, P and Rosende-Roca, M and Cantero-Fortiz, Y and Gurruchaga, MJ and Tárraga, L and Boada, M and Marquié, M and Ruiz, A and Valero, S and , },
title = {Predictive value of the Alzheimer polygenic risk score on cognitive decline in patients with mild cognitive impairment and Alzheimer's disease dementia.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100658},
doi = {10.1016/j.tjpad.2026.100658},
pmid = {42594416},
issn = {2426-0266},
abstract = {BACKGROUND: Polygenic risk scores for Alzheimer's disease (AD-PRS) are widely used to estimate genetic susceptibility to AD, but their relationship with the rate of cognitive decline (CD) after clinical onset remains insufficiently characterized.

OBJECTIVES: To examine the association between AD-PRS and longitudinal CD across the AD spectrum and to evaluate the predictive contribution of individual AD-PRS variants.

DESIGN: Large longitudinal observational study in a single-center cohort, with an external cohort to assess generalizability.

SETTING: Memory clinic cohort from Ace Alzheimer Center Barcelona (Ace) with external cohort using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

PARTICIPANTS: The study included 7,233 patients from Ace and 863 from ADNI, with a mean follow-up of 5.4 years in Ace and 3.6 years in ADNI. A biomarker sub-cohort included 1075 participants from Ace and 569 from ADNI.

MEASUREMENTS: CD was quantified as the annual change in Mini-Mental State Examination (MMSE) scores estimated using linear mixed-effects models. Associations between AD-PRS and longitudinal MMSE trajectories were tested adjusting for clinical and sociodemographic (CSD) variables and APOE genotype. Machine learning models and SHapley Additive exPlanations (SHAP) were used to evaluate the predictive relevance of individual variants.

RESULTS: Higher AD-PRS was associated with faster CD in the full clinical cohort and in biomarker subset, independently of APOE genotype. AD-PRS was not associated with baseline MMSE. APOE ε4 was associated with lower baseline MMSE and faster CD only in the full clinical sample. Genetic predictors provided limited improvement beyond CSD variables, and model performance showed limited reproducibility across cohorts.

CONCLUSIONS: AD-PRS is associated with longitudinal CD across the AD spectrum. Although polygenic burden contributes to variability in cognitive trajectories, its added predictive value beyond routinely available clinical variables remains modest.},
}

@article {pmid42594417,
year = {2026},
author = {Zamboni, G and Tondelli, M and Vinceti, G and Gallingani, C and Bercini, Z and Barbieri, A and Carbone, C and Iacovino, N and Cossutti, S and Ballotta, D and Salemme, S and Chiari, A},
title = {From regulatory approval to clinical practice: real-world eligibility for anti-amyloid monoclonal antibodies in an Italian dementia-care network.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100655},
doi = {10.1016/j.tjpad.2026.100655},
pmid = {42594417},
issn = {2426-0266},
}

@article {pmid42594686,
year = {2026},
author = {Xu, Z and Yang, Y and Xiang, K and Zhuo, L and Fang, Z and Lin, X and Dai, C and Liu, J and Sun, J and Tong, Q},
title = {Integrative machine learning and single-nucleus transcriptomics reveal MAPK-centered neuronal responses underlying the potential Alzheimer's disease risk of GenX.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {5},
pages = {e01047},
doi = {10.1016/j.neurot.2026.e01047},
pmid = {42594686},
issn = {1878-7479},
abstract = {Hexafluoropropylene oxide-dimer acid (GenX or HFPO-DA) is a novel per- and polyfluoroalkyl substance developed as a replacement for legacy compounds, yet its potential neurotoxic effects remain poorly understood. In this study, we combined bibliometric profiling, in silico target prediction, in vivo behavioral assessments, single-nucleus RNA sequencing (snRNA-seq), network biology, machine learning, molecular docking, and in vitro validation to explore the potential relevance of GenX in Alzheimer's disease (AD). Bibliometric analysis revealed increasing research attention to GenX-associated health hazards, including emerging concerns regarding brain-related effects. Target prediction identified 301 putative GenX-related genes, which were significantly enriched in AD-related pathways. Behavioral analyses demonstrated that chronic GenX exposure impaired recognition memory and spatial learning in mice. Analysis of human prefrontal cortex snRNA-seq data revealed pronounced transcriptional alterations in AD neurons and identified 200 AD-related neuronal DEGs. Integration with GenX targets yielded 10 overlapping genes, which were further prioritized through protein-protein interaction (PPI) network analysis. Machine learning further identified an 8-gene signature with robust diagnostic performance across training and external validation cohorts. Molecular docking showed favorable binding affinities between GenX and core target proteins. Finally, GenX exposure reduced SH-SY5Y cell viability, activated the RAS-RAF-MEK-ERK cascade, and promoted apoptosis-related alterations, supporting a MAPK-centered neurotoxic mechanism potentially relevant to AD-associated neuronal vulnerability. Collectively, this integrative multi-level analysis provides mechanistic insights into the potential neurotoxic effects of GenX and underscores its possible relevance to neurodegeneration-associated molecular processes in AD.},
}

@article {pmid42594906,
year = {2026},
author = {Koychev, I and Holman, RR},
title = {Semaglutide treatment fails but might prevent Alzheimer's disease.},
journal = {Lancet (London, England)},
volume = {408},
number = {10555},
pages = {602-603},
doi = {10.1016/S0140-6736(26)01647-8},
pmid = {42594906},
issn = {1474-547X},
}

@article {pmid42594919,
year = {2026},
author = {Yang, X and Wang, C and Li, X and Duan, A and Zhou, J and Jiang, Z and Wang, J and 陈, 元},
title = {Bidirectional cross-modal attention with adaptive gating for multimodal alzheimer's disease classification.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae995e},
pmid = {42594919},
issn = {2057-1976},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder, and mild cognitive impairment (MCI) represents a transitional stage between AD and cognitively normal (CN) individuals. Early diagnosis is clinically important for delaying disease progression. To address the limitations of single-modal approaches and the insufficient modeling of complex cross-modal interactions in existing multimodal fusion methods, this paper proposes a multimodal deep learning classification framework integrating structural magnetic resonance imaging (sMRI) and clinical features. The framework employs a 3D ResNet-34 to extract imaging features and a multilayer perceptron (MLP) to encode clinical data. A bidirectional cross-modal attention mechanism enhances associations between imaging and clinical modalities, followed by an adaptive gated fusion module that dynamically integrates concatenated global multimodal features with cross-modal interaction features. To evaluate the robustness of the proposed framework, all experiments were repeated using five different random seeds, and the results are reported as mean ± standard deviation. Experimental results demonstrate competitive performance across multiple classification tasks, achieving accuracies of 95.67% ± 1.70% for three-class classification (CN vs. MCI vs. AD) and 93.64% ± 2.36% for four-class classification (CN vs. early MCI (EMCI) vs. late MCI (LMCI) vs. AD). For binary classification (AD vs. CN, AD vs. MCI, MCI vs. CN, and EMCI vs. LMCI), the method achieves accuracies of 96.83% ± 1.53%, 95.33% ± 1.00%, 95.83% ± 1.39%, and 93.61% ± 2.35%, respectively. The proposed framework provides an effective solution for multimodal deep learning-based computer-aided diagnosis of AD.},
}

@article {pmid42595023,
year = {2026},
author = {Guo, R and Li, D and Zhang, X and Liu, S and Wang, D and Du, Y and , },
title = {Alterations in dynamic connectivity in Alzheimer's disease: Network changes and improved multi-stage classification.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113285},
doi = {10.1016/j.exger.2026.113285},
pmid = {42595023},
issn = {1873-6815},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by large-scale network disruption. While static functional connectivity (sFC) has been extensively studied, dynamic functional connectivity (dFC) and its discriminative value across the AD spectrum remain insufficiently understood. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) data from 174 participants in the Alzheimer's Disease Neuroimaging Initiative, including cognitively normal (CN, n = 44), subjective memory concern (SMC, n = 24), early mild cognitive impairment (EMCI, n = 46), late MCI (LMCI, n = 30), and AD (n = 30), were analyzed to assess group differences in sFC, dFC, and graph-theoretical metrics, as well as their associations with cognition. A BrainNetCNN model was further employed to evaluate the classification performance of sFC, dFC, and their combined features. The results revealed that sFC decreased across MCI stages but increased in AD, whereas dFC variability was predominantly reduced in the pre-dementia groups and increased in AD, particularly in frontal and temporal regions. Several static graph-theoretical metrics were significantly correlated with Mini-Mental State Examination (MMSE) scores, while dFC provided complementary information. In classification tasks, dFC showed higher accuracy than sFC in binary and five-class tasks, and their integration achieved the highest accuracy (CN vs. SMC: 89.6%; five-class: 82.7%). These findings suggest that dFC may provide complementary imaging information for characterizing stage-related network alterations and differentiating diagnostic groups across the AD spectrum.},
}

@article {pmid42595185,
year = {2026},
author = {Liu, WZ and Piao, ZJ and Zhu, TL and Lim, V and Ooi, JP and Niu, QQ},
title = {Peroxynitrite: A Potential Therapeutic Target for Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103299},
doi = {10.1016/j.arr.2026.103299},
pmid = {42595185},
issn = {1872-9649},
abstract = {The pathogenesis of Alzheimer's disease (AD) involves multiple pathological processes, including β-amyloid (Aβ) deposition, aberrant tau modification, oxidative stress, and neuroinflammation. The molecular interaction mechanism among them remains to be further clarified. Peroxynitrite (ONOO[-]) is a potent oxidizing and nitrating reactive nitrogen species formed from the rapid reaction between nitric oxide and superoxide. It mediates protein nitration, lipid peroxidation, and mitochondrial damage, thereby contributing to multiple pathological events in AD. This review outlines the physicochemical properties and biological behavior of ONOO[-], and summarizes recent advances in detection techniques such as fluorescent probes and electrochemical sensors. It focuses on the role of ONOO[-] within the AD pathological network and its interconnections with Aβ deposition, tau pathology, neuroinflammation, and blood-brain barrier disruption. Additionally, this review discusses the therapeutic potential of ONOO[-]-targeted strategies, aiming to provide novel insights into the crosstalk among multiple pathological pathways in Alzheimer's disease.},
}

@article {pmid42595198,
year = {2026},
author = {Seo, J and Kim, K and Park, M},
title = {Distinct Roles of AMPA Receptor Subunits as Potential Therapeutic Targets in Alzheimer's Disease.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108394},
doi = {10.1016/j.phrs.2026.108394},
pmid = {42595198},
issn = {1096-1186},
abstract = {AMPA receptors (AMPARs) mediate fast excitatory neurotransmission and play central roles in synaptic plasticity, learning, and memory. They are heterotetrameric complexes organized as two dimers, with subunits from GluA1 to GluA4. Dysregulation of AMPAR trafficking, localization, and function has been increasingly implicated in amyloid beta (Aβ)- and tau-associated synaptic deficits, which are the pathological hallmarks for Alzheimer's disease (AD). Accumulating evidence suggests that AMPARs play distinct, subunit-specific roles in synaptic plasticity and learning and memory in physiological and pathological contexts. This review synthesizes current understanding of subunit-specific AMPAR-mediated pathological mechanisms in AD and discusses emerging pharmacological strategies targeting AMPARs as potential therapeutic approaches to delay or attenuate disease progression.},
}

@article {pmid42595220,
year = {2026},
author = {Liu, CW and Liu, YM and Li, WJ and Qu, QW and Shan, ZX and Dong, FX and Hou, XQ},
title = {Osthol Ameliorates Alzheimer's Disease-Associated Cognitive Impairment by Targeting the Estrogen-Cholinergic Axis in Age-Stratified Female 3×Tg-AD Mice.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106241},
doi = {10.1016/j.neuint.2026.106241},
pmid = {42595220},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) represents a devastating neurodegenerative disorder globally. It is clinically characterized by cognitive dysfunction, predominantly learning and memory impairments, and is closely associated with cholinergic system damage. Osthol (OST), a bioactive compound with well-documented neuroprotective properties, has been shown to enhance learning and memory functions. However, the precise molecular mechanisms underlying its therapeutic effects on AD-related cognitive impairment remain unclear. This study elucidates the critical interplay between estrogen-cholinergic system imbalance and AD progression across distinct temporal windows in female AD models. By focusing on this sex-specific regulatory axis, we aimed to address a key gap in understanding AD pathogenesis and OST's targeted efficacy. We employed age-stratified 3×Tg-AD mice as an experimental model and utilized comprehensive behavioral paradigms to assess learning and memory functions. An age-dependent gradient of cognitive impairment, accompanied by varying degrees of neuropathological damage, was observed in 3×Tg AD mice across different age groups. OST significantly improved learning and memory performance in 3×Tg AD mice of all age groups. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment effectively alleviated damage to the estrogen-cholinergic-NGF axis through multiple synergistic mechanisms: upregulation of Acetylcholine (ACh), Choline acetyltransferase (ChAT), Tyrosine kinase-A (TrkA), and Nerve growth factor (NGF) expression; downregulation of Acetylcholinesterase (AChE) activity; and increased expression of Estradiol (E2), Estrogen receptor-α (ERα), and Estrogen receptor-β (ERβ). In addition, OST improved synaptic plasticity (Postsynaptic density protein-95 (PSD95), Synuclein (SYN), and Brain-derived neurotrophic factor (BDNF)), inhibited neuronal apoptosis (B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX)), and enhanced neurotransmitter signaling cascades (γ-aminobutyric acid (GABA), Glutamic acid (Glu), Epinephrine (E), and ACh). These findings provide new insights into the mechanisms of AD and support OST as a promising candidate for targeted AD therapy.},
}

@article {pmid42595239,
year = {2026},
author = {Zhang, Z and Zhang, W and Jin, L and Wei, C and Chen, H and Cheng, X and Wei, J},
title = {Decoding TREM2: A microglial receptor governing the fate of myelin.},
journal = {Cellular signalling},
volume = {148},
number = {},
pages = {112815},
doi = {10.1016/j.cellsig.2026.112815},
pmid = {42595239},
issn = {1873-3913},
abstract = {Impaired myelin integrity and defective myelin regeneration represent core pathological features shared by central nervous system (CNS) diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), ischemic cerebral white matter lesions and spinal cord injury (SCI). Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is highly enriched in central resident microglia; it is also expressed by border-associated macrophages and lesion-infiltrating monocyte-derived macrophages, rather than being restricted to parenchymal microglia, acting as a key membrane receptor regulating microglial immune balance, lipid transport, lysosomal degradation and cell polarization. Existing studies demonstrate that TREM2 binds various ligands including myelin lipid debris, apolipoprotein E (APOE) and apoptotic cell components, then activates multiple DNAX-activating protein of 12 kDa (DAP12)-dependent signaling cascades: spleen tyrosine kinase (SYK)-phosphatidylinositol 3-kinase (PI3K), phospholipase C gamma 2 (PLCγ2), beta-catenin and transcription factor EB (TFEB). These pathways jointly clear myelin debris, remodel cholesterol circulation, restrain pro-inflammatory microenvironment and promote oligodendrocyte precursor cell (OPCs) differentiation, exerting bidirectional functions in physiological myelin homeostasis, acute injury response and chronic repair. This narrative review summarizes TREM2's gene and protein structure, ligand recognition modes and full signal transduction network. It illustrates the molecular mechanisms of TREM2 in myelin maintenance, debris clearance and regeneration, compares its distinct pathological roles in various demyelinating diseases, and concludes translational strategies including TREM2 agonism, downstream pathway intervention and biomarker exploitation. Furthermore, this narrative review analyzes unsolved core scientific issues and puts forward research routes for mechanistic research and clinical transformation, offering systematic theoretical basis for targeted drug development against demyelinating encephalopathies.},
}

@article {pmid42595331,
year = {2026},
author = {Amorim Molina, AR and Ansai, JH and Bueno Neto, D and Tsen, C and Gerassi, RC and Silva, MJGD and Gomes, GAO and de Andrade, LP},
title = {Physical Activity, Stress, Burden, and Quality of Life of Caregivers of Older Adults With Dementia: A Cross-Sectional Study During the COVID-19 Pandemic.},
journal = {Journal of aging and physical activity},
volume = {},
number = {},
pages = {1-10},
doi = {10.1123/japa.2024-0304},
pmid = {42595331},
issn = {1543-267X},
abstract = {BACKGROUND/OBJECTIVES: Providing care for older adults with dementia generates stress and challenges, impacting quality of life (QoL). Physical activity offers benefits, and the link between physical activity levels (PAL) and these factors during the pandemic can be further explored. This study aimed to examine associations between PAL, stress, burden, and QoL among dementia caregivers during COVID-19.

METHODS: Eighty-nine caregivers of older adults with mild to moderate dementia participated in the study. The online assessment included a medical history questionnaire, the short version of the International Physical Activity Questionnaire, Zarit Burden Scale, Perceived Stress Scale, and the Alzheimer's Disease Quality of Life Scale-Caregiver Version. Spearman's rho was used to examine correlations between PAL and stress, burden, and QoL. A generalized linear model (gamma distribution) analyzed associations between metabolic equivalents per week and stress, burden, and QoL.

RESULTS: A negative correlation between metabolic equivalents per week and burden (ρ = -.26, p = .014) indicated that higher PAL was correlated to lower burden. A positive correlation between metabolic equivalents per week and QoL (ρ = .34, p = .001) showed that higher PAL was associated with better QoL. No correlation was found between PAL and stress. However, significant associations were observed between PAL and both burden, χ2(1) = 5.065, p = .024, and QoL, χ2(1) = 6.983, p = .008.

CONCLUSIONS: Higher PAL in dementia caregivers is associated with lower burden and better QoL. Significance/Implications: Promoting physical activity may improve caregivers' QoL and reduce burden, guiding future research.},
}

@article {pmid42595466,
year = {2026},
author = {Dowling, T and Zhu, S and Ford, J and Ganem Chagui, O and Omid-Fard, N and Martinez Imbett, RE and Wleklinski, M and Yu, E and Romero, J and Rohatgi, S},
title = {Baseline Amyloid PET Centiloid Score and Risk of Amyloid-Related Imaging Abnormalities in Patients Treated With Lecanemab.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9590},
pmid = {42595466},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Amyloid-related imaging abnormalities (ARIA) are a known complication of anti-amyloid monoclonal antibody therapy for Alzheimer's disease. Centiloid score, derived from amyloid PET/CT, provides a quantitative assessment of baseline amyloid burden; however, its relationship with ARIA risk remains uncertain. This study evaluated whether baseline Centiloid score was associated with ARIA in patients treated with lecanemab and included a secondary exploratory analysis of regional amyloid uptake.

MATERIALS AND METHODS: We retrospectively identified patients treated with lecanemab within a single academic health system who underwent pretreatment florbetaben amyloid PET/CT. Centiloid scores were generated using a standardized processing pipeline. Multivariable logistic regression evaluated the association between baseline Centiloid and ARIA, adjusting for age, sex, APOE ε4 carrier status, and baseline cerebral microbleed presence. ARIA-H and ARIA-E subgroups were evaluated separately using Firth penalized logistic regression. A secondary Cox proportional hazards analysis accounted for unequal follow up durations. Exploratory regional analysis compared baseline amyloid uptake in regions that subsequently developed ARIA-E with that in mirrored contralateral regions.

RESULTS: The primary analysis included 41 patients with ARIA and 72 controls who completed at least 14 lecanemab infusions without ARIA. Baseline Centiloid was not independently associated with ARIA (adjusted OR per 10-Centiloid increase, 1.01 [95% CI, 0.89-1.15]; P = .90), ARIA-H (OR, 1.01 [95% CI, 0.89-1.14]; P = .91), or ARIA-E (OR, 1.02 [95% CI, 0.87-1.21]; P = .78). In the Cox analysis of 41 patients with ARIA and 100 patients without ARIA, baseline Centiloid was not associated with time to ARIA (adjusted HR, 1.01 [95% CI, 0.91-1.11]; P = .91). Among 19 patients with ARIA-E included in the regional analysis, baseline uptake was modestly greater in regions that subsequently developed ARIA-E than in mirrored contralateral regions for SUVmax (3.44 ± 0.78 versus 3.25 ± 0.77; P = .02) and SUVmean (2.60 ± 0.56 versus 2.45 ± 0.64; P = .01).

CONCLUSIONS: Baseline global Centiloid was not independently associated with ARIA in patients treated with lecanemab. Exploratory regional analysis demonstrated modest differences in baseline amyloid uptake in regions that subsequently developed ARIA-E, warranting confirmation in larger prospective studies.},
}

@article {pmid42595483,
year = {2026},
author = {Zhou, L and Keil, S and Wang, XH and Hojjati, SH and Castellanos, CB and Wartchow, KM and Dartora, WJ and Mclntire, LB and Chiang, GC and Li, Y and Butler, TA},
title = {Contribution of Myelin Content to the PET-Measured Amyloid Burden.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.126.272591},
pmid = {42595483},
issn = {1535-5667},
abstract = {Off-target binding to white matter myelin is well established in amyloid-β (Aβ) PET. Whether tracer binding to intracortical myelin influences cortical PET quantification remains unknown. We tested whether accounting for myelin water fraction (MWF), an MRI measure of myelin, improves the correlation between Aβ PET and the Alzheimer disease (AD) plasma biomarker phosphorylated tau 217 (p-tau217). Methods: This study included 114 participants with and without AD who underwent Aβ PET with [11]C-Pittsburgh compound B (n = 60) or [18]F-florbetaben (n = 54), multiecho fast T2 MRI to quantify MWF, and semiquantitative in vitro diagnostic immunoassay to measure plasma p-tau217 levels. Cortical Aβ burden was quantified using SUV ratio and Centiloids. Nested regression models predicted PET signal using age and p-tau217 level, with and without cortical MWF. Results: MWF independently predicted PET-measured Aβ signal and improved model fit by approximately 6% in both the combined and tracer-specific cohorts. Conclusion: Intracortical myelin contributes to Aβ PET signal. Incorporating MWF may improve Aβ PET quantification, with implications for AD diagnosis, patient selection, and monitoring response to anti-Aβ therapies.},
}

@article {pmid42595486,
year = {2026},
author = {Mathoux, G and Boccalini, C and Peretti, DE and Scheffler, M and Margot, H and Ashton, NJ and Zetterberg, H and Frisoni, GB and Garibotto, V},
title = {Clinical and Biologic Characterization of a 3-Level Centiloid-Based Classification of Amyloid PET.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.126.272655},
pmid = {42595486},
issn = {1535-5667},
abstract = {Amyloid PET is commonly interpreted using binary visual classification. However, quantitative assessment on the Centiloid scale identifies an intermediate range of amyloid burden not always captured by dichotomous interpretation. The biologic and clinical relevance of this intermediate category remain unclear, despite its implications for biomarker interpretation, prognostic stratification, and eligibility for amyloid-targeting therapies. Our aim was to characterize individuals within this intermediate range using multimodal biomarker profiles and longitudinal cognitive outcomes, as well as deriving Centiloid thresholds for early tau PET positivity, advanced tau PET positivity, and cognitive decline. Methods: We retrospectively analyzed participants who underwent amyloid PET between 2016 and 2024 at the Geneva Memory Center, including cognitively unimpaired individuals and patients with mild cognitive impairment or dementia. Global amyloid burden was quantified in Centiloids, and participants were categorized into low (<12), intermediate (12-37), or high (>37) groups. Group comparisons, receiver-operating-characteristic curve analyses, and linear mixed-effects models were used to assess fluid biomarker differences, define Centiloid thresholds for tau positivity and cognitive decline, and evaluate longitudinal change in Mini-Mental State Examination scores. Results: Among the 512 participants, 202 (39%) had low, 63 (12%) had intermediate, and 247 (48%) had high Centiloid values. The intermediate-Centiloid group showed biomarker profiles, including cerebrospinal fluid and plasma markers of amyloid, tau pathology, and neurodegeneration, between those of the low and high groups. Both the intermediate- and high-Centiloid groups exhibited faster cognitive decline than did individuals in the low-Centiloid group, with a moderate rate in the intermediate-Centiloid group. Thresholds of 13 and 14 Centiloids best identified individuals with cognitive decline and tau accumulation in the mesial temporal lobe, respectively, whereas 51 Centiloids best discriminated advanced neocortical tau involvement. Conclusion: Centiloid-based classification delineates biologically and clinically distinct stages along the amyloid continuum. Individuals with intermediate Centiloid values already show tau involvement and increased risk of cognitive decline, whereas higher amyloid levels are associated with advanced tau pathology. These findings support a 3-level interpretation of amyloid PET beyond binary classification and highlight the clinical relevance of the intermediate zone.},
}

@article {pmid42595893,
year = {2026},
author = {Konrad-Vicario, KD and Paradise, V and Demir, LY and Nguyen, C and Makinson, CD and Ming, Z and Ramachandran, KV},
title = {Dendritic translation and neuroproteasome-mediated degradation of endogenous tau revealed by STARFISH.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42595893},
issn = {1546-1726},
support = {7DP5OD028133//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; AARFD-23-1151195/ALZ/Alzheimer's Association/United States ; },
abstract = {In Alzheimer's disease, the protein tau is thought to redistribute from axons to the somatodendritic compartment and form fibrillar aggregates. Although tau aggregation is a hallmark of Alzheimer's disease, the dynamics of its synthesis and degradation are not well characterized. Given that nascent polypeptides are particularly susceptible to misfolding, local control of tau synthesis and degradation may be essential to prevent aggregation. Here we develop STARFISH, a method for visualizing the subcellular site of endogenous mRNA translation in primary neurons and in vivo with single-molecule sensitivity and near-codon resolution, without modifying the nascent polypeptide. Using STARFISH, we show that despite the broad distribution of Mapt mRNA, tau is translated exclusively in neuronal dendrites. About one-third of newly synthesized tau is co-translationally or peri-translationally degraded in dendrites by a neuronal-specific plasma-membrane-associated proteasome, the neuroproteasome. Failure of neuroproteasome-mediated degradation leads to the protein synthesis-dependent accumulation of somatodendritically mislocalized endogenous tau aggregates. These findings define a proteostasis mechanism that counterbalances the constitutive physiological overproduction of tau. We speculate that failure of this proteostasis system contributes to tau aggregation in dendrites in Alzheimer's disease.},
}

@article {pmid42596024,
year = {2026},
author = {Reeves, MM and Aviles Carpintero, S and Zanovello, M and Jansen-West, K and Yue, M and Calliari, A and Song, Y and Dunmore, J and Maroto Cidfuentes, C and Ball, S and Kachergus, JM and Killeen, HE and Rawlinson, B and Engelberg-Cook, E and DeTure, M and Day, GS and Graff-Radford, NR and Boeve, BF and Knopman, DS and Petersen, RC and Murray, M and Thompson, AE and Dickson, DW and Fratta, P and Petrucelli, L and Josephs, KA and Prudencio, M},
title = {The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42596024},
issn = {1758-9193},
support = {P30AG062677/AG/NIA NIH HHS/United States ; U01AG006786/AG/NIA NIH HHS/United States ; U54NS123743, R35NS097273//NIH/ ; R01NS120992, R01AG037491//NIH/ ; R01NS120992, U54NS123743//NIH/ ; MR/M008606/1 and MR/S006508/1//Lady Edith Wolfson Fellowship/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/complications ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; DNA-Binding Proteins/metabolism ; *Exons/genetics ; *Nerve Tissue Proteins/genetics ; Aged ; Brain/pathology/metabolism ; Aged, 80 and over ; Cohort Studies ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion.

OBJECTIVE: To investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD.

METHODS: We evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis.

RESULTS: In AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2-another well-known CE target-exhibited no such association.

CONCLUSIONS: These findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.},
}

Humans
*Alzheimer Disease/genetics/pathology/complications
Polymorphism, Single Nucleotide/genetics
Male
Female
DNA-Binding Proteins/metabolism
*Exons/genetics
*Nerve Tissue Proteins/genetics
Aged
Brain/pathology/metabolism
Aged, 80 and over
Cohort Studies
Genetic Predisposition to Disease

@article {pmid42596083,
year = {2026},
author = {Gupta, R and Charankevich, H and Drabo, EF and Brown, T and Gross, AL and Polsky, D and Segal, JB and Ornstein, KA},
title = {Comparison of Claims-Based Algorithms for Dementia Identification: A Cross-Sectional Analysis of the National Health and Aging Trends Study (NHATS).},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70650},
pmid = {42596083},
issn = {1532-5415},
support = {P30AG066587//Hopkins' Economics of Alzheimer's Disease and Services (HEADS) Center of the National Institute on Aging/ ; R01AG060967/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Accurate identification of Alzheimer's disease and related dementias (ADRD) in administrative data is increasingly important for research, care delivery innovation, and policy applications such as risk adjustment. Despite the widespread use of existing claims-based algorithms to identify ADRD, few studies have compared their use to ongoing longitudinal aging studies.

METHODS: In this cross-sectional study, we included 2204 NHATS respondents aged 65 years or older classified as having dementia and enrolled in fee-for-service Medicare in 2019. We determined the performance characteristics of 3-claims-based dementia algorithms using NHATS as a reference standard.

RESULTS: Among NHATS respondents classified as having "probable" dementia, sensitivity was generally low (48.8%-70.5%), while specificity was high (91.5%-97.8%) across all 3 algorithms. The Chronic Conditions Warehouse (CCW) algorithm had the highest sensitivity (70.5, 95% CI: 64.3-76.6), followed by Bynum-Standard 3-year (65.8, 95% CI: 59.6-71.9). Bynum-Standard 1-year had the highest PPV (65.6, 95% CI: 56.9-74.4). The Youden Index and F1 score were generally low and clustered closely across the three algorithms. Odds of ADRD misclassification differed across patient characteristics.

CONCLUSION: Commonly used claims-based algorithms to identify ADRD had reasonable validity, though each presented important context-dependent tradeoffs and none was uniformly superior. These findings highlight the importance of accurately diagnosing ADRD in clinical settings and of understanding each algorithm's strengths and limitations based on the use case. Limitations include that NHATS is not a "gold standard" for comparison of claims-based algorithms and we only analyzed NHATS respondents in a single year.},
}

@article {pmid42596580,
year = {2026},
author = {Desai, P and Howard, M and Tangney, CC and Stone, KL and Redline, S and Holland, TM and Halloway, S and Ba, KK and Santana, JA and Whitmer, RA and Espeland, MA and Hayden, KM and Baker, LD},
title = {Napping, Sleep Apnea, and Cognitive Function: Cross-sectional Results from the U.S. POINTER-zzz Sleep Ancillary Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag198},
pmid = {42596580},
issn = {1758-535X},
abstract = {BACKGROUND: The relationship between the duration of napping and cognitive function is unclear. We examine this association by analyzing baseline data from the US POINTER-zzz Sleep Ancillary Study.

METHODS: This study evaluates sleep assessments obtained via home apnea-screening device, wrist actigraphy, and sleep diaries among 686 older adult participants. Naps were defined as sleep periods with at least 30 continuous minutes outside of the primary period of sleep or the longest sleep duration. We conducted linear regression analyses to test the association between napping minutes and baseline global cognitive function and its domains, including executive function, episodic memory, and processing speed. We also examined whether the association between duration of napping and cognitive function outcomes differed by the presence (n = 223) or absence of sleep apnea (n = 463).

RESULTS: For the total sample, greater minutes of napping were associated with decreased processing speed (β= - 0.0973 (95% CI= - 0.1664, -0.0282)). The interaction analyses between sleep apnea and napping did not reach statistical significance, providing no evidence that sleep apnea modifies the association between napping and cognition in the total sample. Greater minutes of napping were associated with poor executive function in participants with sleep apnea and who were in an under-represented ethno-racial group (β=-0.2493 (95% CI=-0.4943, -0.0042)).

CONCLUSIONS: Study findings are exploratory and suggest that it may be important to detect and treat sleep apnea for possible cognitive benefits, especially in certain subgroups of older adults.},
}

@article {pmid42596624,
year = {2026},
author = {Zhang, Z and Tan, H and Shi, F and Dai, J and Ding, W and Li, J and Wang, Y and Yang, R and Xu, X and Chen, C and Xiao, F and Huang, LA and Liu, X and Liao, R and Yan, L},
title = {A Novel Nogo-A Receptor Antagonist Peptide Impedes Alzheimer's Disease Pathology by Nogo-A/NgR/ROCK Signaling Pathway.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {8},
pages = {e71052},
doi = {10.1002/cns.71052},
pmid = {42596624},
issn = {1755-5949},
support = {82102690//National Natural Science Foundation of China/ ; 2026A1515011575//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 20211128182437730//Guangdong Provincial Medical Science and Technology Research Fund/ ; 2024A03J0902//2024 Joint between City, University (College) and Enterprise/ ; 21626406//Fundamental Research Funds for the Central Universities/ ; 2025-WJHX-31//Horizontal Research from the Guangdong Provincial Health Economics Association/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism/genetics ; *Signal Transduction/drug effects/physiology ; *rho-Associated Kinases/metabolism ; Mice, Transgenic ; *Nogo Proteins/metabolism/antagonists & inhibitors ; Mice ; Amyloid beta-Peptides/metabolism ; *Nogo Receptor 1/antagonists & inhibitors/metabolism ; Humans ; Peptide Fragments/metabolism ; Amyloid beta-Protein Precursor/genetics ; Male ; Disease Models, Animal ; tau Proteins/metabolism ; Presenilin-1/genetics ; *Peptides/therapeutic use/pharmacology ; },
abstract = {AIMS: To evaluate the therapeutic effects of NAP2, a novel NgR1 antagonist peptide, on Alzheimer's disease (AD) pathology and to determine whether inhibition of the Nogo-A/NgR1/ROCK signaling axis can ameliorate neurodegenerative alterations in APP/PS1 mice.

METHODS: APP/PS1 transgenic mice received a three-month NAP2 intervention. Cognitive performance was assessed using standard learning and memory tests. Amyloid-β plaque burden, dendritic spine density, tau phosphorylation, and Aβ42 levels were examined by histological and biochemical analyses. Mitochondrial function and downstream ROCK signaling activity were also evaluated.

RESULTS: NAP2 treatment significantly improved cognitive performance in APP/PS1 mice. NAP2 reduced amyloid-β plaque deposition, decreased Aβ42 expression, and increased hippocampal dendritic spine density. Tau hyperphosphorylation was notably attenuated. In addition, NAP2 alleviated Aβ42-induced mitochondrial dysfunction. Mechanistic studies revealed that NAP2 interfered with ROCK signaling downstream of Nogo-A.

CONCLUSION: NAP2 ameliorates multiple AD-related pathological features, an effect accompanied by the inhibition of the Nogo-A/NgR1/ROCK pathway. These findings highlight the therapeutic potential of NAP2 to enhance resilience against Alzheimer's disease pathology.},
}

Animals
*Alzheimer Disease/pathology/drug therapy/metabolism/genetics
*Signal Transduction/drug effects/physiology
*rho-Associated Kinases/metabolism
Mice, Transgenic
*Nogo Proteins/metabolism/antagonists & inhibitors
Mice
Amyloid beta-Peptides/metabolism
*Nogo Receptor 1/antagonists & inhibitors/metabolism
Humans
Peptide Fragments/metabolism
Amyloid beta-Protein Precursor/genetics
Male
Disease Models, Animal
tau Proteins/metabolism
Presenilin-1/genetics
*Peptides/therapeutic use/pharmacology

@article {pmid42596762,
year = {2026},
author = {Mokdad, AH and Dwyer-Lindgren, L and Murray, CJL},
title = {Chronic Disease and Disability in the United States: Trends, Inequities, and Imperatives for Policy Reform.},
journal = {The Milbank quarterly},
volume = {},
number = {},
pages = {},
doi = {10.1111/1468-0009.70109},
pmid = {42596762},
issn = {1468-0009},
abstract = {UNLABELLED: Policy Points Position Universal, High-Quality Education as a Foundational Public Health Strategy. Long-term health and life expectancy in the United States are shaped more by educational attainment than by any other single factor. Disparities in access to early childhood, K-12, and higher education perpetuate cycles of chronic disease, economic hardship, and shortened lifespan, particularly in marginalized communities. Policymakers must recognize education as a critical public health intervention and commit to providing universal access to high-quality education at every stage of life. This transformation requires shifting the focus from mere per-pupil spending toward the national scaling of high-impact instructional models, such as intensive, high-dosage tutoring and adaptive learning. Leveraging generative AI to provide personalized, real-time instruction tailored to individual student needs is essential to bridge the achievement gap at scale. Furthermore, achieving true educational equity requires decoupling school quality from local property taxes, integrating health literacy and nutrition into curricula, and ensuring higher education remains affordable and accessible for all. Transform the Food and Built Environment to Advance National Metabolic Resilience. The structure of America's food system and built environment directly fuels the escalating burden of obesity, diabetes, and related chronic diseases. Federal and state policies must fundamentally shift agricultural subsidies away from calorie-dense, nutrient-poor commodities toward specialty crops and fresh produce. To ensure these healthy choices are the default for every household, the federal government must finalize and enforce mandatory, interpretive front-of-package warning labels for ultra-processed foods. This shift, designed to move beyond the passive Nutrition Facts panel, will provide at-a-glance transparency and incentivize industrywide reformulation. Furthermore, metabolic health must be integrated into the K-12 experience through mandatory daily high-intensity physical activity to improve cardiorespiratory fitness and cognitive performance and minimally processed school meals. Finally, investments in active transportation infrastructure, including pedestrian greenways and safe routes to school, are essential to encourage movement as a default, closing the "convenience gap" that disproportionately burdens low-income and rural Americans. Normalize Chronic Obesity Management. Acknowledging that no nation has successfully reversed the obesity epidemic through behavioral advice alone, the United States must treat obesity as a chronic biological condition rather than a temporary lifestyle lapse. It is imperative that public and private payers guarantee universal, affordable access to evidence-based treatments, including next-generation pharmacotherapies (such as GLP-1 receptor agonists). These clinical strategies must be coupled with a modernized, real-time health data infrastructure to monitor outcomes and ensure equitable access at the neighborhood level.

CONTEXT: Over the past three decades, mortality from leading causes such as cardiovascular disease and cancer has declined in the United States, but the burden of chronic, disabling conditions, including musculoskeletal disorders, mental and substance use disorders, and obesity, has grown or stagnated, widening the gap between total years lived and years lived in good health. These shifts are accompanied by persistent and widening inequities in longevity by geography, race/ethnicity, and socioeconomic status.

METHODS: This analysis draws on the 2023 Global Burden of Disease Study, which estimates mortality, disability, and risk factor burden for 375 diseases and 88 risk factors nationally and at the state level, combined with findings from the US Health Disparities project. The latter uses small-area estimation to evaluate county-level life expectancy and mortality across five racial/ethnic groups and four educational strata, and the "Ten Americas" framework, which stratifies the population by race/ethnicity, geography, and socioeconomic context.

FINDINGS: In 2023, US life expectancy reached 78.5 years and healthy life expectancy 64.5 years, both still below prepandemic 2019 levels, with a persistent 13-14-year gap between life expectancy and healthy life expectancy. Ischemic heart disease remained the leading cause of death, but drug use disorders rose from the 26th to the leading cause of disability, a 562% increase since 1990, while Alzheimer disease and musculoskeletal disorders also climbed in rank. High systolic blood pressure remained the top mortality risk factor despite a large decline, while high body mass index and high fasting plasma glucose burdens grew substantially. State-level disparities widened, with West Virginia and Mississippi trailing Hawaii by wide and increasing margins. Life expectancy gaps by race/ethnicity, education, and place were large and growing, reaching 20.4 years across the "Ten Americas" by 2021, with county-level life expectancy spanning more than 27 years nationally.

CONCLUSIONS: US health trends reflect a shift from fatal to disabling disease, driven substantially by the obesity/metabolic and substance use epidemics, layered onto deep and widening structural inequities by race/ethnicity, place, and education. Reversing these trends requires a multidimensional policy agenda spanning universal, high-quality education; reform of the food and built environment; normalized clinical management of obesity; expanded, integrated substance use and mental health treatment; and modernized, real-time public health data infrastructure.},
}

@article {pmid42597032,
year = {2025},
author = {Bazan, M and Hsieh, TYJ and Wei, JC and Collier, AY},
title = {Association of preeclampsia with long-term risk of neurodegenerative disorders.},
journal = {Pregnancy (Hoboken, N.J.)},
volume = {1},
number = {4},
pages = {e70041},
pmid = {42597032},
issn = {2997-9684},
abstract = {OBJECTIVE: Preeclampsia (PE) is a common complication of pregnancy linked to increased lifetime risk of multiple comorbidities. However, the link between PE and development of adverse neurologic conditions is still poorly understood. Our objective was to investigate the risk of neurodegenerative disorders for women with PE compared to those without PE.

STUDY DESIGN: We utilized the TriNetX database including electronic health records from 66 healthcare organizations and identified women 18+ years old with their last delivery between January 2000 and December 2023. PE was defined using ICD-10 codes that occurred before delivery up until December 2020. The comparator group included pregnant women in the same period without PE diagnosis. After 1:1 propensity score matching on age at index pregnancy, demographics, health utilization, comorbidities, depression, reproductive factors, and body mass index, hazard ratios (HR), and 95% confidence intervals (CIs) for cognitive disorders were estimated between the PE and comparator group using a Cox proportional hazard regression model. Cognitive outcomes were identified by ICD-10 codes and censored until one of the following conditions was met: (1) development of an outcome, (2) July 26, 2024, or (3) loss to follow-up in the system.

RESULTS: The PE group had a 9% increased risk of symptomatic cognitive impairment (HR 1.09; 95% CI 1.03, 1.16) and a 9% increased risk of composite cognitive impairment outcomes, including clinical, symptomatic, mild cognitive impairment, dementia, or related medication use (HR 1.09; 95% CI 1.03, 1.15) compared to the non-PE group. Similar trends were observed in the term birth subgroup for symptomatic cognitive impairment (HR 1.06; 95% CI 1.00, 1.12) and composite outcomes(HR 1.06; 95% CI 1.01, 1.13). No significant associations were found in the preterm subgroup due to limited events. Risk of Parkinson's disease, parkinsonism, or related outcomes was not statistically different in the main model but was higher in sensitivity analyses with natural language processing (NLP) and accounting for death as competing risk. Cognitive impairment, dementia/Alzheimer's, and vascular dementia showed no differences in the main or NLP sensitivity analyses but were elevated in the competing risk sensitivity analysis.

CONCLUSION: Our findings demonstrate an increased risk of cognitive impairment among individuals with a history of PE, with additional associations for Parkinson's disease and parkinsonism identified in sensitivity analyses. These results highlight the importance of obstetrical health as a predictor of lifelong neurocognitive health, underscoring the need for targeted surveillance and early intervention strategies for neurodegenerative diseases in this population.},
}

@article {pmid42597288,
year = {2026},
author = {Miao, X and Zhang, Y and Gao, C and Meng, W and Yan, J and Zeng, T and Tang, G},
title = {The changing epidemiology of infection-associated mortality in Alzheimer's disease in the United States, 1999-2024.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1885030},
pmid = {42597288},
issn = {1663-4365},
abstract = {BACKGROUND: Infections are major immediate causes of death in patients with Alzheimer's disease, trends across infection subtypes remain poorly characterized. We examined temporal trends, demographic geographic disparities, COVID-19-era patterns, projected infection-associated mortality in United States, 1999-2024.

METHODS: Using CDC Multiple Cause of Death database, infection-associated AD deaths were classified into six subtypes. AAMRs and temporal trends were estimated using joinpoint regression. Kitagawa decomposition assessed demographic age-specific contributions to sex disparities, Bayesian Structural Time Series models projected burden through 2034.

RESULTS: Among 2,342,153 AD-related deaths, 308,045 (13.2%) were infection-associated. Overall infection-associated AAMR declined by 57.6% (AAPC -3.72% per year), diverging from rising AD mortality. Respiratory infections showed the steepest decline (AAMR -68.3%) with improvements across all regions and urbanization strata. By contrast, genitourinary infections were the only subtype with rising burden-absolute deaths increased 75.1%, rural AAMR rose 73.1% over 1999-2020, and central trend-continuation projections suggest a possible further increase, particularly over the near-term horizon, although uncertainty becomes substantial in the longer term. Kitagawa decomposition showed that the female excess in genitourinary mortality was attributable to higher age-specific female rates rather than to population age structure-uniquely among the subtypes examined (cumulative risk effect +11,337; 47.4% of the female excess; cumulative female deaths exceeding male by 170%); the increase in this risk component over time was directionally consistent but of model-dependent statistical significance. Mortality was overwhelmingly concentrated in the oldest age stratum (≥ 85-year rate 2,516-fold that of < 65 years). During the COVID-19 era, overall infection-associated AD mortality fell below pre-pandemic projections, with genitourinary infections showing the smallest cumulative deficit of any subtype. Hispanic individuals had the highest AAMR by 2024, while Non-Hispanic Black individuals maintained elevated septicemia mortality throughout.

CONCLUSION: Although infection-associated AD mortality declined substantially, a growing genitourinary infection burden widened across sex, rural, and racial strata, with trend-continuation projections suggesting a possible further increase, particularly over the near-term horizon. These findings, combined with external clinical evidence on infection prevention, suggest that targeted measures-including CAUTI prevention, sex-specific bladder health programs, and rural infection prevention investment-merit priority attention as baby boomers enter peak AD risk.},
}

@article {pmid42597411,
year = {2026},
author = {Zhang, J and Burkett, BJ and Schwarz, CG and Dizdar, N and Johnson, MP and Bilgin, C and Kemp, BJ and Durski, JM and Lowe, V and Johnson, DR},
title = {Inter-software variability of Centiloid quantification in amyloid PET: A head-to-head comparison of five software platforms.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70443},
pmid = {42597411},
issn = {2352-8729},
abstract = {INTRODUCTION: Centiloid (CL) scaling standardizes amyloid positron emission tomography (PET) quantification across tracers and platforms; however, variability across software implementations may affect diagnostic classification. This study evaluated inter-software variability and diagnostic performance across five platforms using identical [1] [8]F-florbetapir datasets.

METHODS: Retrospectively, 192 patients undergoing [1] [8]F-florbetapir PET/computed tomography (CT) and magnetic resonance imaging (MRI) were analyzed. CL values were generated using four US Food and Drug Administration (FDA) -cleared platforms and an in-house Centiloid standard pipeline. Agreement was assessed using intraclass correlation coefficient, with bias and limits of agreement evaluated by linear modeling and Bland-Altman analysis. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis and classification against visual interpretation.

RESULTS: Agreement was excellent (intraclass correlation coefficient [ICC] 0.969; 95%CI 0.961-0.975). Some platforms produced systematically higher CL values versus others slightly lower. LoA reached ± 30 CL. Diagnostic accuracy was high (area under the curve [AUC]: 0.949-0.975), with sensitivity 0.923-0.968 and specificity 0.667-0.806.

DISCUSSION: Despite excellent agreement, systematic differences persist and may affect classification near thresholds, supporting consistent use of a single processing pipeline.},
}

@article {pmid42597430,
year = {2026},
author = {Powell, WJB and Schindler, SE and Jiménez-Mausbach, M and Oh, IY and Hofmann, A and Snider, BJ and Paczynski, M and Ghoshal, N and Payne, PRO and Lai, AM and Hofford, MR and Gupta, A},
title = {Medical comorbidities of patients receiving amyloid-targeting treatments in a memory clinic.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70445},
pmid = {42597430},
issn = {2352-8729},
abstract = {INTRODUCTION: Trials of amyloid-targeting treatments (ATTs) for early symptomatic Alzheimer's disease (AD) enrolled selected patients with minimal medical comorbidities. We investigated whether real-world memory clinic patients who received ATTs also had fewer comorbidities than the broader clinic population.

METHODS: We extracted data on demographics, comorbidities, and medications from patients who were seen at the Washington University Memory Diagnostic Center from July 1, 2023, through July 1, 2025. We compared the characteristics of patients by biomarker testing status and ATT treatment status.

RESULTS: Of 9938 unique patients, 1948 underwent AD biomarker testing and 335 received ATT infusions (304 lecanemab, 31 donanemab). The patients who underwent biomarker testing or received ATTs were more likely to be White individuals and to have fewer comorbidities than patients who did not undergo testing or receive ATTs.

DISCUSSION: Real-world ATT patients were healthier than the general clinic population and more similar to clinical trial participants.},
}

@article {pmid42597443,
year = {2026},
author = {Tolosa-Tort, P and Okorie, M and Chatterjee, A and Boeriu, AI and Sharma, RU and Andrews, SJ},
title = {Toward personalized medicine in AD/ADRD through genetic-exposome dementia risk assessments.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {70},
pmid = {42597443},
issn = {3005-1940},
abstract = {Genetic-Exposome Dementia Risk Assessments (GEDRA) integrate genomic and environmental risk factors into actionable, patient-centered tools for Alzheimer's disease and related dementias (AD/ADRD). By enabling midlife risk stratification before biomarker or cognitive changes, GEDRA supports personalized medicine through targeted screening, tailored interventions, treatment guidance, and proactive planning. Strategic investment in GEDRA will advance responsible risk communication and translate precision prevention strategies into equitable, clinically meaningful practice.},
}

@article {pmid42597683,
year = {2026},
author = {Ding, S and Guo, Z and Ji, H and He, J},
title = {Metabolic cell death networks in Alzheimer's disease: mechanistic links and therapeutic perspectives of ferroptosis, cuproptosis, and disulfidptosis.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1879368},
pmid = {42597683},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized primarily by progressive cognitive impairment, whose pathogenesis involves multiple pathological processes including protein deposition, metal homeostasis dysregulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. In recent years, metabolism-related cell death modalities such as ferroptosis, cuproptosis, and disulfidptosis have gradually been recognized as potentially involved in neuronal damage in Alzheimer's disease. This review summarizes the fundamental mechanisms of ferroptosis, cuproptosis, and disulfidptosis, along with their research evidence in AD. Ferroptosis is primarily driven by iron imbalance, lipid peroxidation buildup, and impaired GPX4 defense. This process exhibits a bidirectional amplification loop with Aβ and tau pathologies. Cuproptosis contributes to neuronal damage through abnormal copper accumulation, FDX1-related mitochondrial protein lipoylation dysfunction, loss of iron-sulfur cluster proteins, and proteotoxic stress. Disulfidptosis links glucose metabolism disorders, insufficient reducing power, and actin cytoskeleton vulnerability, providing novel insights into metabolic stress and structural damage in AD. Furthermore, the three modes of cell death can undergo cross-regulation through the SLC7A11-NADPH-GSH/GPX4 axis, the FDX1-DLAT/DLST-iron-sulfur cluster axis, as well as upstream factors such as p53, NRF2, and AMPK. Metabolic cell death may constitute a critical pathological network in AD. Targeting these death pathways and their shared hubs is expected to provide new directions for disease stratification, biomarker development, and disease-modifying therapies.},
}

@article {pmid42597738,
year = {2026},
author = {Wang, W and Xu, H and Wu, T and Zhang, Y and Tao, M and Zhao, X and Lu, J and Tang, X and Zhang, S and Zhang, Y and Nan, H},
title = {Differential detectability of pericyte and blood-brain barrier readouts across the Alzheimer's disease clinical continuum: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1870764},
pmid = {42597738},
issn = {1663-4365},
abstract = {BACKGROUND: In Alzheimer's disease (AD), neurovascular unit and blood-brain barrier (BBB) abnormalities are assessed using biologically distinct readouts, often across separate cohorts, complicating interpretation across clinical stages and biomarker domains.

METHODS: We searched major databases (inception to February 7, 2026) for human observational studies quantifying cerebrospinal fluid (CSF) soluble platelet-derived growth factor receptor-β (sPDGFRβ), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) K [trans], or the CSF/serum albumin quotient (QAlb) in cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia groups. Primary contrasts were MCI versus CN, AD dementia versus CN, and AD dementia versus MCI. Outcomes were analyzed separately using standardized mean differences (SMDs) in random-effects models with restricted maximum-likelihood estimation and Hartung-Knapp adjustment. Sensitivity analyses incorporated amyloid/AT (N)-informed biologic anchoring and evidence-tier restrictions where possible.

RESULTS: We included 24 cross-sectional studies (3,644 participants). Compared to CN, MCI showed higher CSF sPDGFRβ (SMD 0.38, 95% CI 0.03-0.73) and DCE-MRI K [trans] (SMD 0.91, 95% CI 0.09-1.73; highly heterogeneous and based on five studies), whereas the difference for QAlb was smaller (SMD 0.19, 95% CI 0.01-0.37). Stricter etiologic restriction weakened the robustness of MCI-stage estimates, particularly for early AD-specific inferences in cohorts without consistent biomarker confirmation. Tier 1-only pooling was not feasible because biomarker-confirmed MCI-stage evidence was sparse. AD dementia versus CN comparisons showed higher values across all readouts: CSF sPDGFRβ (SMD 0.43, 95% CI 0.12-0.73), K [trans] (SMD 0.90, 95% CI 0.56-1.25; based on four studies), and QAlb (SMD 0.28, 95% CI 0.10-0.45). AD dementia versus MCI comparisons showed no significant pooled differences for CSF sPDGFRβ or QAlb; K [trans] pooling was precluded by insufficient data.

CONCLUSION: Pericyte- and BBB-related readouts showed readout-specific, cross-sectional detectability patterns across the AD clinical continuum. K [trans] findings should be considered preliminary because of the small evidence base, and MCI-stage estimates remain limited by etiologic uncertainty. Overall, CSF sPDGFRβ, DCE-MRI K [trans], and QAlb appear related but non-interchangeable, and the present cross-sectional evidence should not be interpreted as demonstrating temporal priority, within-person progression, or head-to-head biomarker superiority.

PROSPERO, CRD420251142518.},
}

@article {pmid42597739,
year = {2026},
author = {Skourti, K and Katsaitis, F and Pavlidi, P and Anesti, M and Balla, J and Emvalomatis, A and Kokras, N and Dalla, C and Sotiropoulos, I},
title = {Mental health and gut-brain crosstalk: implications for depression and Alzheimer's disease.},
journal = {Neuroscience applied},
volume = {5},
number = {},
pages = {107023},
pmid = {42597739},
issn = {2772-4085},
abstract = {Brain health and mental health disorders are increasingly becoming an essential priority for modern societies as they affect different parameters of life, such as brain health, quality of life, and productivity with a heavy societal and economic burden. Among mental health disorders, depression and Alzheimer disease (AD) have the higher impact on mental health globally as they are highly prevalent, cause long-term cognitive and mood deficits while they are deeply interconnected, with chronic stress raising as a risk factor and potential link between both disorders. This review focuses on the gut-brain axis, a bidirectional communication network that links the gut microbiome with the central nervous system, and its role in brain malfunction and pathology related to stress, depression and AD. This intricate gut-brain crosstalk is orchestrated through top-down and bottom-up mechanisms implicating the HPA axis, the enteric nervous system as well as gut microbiota-derived metabolites, neurotransmitters, epigenetic processes and extracellular vesicles/exosomes that can contribute to depression and AD. The current work provides a comprehensive summary of evidence linking gut microbial alterations to these brain pathologies, with particular focus on lifestyle and nutrition (e.g. food, water) as critical regulators. Lastly, we explore the therapeutic potential of microbiome-targeted interventions including pro/pre/post-biotics, and trace elements (e.g. lithium and silicon). Overall, this review highlights the potential of microbiome-centered strategies as novel interventions to support mental health and wellbeing.},
}

@article {pmid42597745,
year = {2026},
author = {Martínez-Molina, N and Orte, S and Migliorelli, C and Ribas, V},
title = {Toward precision neuroscience in Alzheimer's disease: the role of multimodal AI.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1903637},
pmid = {42597745},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly understood as a biologically defined and heterogeneous continuum, requiring models that move beyond symptom-based diagnosis toward individualized risk prediction, stratification, and intervention.

OBJECTIVE: This mini-review outlines how precision neuroscience frameworks may support the characterization of AD by integrating multimodal biomarkers, systems biology, systems neurophysiology, digital health markers, and artificial intelligence (AI).

METHODS: We synthesize recent developments across multi-omics profiling, neuroimaging and electrophysiological biomarkers, AI-based speech analysis, and multimodal machine learning approaches, with emphasis on their potential contribution to biologically informed disease staging and personalized clinical decision-making.

RESULTS: Omics and systems biology approaches are expanding the characterization of molecular pathways involved in AD susceptibility, progression, and treatment response. Systems neurophysiology, including multimodal neuroimaging, electrophysiology, and whole-brain modeling, provides complementary markers of large-scale network disruption across the AD continuum. Digital health technologies, particularly AI-based speech analysis, offer scalable and ecologically valid tools for early risk enrichment and longitudinal monitoring. Multimodal AI models further enable the integration of heterogeneous clinical, molecular, imaging, genetic, and behavioral data into probabilistic representations of disease burden and progression. However, clinical translation remains constrained by interpretability, harmonization, validation, fairness, and accessibility challenges.

CONCLUSION: Precision neuroscience offers a promising framework for reconceptualizing AD as a dynamically modeled and biologically stratified disorder. Future progress will depend on robust multimodal datasets, transparent AI methods, longitudinal validation, and equitable implementation strategies capable of supporting early detection, trial enrichment, and personalized prevention or treatment.},
}

@article {pmid42597859,
year = {2026},
author = {Kang, H and Kang, J and Zeki, M and Seo, JH},
title = {Clustered pattern projection for EEG dementia classification: evaluating the reliability of disorder patterns.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1871265},
pmid = {42597859},
issn = {1662-4548},
abstract = {INTRODUCTION: Electroencephalography (EEG)-based classification of Alzheimer's disease (AD) and frontotemporal dementia (FTD) relative to cognitively normal (CN) controls is commonly interpreted through stable disease-related patterns. However, classification-relevant EEG responses in computational models may also appear fragmented or weakly preserved, making subject-level reliability difficult to assess. This study investigated whether recurrent disorder-like EEG patterns can provide exploratory evidence of subject-wise discriminative organization in dementia classification.

METHODS: We analyzed a publicly available resting-state EEG dataset including AD, FTD, and CN subjects. Clustered Pattern Projection (CPP) was applied to Dynamic Mode Decomposition (DMD)-based epoch descriptors to construct prototype-based EEG representations. Classification was performed using a linear support vector machine under a nested leave-one-subject-out cross-validation (LOSO-CV) framework. Subject-level reliability was further examined using margin-based analysis.

RESULTS: CPP showed competitive subject-level performance, particularly in the FTD vs. CN classification task, a setting in which resting-state discriminative patterns are often less consistently preserved than in AD. In addition, task-dependent subject-level margin patterns were observed under strict subject-wise validation, suggesting that margin analysis may provide a useful exploratory tool for evaluating the reliability of learned EEG representations.

DISCUSSION: These findings suggest that EEG generalization in dementia classification should not be interpreted only through preserved canonical biomarkers. Instead, recurrent disorder-like patterns may contribute to computationally detectable decision structure, and CPP provides a framework for examining such patterns under strict subject-wise validation.},
}

@article {pmid42598237,
year = {2026},
author = {Zhang, M and Zhang, Y and Zhang, Z and Jia, X and Lei, S and Bu, N and Wang, Y and Bai, Y and Wang, S},
title = {Effects of mindfulness-based exercise on Parkinson's disease and Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860499},
pmid = {42598237},
issn = {1664-2295},
mesh = {Humans ; *Parkinson Disease/therapy/psychology ; *Alzheimer Disease/therapy/psychology ; *Mindfulness/methods ; *Exercise Therapy/methods ; Yoga ; Qigong ; Tai Ji ; },
abstract = {OBJECTIVE: Currently, there is a lack of robust evidence demonstrating the efficacy of mindfulness-based exercise (MBE) on motor and cognitive outcomes in individuals with Parkinson's disease (PD) and Alzheimer's disease (AD), resulting in the absence of standardized and effective MBE treatment protocols. This systematic review and meta-analysis summarizes the available evidence to evaluate the therapeutic effects of MBE on motor and cognitive function in PD and AD.

METHODS: For two common neurodegenerative diseases, PD and AD, we searched PubMed, Embase, Cochrane Library, and Web of Science to identify studies published from inception to January 30, 2026. Search terms included neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, mindfulness, Tai Chi, yoga, and Qigong. Two independent reviewers assessed the risk of bias of included studies, performed data extraction, and evaluated the evidence. Treatment effects were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS-III), Timed Up and Go Test (TUG), Berg Balance Scale (BBS), Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), Parkinson's Disease Sleep Scale (PDSS), Activities of Daily Living (ADL), and Parkinson's Disease Questionnaire-39 (PDQ-39). Data analysis was performed using Review Manager 5.4 software to evaluate effect sizes and 95% confidence intervals (CIs). Heterogeneity tests were conducted to assess differences in treatment effects among Tai Chi, yoga, and Qigong.

RESULTS: We screened 4,576 articles and identified 28 studies that met the inclusion criteria. Of the included studies, 23 focused on PD and 5 on AD. Only 7 reported adequate allocation concealment, and 2 implemented participant blinding. GRADE assessment indicated moderate certainty of evidence for UPDRS-III, TUG, BBS, MoCA, and MMSE. BDI, PDSS, ADL, and PDQ-39 were rated as low-quality evidence. The pooled results showed significant effects: UPDRS-III (MD: -4.74, 95% CI [-6.78, -2.70], p < 0.00001); TUG(MD: -1.63, 95% CI [-2.41, -0.85], p < 0.0001); BBS(MD:2.80, 95% CI [1.54, 4.06], p < 0.0001); MoCA (MD: 1.93, 95% CI [1.12, 2.74], p < 0.00001); MMSE (MD: 2.80, 95% CI [0.32, 5.29], p = 0.03); BDI (SMD: -0.18, 95% CI [-0.47, 0.12], p = 0.24); PDSS (SMD: -0.31, 95% CI [-0.91, 0.28], p = 0.30); ADL (MD: -0.59, 95% CI [-3.49, 2.31], p = 0.69); and PDQ-39 (MD: -2.85, 95% CI [-6.36, 0.67], p = 0.11).

CONCLUSION: MBE demonstrated statistically significant improvements in motor function and certain cognitive domains in PD patients, suggesting its potential as a beneficial adjunctive non-pharmacological intervention for ameliorating motor symptoms and delaying cognitive decline, whereas evidence for non-motor symptom improvement remains insufficient. Subgroup analysis further indicated a favorable signal of MBE on cognitive function in AD patients; however, the current evidence is preliminary and warrants validation through additional high-quality studies. Given the inherent challenges in implementing double-blinding due to the nature of MBE interventions, coupled with inadequate allocation concealment, the present findings should be interpreted with caution owing to the substantial risks of performance and selection bias.},
}

Humans
*Parkinson Disease/therapy/psychology
*Alzheimer Disease/therapy/psychology
*Mindfulness/methods
*Exercise Therapy/methods
Yoga
Qigong
Tai Ji

@article {pmid42598344,
year = {2026},
author = {Wang, J and Caiola, C and Teng, CH and Cho, Y and Xu, Z and Finik, J and Siamdoust, S and Chan, YN and Ko, E and Seidenfeld, J and Bankole, AO and Bailey, DE and Mott, C and Wu, B and Plassman, BL and Anderson, RA},
title = {Behavior change techniques in a care partner-assisted oral health intervention for people with mild dementia: a secondary mixed-methods analysis.},
journal = {Innovation in aging},
volume = {10},
number = {9},
pages = {igag069},
pmid = {42598344},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: Oral hygiene declines early in mild dementia (MD), yet few interventions specify which behavior change techniques (BCTs) drive improvement. We examined the use of BCTs in relation to oral health outcomes in a care-partner-assisted intervention for persons living with MD.

RESEARCH DESIGN AND METHODS: Using a secondary convergent mixed-methods design, we analyzed the coaching arm of a three-arm randomized trial. Seventeen dyads (persons living with MD-care partners) completed four coaching sessions (68 coaching session transcripts). Seventeen BCTs were specified for use in the coaching manual. Transcripts were double-coded to denote frequency of BCTs used. Changes in the Gingival Index (GI) of persons living with MD between pre- and post-intervention were categorized as Stable/Worsened, Improved, or Meaningfully Improved. BCT frequencies were compared across these categories and integrated with qualitative data using joint displays.

RESULTS: The most frequently used BCTs were reviewing behavior goals, problem-solving, behavioral instruction, and prompts/cues. Two unspecified BCTs (action planning and emotional/relational support) were also commonly used. Meaningfully Improved dyads showed coordinated routines, greater autonomy for persons living with MD, and flexible BCT adaptation; Improved dyads used iterative action planning; Stable/Worsened dyads relied more on coach-led BCTs with limited adaptation. Care partners most often delivered prompts/cues and problem-solving, whereas persons living with MD engaged in goal setting and skill acquisition.

DISCUSSION AND IMPLICATIONS: While planned instructional BCTs established a necessary foundation, adaptive elements (e.g., action planning and relational support) proved essential for integrating oral care into daily life and achieving meaningful health improvement.},
}

@article {pmid42598552,
year = {2026},
author = {Bhatt, Y},
title = {Mechanistic convergence of Astragalus-derived phytochemicals in Alzheimer's disease: A systematic review.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {450-463},
pmid = {42598552},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β aggregation, tau pathology, oxidative stress, and neuroinflammation. Despite extensive research, effective disease-modifying therapies remain limited, underscoring the need for multi-target therapeutic strategies. Species of the genus Astragalus, widely used in traditional medicine, have gained attention for their neuroprotective potential due to diverse bioactive constituents, including saponins, flavonoids, and polysaccharides. This systematic review synthesizes current preclinical and emerging clinical evidence on the neuroprotective mechanisms of Astragalus species in AD. Literature was systematically analyzed in accordance with PRISMA guidelines. The findings indicate that Astragalus-derived compounds exert multi-target effects through modulation of key signaling pathways, including PI3K/Akt, Nrf2/ARE, MAPK, and NF-κB. These interactions collectively reduce oxidative stress, attenuate neuroinflammation, inhibit neuronal apoptosis, and improve synaptic function. Several studies further suggest roles in mitigating amyloid-β toxicity and tau hyperphosphorylation. Collectively, the evidence supports a systems-level pharmacological model in which Astragalus species mediate convergent neuroprotective effects across interconnected molecular pathways. However, translation to clinical application remains limited by insufficient human studies, variability in species-specific phytochemical profiles, and lack of standardized formulations. Future research should prioritize well-designed clinical trials, comparative species-level analyses, and mechanistic validation to establish the therapeutic potential of Astragalus in AD.},
}

@article {pmid42598558,
year = {2026},
author = {Abbasi, H and Hawn, SE and Javanbakht, A and Seedat, S and Bourassa, K and Sinnott, SM and Seligowski, AV and Hemmings, S and Kimbrel, NA and Wolf, E and Smith, AK and Brick, L and Mehta, D},
title = {From molecules to minds: Integrative multi-omics in psychiatry.},
journal = {Journal of mood and anxiety disorders},
volume = {15},
number = {},
pages = {100194},
pmid = {42598558},
issn = {2950-0044},
abstract = {Psychiatric disorders are biologically complex conditions arising from interactions across genomic, epigenomic, transcriptomic, proteomic, metabolomic, and metagenomic layers. Single-omics approaches rarely capture more than a fraction of the variance in complex conditions, underscoring the importance of integrative multi-omics frameworks. This mini-review summarizes key methodologies and their application in psychiatric research, with a focus on systems-level integration of genomic risk scores, transcriptomic networks, and neuroimaging data to advance biological understanding of disorders such as depression, schizophrenia, and Alzheimer's disease. We also outline the infrastructural requirements for effective multi-omics research, including standardized biobanking, Laboratory Information Management Systems, adherence to FAIR data principles, and federated learning approaches for privacy-preserving analysis. Importantly, we highlight the need for greater global inclusivity in psychiatric genomics. Current datasets are heavily biased toward relatively high-resourced and predominantly White, non-Hispanic populations, limiting generalizability. Initiatives such as the Psychiatric Genomics Consortium-Africa and H3ABioNet demonstrate how locally led efforts can strengthen capacity, promote data sovereignty, and support equitable research practices. Advancing multi-omics psychiatry will require coordinated investment in infrastructure, training, and inclusive international collaboration. This mini-review serves primarily as a conceptual roadmap, highlighting what integrative approaches have demonstrated so far and future directions for the field.},
}

@article {pmid42598675,
year = {2026},
author = {van de Zande, NA and Ruiter, CCC and Polman, MA and Brama, SCM and Roos, RAC and Kremer, PHC and de Bot, ST},
title = {Tracing neuroinflammation in neurodegeneration: insights from a scoping review on biofluid biomarkers.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag289},
pmid = {42598675},
issn = {2632-1297},
abstract = {Neuroinflammation is increasingly recognized as a key pathological process in neurodegenerative disease and can be monitored using biofluid biomarkers. Objective biomarkers may aid diagnosis, prognosis and progression. We conducted a scoping review of neuroinflammation biomarkers across major neurodegenerative diseases covering the past 23 years, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, Lewy body dementia, multiple system atrophy and progressive supranuclear palsy. PubMed and Web of Science were systematically searched for observational studies from 2003 to 2025 reporting neuroinflammation biomarkers in adult human subjects. Included markers encompassed blood, cerebrospinal fluid, saliva and urine, providing possible complementary information. Original studies on non-neuroinflammatory mechanisms, cellular or post-mortem biomarkers, animal models, genetics and comparisons between diseases were excluded. Two reviewers independently screened articles; biomarkers reported in ≥3 independent cohorts per disease were analysed. A total of 388 studies were included, predominantly in Alzheimer's disease/mild cognitive impairment (n = 214) and Parkinson's disease (n = 92). Eight biomarkers were most frequently reported: IL-6, TNF-α, IL-1β, CRP/hs-CRP, IL-10, MCP-1, YKL-40 and neutrophil-to-lymphocyte ratio (NLR), measured in blood or cerebrospinal fluid (CSF) as indicators of inflammatory processes associated with neurodegeneration. Across biomarkers, the strength and scope of evidence varied. Most studies demonstrated higher biomarker levels in disease, with more advanced stages, greater clinical severity and faster progression. NLR showed the most consistent pattern across staging, severity and progression, but is currently under-represented across diseases. CSF YKL-40 generally increased with disease presence and advancement; IL-6 showed consistent increases in advanced stages and with severity, although significant results were limited; MCP-1, CRP and TNF-α were mostly linked to severity and progression; IL-1β and IL-10 remained largely inconsistent. Other markers, including GFAP, showed associations in Alzheimer's disease but remain underexplored in other neurodegenerative diseases. Variability across studies, including differences in biofluid source, assay sensitivity, population characteristics and statistical approaches, limits interpretability and comparability. Although neuroinflammation is elevated in neurodegenerative diseases and generally intensifies as these diseases progress, potentially contributing to downstream pathology, the precise timing, role and predictive value of these biomarkers remain uncertain. A subset of markers, including NLR, YKL-40 and GFAP, shows relatively consistent associations and may warrant further investigation across diseases. In clinical practice, neuroinflammation biomarkers could serve as complementary tools to capture inflammatory processes related to disease heterogeneity and progression. Future longitudinal studies tracking pre-symptomatic and early-stage individuals, with standardized approaches, are needed to define temporal dynamics and explore their utility for monitoring disease progression and therapeutic response.},
}

@article {pmid42598748,
year = {2026},
author = {Tonietto, M and Silvestri, E and Belder, CRS and Barkhof, F and Fox, NC and Smith, J and Klein, G},
title = {Volume change with gantenerumab: Impact of amyloid-related imaging abnormalities and amyloid removal.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71749},
doi = {10.1002/alz.71749},
pmid = {42598748},
issn = {1552-5279},
support = {//F. Hoffmann-La Roche/ ; },
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/pathology/drug effects ; Female ; Male ; Magnetic Resonance Imaging ; *Amyloid/metabolism ; White Matter/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: Amyloid-lowering antibodies are associated with neuroanatomical volume changes. This study aims to disentangle the contributions of amyloid-related imaging abnormalities (ARIA) and amyloid clearance to these changes.

METHODS: Data from the GRADUATE I and II trials of gantenerumab in early Alzheimer's disease were analyzed. Participants were grouped as placebo, gantenerumab-treated without ARIA, or gantenerumab-treated with ARIA.

RESULTS: Gantenerumab treatment was associated with greater parenchymal volume reduction than placebo, with no difference between ARIA and non-ARIA groups. The ARIA group exhibited greater ventricular enlargement which was offset by reduced external cerebrospinal fluid space expansion. Greater amyloid removal correlated with greater volume reduction, although volume changes also occurred in white matter, where amyloid is minimal. Furthermore, the ARIA group showed a flatter relationship between ventricular expansion and clinical decline.

DISCUSSION: ARIA are not associated with long-term parenchymal reduction; rather, they are linked to a fluid shift from the external space to the ventricles. Amyloid removal correlates with parenchymal changes, but white matter changes suggest additional mechanisms beyond local clearance. Neither phenomenon was associated with worse clinical outcomes.

TRIAL REGISTRATION NUMBER: NCT03444870 and NCT03443973.},
}

Humans
*Antibodies, Monoclonal, Humanized/therapeutic use
*Alzheimer Disease/drug therapy/diagnostic imaging/pathology
*Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/pathology/drug effects
Female
Male
Magnetic Resonance Imaging
*Amyloid/metabolism
White Matter/pathology/diagnostic imaging

@article {pmid42598755,
year = {2026},
author = {Alexopoulos, H and Louka, XP and De Natale, ER and Koutroubi, K and Cashmore, L and Panayotacopoulou, MT and Trougakos, IP and Wilson, H and Politis, M},
title = {Regional astrocyte dysregulation and altered glymphatic-related markers in Alzheimer's disease frontal cortex.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71745},
doi = {10.1002/alz.71745},
pmid = {42598755},
issn = {1552-5279},
support = {//City Electrical Factors Ltd/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Astrocytes/metabolism/pathology ; *Frontal Lobe/pathology/metabolism ; *Aquaporin 4/metabolism ; *Glial Fibrillary Acidic Protein/metabolism ; Female ; Male ; Aged ; Aged, 80 and over ; *Glymphatic System/metabolism/pathology ; White Matter/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Gray Matter/metabolism/pathology ; tau Proteins/metabolism ; },
abstract = {INTRODUCTION: Astrocyte dysfunction is central to Alzheimer's disease (AD), yet expression patterns of astrocytic markers remain poorly defined. We measured Aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) in post-mortem frontal cortex of AD patients and controls across BrainNet Europe (BNE) stages.

METHODS: We assessed marker expression across gray and white matter with immunohistochemistry and immunofluorescence.

RESULTS: In AD, gray-matter AQP4 area-fraction did not differ significantly overall by immunohistochemistry, while a stage-dependent increase emerged by BNE VI in both gray and white matter. AQP4/amyloid-β (Aβ) and AQP4/tau ratios were significantly reduced, consistent with reduced AQP4 retention relative to local proteinopathy burden. GFAP intensity was significantly decreased in both gray and white matter of AD patients, with disorganized peri-plaque morphology in gray matter.

DISCUSSION: These findings reveal compartment- and stage-specific astrocytic dysregulation in AD frontal cortex and identify local loss of AQP4 around proteinopathy. They support investigation of astrocyte/glymphatic-related pathways as biomarkers and therapeutic targets.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*Astrocytes/metabolism/pathology
*Frontal Lobe/pathology/metabolism
*Aquaporin 4/metabolism
*Glial Fibrillary Acidic Protein/metabolism
Female
Male
Aged
Aged, 80 and over
*Glymphatic System/metabolism/pathology
White Matter/metabolism/pathology
Amyloid beta-Peptides/metabolism
Biomarkers/metabolism
Gray Matter/metabolism/pathology
tau Proteins/metabolism

@article {pmid42585316,
year = {2026},
author = {Gallego-Rudolf, J and Wiesman, AI and Yakoub, Y and Zetterberg, H and Blennow, K and Baillet, S and Villeneuve, S and , },
title = {Prediction of mild cognitive impairment progression using time-sensitive multimodal biomarkers.},
journal = {Science advances},
volume = {12},
number = {33},
pages = {eaee2305},
pmid = {42585316},
issn = {2375-2548},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/blood/diagnostic imaging/metabolism ; *Biomarkers/blood ; Disease Progression ; Female ; Aged ; Male ; Alzheimer Disease/diagnosis ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Magnetoencephalography ; },
abstract = {Alzheimer's disease (AD) develops silently for years before symptoms emerge, making early identification of at-risk individuals essential for prevention trials and early intervention. We tested whether combining neurophysiological, imaging, and blood biomarkers improves prediction of progression to mild cognitive impairment (MCI) in cognitively unimpaired older adults with a family history of AD (n = 102; 31 progressors; mean follow-up of 5.9 years). Magnetoencephalography, magnetic resonance imaging, plasma biomarkers, and amyloid and tau positron emission tomography each captured complementary aspects of disease biology. Multimodal models predicted progression more accurately than demographic and genetic factors alone. Higher MEG alpha power was associated with increased near-term risk, whereas higher gamma activity predicted lower near-term risk; both effects weakened over time. Higher neocortical amyloid burden predicted increasing risk over follow-up, whereas plasma biomarkers and entorhinal tau predicted higher risk without significant time-varying effects. These findings support a time-sensitive multimodal framework for identifying cognitively unimpaired individuals at risk of MCI due to AD.},
}

Humans
*Cognitive Dysfunction/diagnosis/blood/diagnostic imaging/metabolism
*Biomarkers/blood
Disease Progression
Female
Aged
Male
Alzheimer Disease/diagnosis
Positron-Emission Tomography
Magnetic Resonance Imaging
tau Proteins/metabolism
Magnetoencephalography