@article {pmid42663490,
year = {2026},
author = {Dejgaard, MS and Eide, PK and Tangen, GG and Skovlund, E and Selbæk, G and Wyller, TB},
title = {Cognitive profiles in idiopathic normal pressure hydrocephalus and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478264},
doi = {10.1177/13872877261478264},
pmid = {42663490},
issn = {1875-8908},
abstract = {BackgroundIdiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) are neurodegenerative disorders with partly overlapping clinical features. Since the treatment is different, we need better knowledge about how the cognitive profile differs between these conditions.ObjectiveWe aimed to compare the cognitive profile of iNPH patients with that of a large cohort of confirmed AD patients.MethodsPatients diagnosed with iNPH and accepted for shunt surgery were compared with patients with biomarker verified Alzheimer's disease in The Norwegian Register of Persons Assessed for Cognitive symptoms (NorCog). All patients underwent a standardized cognitive assessment with age and education adjusted z-scores. We used the Clinical Dementia Rating Scale (CDR) to adjust for disease severity. Since the cognitive score distributions were highly skewed, we used nonparametric analyses stratified by CDR stage combined with multinomial logistic regression.ResultsIn total, 276 iNPH patients were compared to 1113 AD patients. iNPH patients performed significantly poorer on phonemic fluency [median z-score difference (AD-iNPH) 0.30, 95% confidence interval (CI) 0.20 to 0.50], but significantly better on other cognitive tests, in particular immediate (median difference -0.35, 95% CI -0.49 to -0.20) and delayed recall (median difference -0.46, 95% CI -0.59 to -0.34). The differences persisted after adjustment for CDR and were most pronounced in early stages of the disease.ConclusionsiNPH seems to affect phonemic fluency more and memory less than AD. As the disease progresses, the cognitive profiles become more similar, and the conditions cannot be distinguished by cognitive tests.},
}

@article {pmid42663491,
year = {2026},
author = {Seo, EH and Kang, S and Kim, SG and Kim, JH and Yoon, HJ and Choi, KY and Yoon, HJ and Lee, KH and Choi, KH},
title = {Multistrain probiotics modulate tau pathology and preserve visuospatial cognition in early cognitive impairment: A double-blind, randomized, placebo-controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477084},
doi = {10.1177/13872877261477084},
pmid = {42663491},
issn = {1875-8908},
abstract = {BackgroundThe gut-brain axis is increasingly implicated in Alzheimer's disease (AD) pathogenesis.ObjectiveTo investigate whether a multistrain probiotic supplement is associated with changes in AD-related plasma biomarkers and cognitive function in older adults with early cognitive impairment.MethodsIn this randomized, double-blind, placebo-controlled trial, eighty-seven participants from the Gwangju Alzheimer's Disease and Related Dementias cohort were randomized to receive a multistrain probiotic (n = 40) or placebo (n = 47) for 24 weeks. Plasma phosphorylated tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were evaluated at baseline and 24 weeks. Cognitive assessments included the Clinical Dementia Rating Sum of Boxes (CDR-SB), CERAD battery, Stroop test, and Rey-Osterrieth Complex Figure (ROCF). Analyses utilized linear mixed models and ANCOVA.ResultsCompared to placebo, the probiotic group exhibited a significant reduction in plasma pTau181 (p < 0.001). While GFAP and NfL remained stable with probiotics, the placebo group showed significant within-group increases (p = 0.014, p = 0.041). Clinically, the probiotic group demonstrated improved CDR-SB scores (p = 0.010), primarily driven by the memory domain. Probiotics were associated with improved performance in visuospatial construction tasks (Constructional Praxis, p = 0.036; ROCF copy, p = 0.027) and preserved constructional recall, whereas the placebo group exhibited significant decline (p = 0.025). No significant between-group differences were observed in Mini-Mental State Examination, verbal memory, or executive scores.ConclusionsMultistrain probiotics modulated plasma tau and neuroinflammatory biomarkers, and selectively preserved visuospatial cognition in this study. These findings suggest the potential role of microbiota-targeted interventions as a non-pharmacological adjunct for early cognitive impairment, although further studies are required to confirm underlying mechanisms.},
}

@article {pmid42663652,
year = {2026},
author = {Xia, Z and Cheng, W and Ng, YL and Li, K and Cheng, Z and Duan, Y},
title = {Associations of visceral adipose tissue metabolism with DMN-centered cross-network metabolic expression concordance and cognitive impairment in Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42663652},
issn = {1619-7089},
support = {82202235//National Natural Science Foundation of China/ ; ZR2022MH165//Natural Science Foundation of Shandong Province/ ; tsqn202312358//Taishan Scholar Foundation of Shandong Province/ ; },
abstract = {PURPOSE: Visceral adipose tissue (VAT) has been identified as a risk factor for Alzheimer's disease (AD). This study aimed to investigate the associations between glucose metabolism in VAT and subcutaneous adipose tissue (SAT) with abnormalities in large-scale brain metabolic networks and cognitive impairment in patients with AD.

METHODS: Ninety-eight patients with AD and 51 normal controls (NCs) underwent total-body [18]F-FDG PET/CT examination. Glucose metabolic activity in VAT and SAT was quantified using lean body mass-corrected standardized uptake values (SULs). Independent component analysis (ICA) was applied to brain PET images to identify large-scale metabolic networks, from which subject-specific metabolic load scores were derived. A default mode network (DMN)-centered metabolic expression concordance (DMN-MEC) index was further derived to characterize individual-level relative metabolic expression patterns between the DMN and other large-scale brain networks. Group differences in adipose tissue metabolism and brain metabolic network metrics were examined. Within the AD group, correlations among abdominal adipose tissue metabolism, DMN-MEC index, and cognitive performance were assessed.

RESULTS: Compared with NCs, patients with AD showed significantly increased glucose metabolism in both VAT and SAT, accompanied by reduced metabolic load scores in the DMN, dorsal attention network (DAN), frontoparietal network (FPN), and sensorimotor network (SMN), and lower global DMN-MEC. Correlation analyses within the AD group showed that the DMN metabolic load score was significantly positively correlated with the metabolic load scores of multiple other networks. Furthermore, VAT metabolism was significantly negatively associated with the global DMN-MEC index, whereas SAT metabolism showed no such association. VAT metabolic activity was also negatively correlated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. In contrast, DMN metabolic load and global DMN-MEC index showed positive associations with cognitive performance.

CONCLUSION: These findings revealed concomitant abdominal adipose tissue metabolic dysfunction and disruption of large-scale brain metabolic network expression in AD. Importantly, higher VAT metabolism was associated with lower global DMN-MEC and poorer cognitive performance.},
}

@article {pmid42663797,
year = {2026},
author = {Martínez-Flores, R and Martín-Sobrino, I and Falgàs, N and Grau-Rivera, O and Suárez-Calvet, M and Cristi-Montero, C and Ibañez, A and Fernández-Lebrero, A and Contador, J and Navalpotro-Gómez, I and Puig-Pijoan, A and Supèr, H},
title = {Cognitive vergence and pupillary responses as functional oculomotor signatures to differentiate AT(N) biological profiles in older adults with mild cognitive impairment.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42663797},
issn = {2509-2723},
support = {PID2022-139968OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; },
abstract = {The locus coeruleus (LC), the earliest site of tau accumulation in Alzheimer's disease, directly influences pupillary and vergence oculomotor systems. Whether task-evoked oculomotor dynamics can non-invasively differentiate AT(N) profiles, A+T+ (biological Alzheimer's disease) and A-T+ (suspected non-Alzheimer's tauopathy), remains unexamined despite their differential impact on LC-mediated modulation and cortical network integrity. Thirty-eight MCI individuals (12 A-T+, 26 A+T+), classified using validated CSF biomarker thresholds, completed a visual oddball paradigm under binocular eye-tracking. Linear mixed-effects models examined profile × condition interactions across full time series and six trial-level features; participant-level associations were tested using Firth-penalized logistic regression to account for the small and imbalanced sample. Profiles did not differ in oculomotor magnitude but diverged in temporal organization. Profile × condition interactions were significant for vergence global slope, vergence time to peak, and pupillary time to peak (all p-Holm ≤ 0.048). Timing differences were condition-dependent: A-T+ showed later responses during distractor trials, while A+T+ showed the most delayed timing during target trials. Subject-level associations were significant for vergence and pupillary time to peak, with greater condition-dependent modulation predicting higher A+T+ probability (ORs = 0.43 and 0.35; both p < 0.05); vergence global slope delta did not reach significance at the subject level. A-T+ showed superior target detection accuracy (89.7% vs. 82.5%, p = 0.003). Cognitive vergence and pupillary dynamics showed condition-dependent patterns differentiating AT(N) biological profiles in this MCI sample, supporting portable, low-cost eye-tracking as a non-invasive complement to CSF-based characterization, pending confirmation in larger, independent cohorts.},
}

@article {pmid42663999,
year = {2026},
author = {Chang, H and Liu, Y and Yang, X and Han, Y},
title = {Transcriptomic Signatures of Microglial Phagocytosis Reveal Diagnostic Markers and Immune Landscape in Alzheimer's Disease.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {17},
pages = {e72240},
pmid = {42663999},
issn = {1530-6860},
mesh = {*Alzheimer Disease/immunology/diagnosis/genetics/metabolism ; *Microglia/metabolism/immunology/pathology ; Humans ; *Phagocytosis/genetics ; *Transcriptome ; Biomarkers/metabolism ; Gene Expression Profiling ; },
abstract = {The core pathological features of Alzheimer's disease (AD) include Aβ plaques and neurofibrillary tangles, which collectively drive the neurodegenerative process. Meanwhile, the phagocytic function of microglia plays a dual role in AD: it attempts to clear pathological proteins such as Aβ, but its chronic activation may also exacerbate neuroinflammation and synaptic damage. This study integrated microarray data from AD cohorts in the Gene Expression Omnibus (GEO) database. Through differential expression analysis, protein-protein interaction network construction, and three machine learning algorithms (Least Absolute Shrinkage and Selection Operator, Support Vector Machine-Recursive Feature Elimination, and Extreme Gradient Boosting), key microglial phagocytosis-related signature genes were identified. Diagnostic models were subsequently developed and validated, with further investigation of immune infiltration patterns, regulatory networks, and molecular subtypes. Based on comprehensive analysis, this study identified five core signature genes (HLA-DPA1, IL4R, ITGAM, SPP1, TNFRSF1B) that form a highly accurate diagnostic model validated in independent cohorts. Immune infiltration analysis revealed significant increases in neutrophils and M2 macrophages in AD brains, with these genes showing strong correlations with immune cell abundance. The study further identified two molecular subtypes with distinct immune features, constructed regulatory networks, and predicted potential therapeutics including Tamibarotene. By integrating transcriptomics and machine learning, this study identifies key molecular features of microglial phagocytosis in AD, providing a novel diagnostic framework and insights into the immune mechanisms of the disease.},
}

*Alzheimer Disease/immunology/diagnosis/genetics/metabolism
*Microglia/metabolism/immunology/pathology
Humans
*Phagocytosis/genetics
*Transcriptome
Biomarkers/metabolism
Gene Expression Profiling

@article {pmid42664049,
year = {2026},
author = {Melekh, E and Cook, EL and Stante, JG and Marais, AAT and Mohammad, A and Beaudette, SM and Ward, WE and Fajardo, VA and MacPherson, REK},
title = {Metabolic Shifts Precede Cognitive Decline in the Male hAß-KI Alzheimer's Mouse Model.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {17},
pages = {e72241},
pmid = {42664049},
issn = {1530-6860},
support = {//Brock University Explore Grant/ ; //Brock University Chancellor Chair for Research Excellence (CCRE)/ ; },
mesh = {Animals ; Male ; *Alzheimer Disease/metabolism/genetics ; Mice ; Disease Models, Animal ; Female ; *Amyloid beta-Peptides/metabolism/genetics ; *Cognitive Dysfunction/metabolism ; Mice, Transgenic ; Body Composition ; Humans ; },
abstract = {A major barrier in AD research is the lack of animals that recapitulate sporadic AD, which accounts for most human cases. Recently, a novel mouse model (hAβ-KI) was developed by introducing a three-point mutation that humanizes the beta-amyloid peptide. These mice exhibit age-dependent cognitive decline and beta-amyloid accumulation. However, limited research has been conducted related to AD risk factors and sex-specific responses in this model. Male and female control and hAß-KI mice were assessed at ages 4, 8, 10, 12 and 15 months. Body composition (bone mineral density, lean and fat mass) and metabolic function (respiratory exchange rate, energy expenditure, and activity levels) were evaluated, in addition to insulin tolerance testing (ITT). An open field test (OFT) was performed to evaluate anxiety-like behaviors, and novel object location (NOLT) and recognition tests (NORT) were conducted to measure cognitive impairment at endpoint. With aging, the male hAß-KI mice exhibited increased body and fat mass %, decreased lean mass %, decreased activity, and impaired glucose handling prior to confirmed cognitive impairment by NORT and NOLT. In contrast, the female hAß-KI did not display similar differences compared to controls. These findings support the utility of this model as a valuable tool for investigating systemic risk factors related to sporadic AD, and the absence of similar differences in the females highlights the importance of considering sex as a variable in AD pathology.},
}

Animals
Male
*Alzheimer Disease/metabolism/genetics
Mice
Disease Models, Animal
Female
*Amyloid beta-Peptides/metabolism/genetics
*Cognitive Dysfunction/metabolism
Mice, Transgenic
Body Composition
Humans

@article {pmid42664126,
year = {2026},
author = {Sanoop, E and Kumarchandra, R and Madhurya, M and Cherian, A},
title = {Association of Vitamin D Status with Neurobiological Biomarkers in Healthy Elderly Population.},
journal = {La Clinica terapeutica},
volume = {177},
number = {5},
pages = {1067-1073},
doi = {10.7417/CT.2026.2106},
pmid = {42664126},
issn = {1972-6007},
mesh = {Humans ; Biomarkers/blood ; Aged ; Male ; Cross-Sectional Studies ; Female ; *Vitamin D/blood ; Brain-Derived Neurotrophic Factor/blood ; Middle Aged ; Acetylcholinesterase/blood ; Glutathione/blood ; Amyloid beta-Peptides/blood ; Calcium/blood ; Alzheimer Disease/blood ; *Vitamin D Deficiency/blood ; Peptide Fragments/blood ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent type of dementia, is a progressive and irreversible neurological disorder that significantly disrupts social and occupational functioning due to cognitive and behavioral decline. It primarily affects older adults globally. Key factors like synaptic plasticity and neurotransmission in dopaminergic neural circuits is being contributed by vitamin D which offers its therapeutical capability and a new diagnostic tool.

MATERIALS AND METHODS: This cross-sectional study was conducted at the Department of Biochemistry, Centre for Basic Sciences, KMC, Mangalore, involving 90 subjects aged between 45-65 with the different vitamin D status grouping them into Deficient (n=30), Insufficient (n=30) and optimum (n=30). Serum biomarkers, including Aβ42, BDNF, Calcium, Glutathione and Acetylcholinesterase, were analyzed using ELISA and spectrophotometric methods from stored samples. Statistical analysis was performed to explore the relationship between vitamin D status and cognitive related biomarkers.

RESULTS: This study analyzed neurobiological biomarkers in a study population of 90 individuals with different vitamin D status. Vitamin D status was significantly associated with Aβ42, BDNF, Calcium, Glutathione and Acetylcholinesterase. Individuals in the optimum group exhibited lower Aβ 42 levels and higher levels of BDNF, Calcium and Glutathione compared to deficient and insufficient groups indicating potential neuroprotective and antioxidant benefits.

CONCLUSION: Vitamin D offers a protective role in neurodegeneration in healthy aging adults, the more likely mechanisms being enhanced neurogenesis, improved antioxidant status and modulation of neuronal calcium as hallmarks of reducing the levels of the amyloid marker Aβ42. Amongst these, the effect of vitamin D in increasing BDNF was found to be most significant. Vitamin D does not seem to be involved in cholinergic pathway of neurodegeneration as observed in our study.},
}

Humans
Biomarkers/blood
Aged
Male
Cross-Sectional Studies
Female
*Vitamin D/blood
Brain-Derived Neurotrophic Factor/blood
Middle Aged
Acetylcholinesterase/blood
Glutathione/blood
Amyloid beta-Peptides/blood
Calcium/blood
Alzheimer Disease/blood
*Vitamin D Deficiency/blood
Peptide Fragments/blood

@article {pmid42664340,
year = {2026},
author = {Li, S and Jakobs, TC},
title = {Neuron-derived SPP1 instructs microglia to limit degeneration.},
journal = {Science advances},
volume = {12},
number = {35},
pages = {eaee4940},
pmid = {42664340},
issn = {2375-2548},
mesh = {*Microglia/metabolism/pathology ; Animals ; Humans ; Mice ; *Neurons/metabolism/pathology ; *Osteopontin/metabolism/genetics ; Glaucoma/metabolism/pathology ; Autophagy ; Disease Models, Animal ; Neurodegenerative Diseases/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; },
abstract = {Neurons actively shape immune responses that maintain central nervous system integrity. We identify SPP1 (secreted phosphoprotein 1) as a neuron-derived signal that reprograms microglia into a neuroprotective, homeostatic state after injury and during neurodegeneration. In mouse models of glaucoma and optic nerve damage, neuronal SPP1 enhances microglial autophagy, debris clearance, and anti-inflammatory activity, preserving neuronal survival and visual function. SPP1 is elevated in neurons of human and primate glaucomatous retinas, where SPP1[+] cells show increased resilience. In Alzheimer's disease brain, neuronal SPP1 correlates with neuronal survival, while microglia around Aβ plaques display defective autophagy. In human iPSC co-cultures, SPP1 enhances microglial Aβ clearance and prevents neurodegeneration. Thus, SPP1 defines a protective neuron-microglia axis in glaucoma and possibly other neurodegenerative diseases.},
}

*Microglia/metabolism/pathology
Animals
Humans
Mice
*Neurons/metabolism/pathology
*Osteopontin/metabolism/genetics
Glaucoma/metabolism/pathology
Autophagy
Disease Models, Animal
Neurodegenerative Diseases/metabolism/pathology
Alzheimer Disease/metabolism/pathology

@article {pmid42664399,
year = {2026},
author = {Briggs, AM and Schuller, AJ and Hager, MR and Yanouri, OA and Rocha, SM and Bantle, CM and Chatterjee, D and Smeyne, RJ and Tjalkens, RB},
title = {Infection with Western equine encephalitis virus causes severe regional glial reactivity and neurodegeneration in the hippocampus with progressive accumulation of amyloid-β.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag097},
pmid = {42664399},
issn = {1554-6578},
support = {//Farber Development Fund, Thomas Jefferson University/ ; },
abstract = {Encephalitic alphaviruses such as Western equine encephalitis virus (WEEV) result in significant morbidity through acute viremia and postencephalitic neurologic dysfunction. Viral neurotropism is linked to chronic glial-mediated neuroinflammation and increased risk for neurodegenerative disorders including Alzheimer disease and Parkinson disease. We previously showed that sublethal WEEV infection induces nigrostriatal gliosis, neuronal loss, and Parkinsonian-like motor deficits in mice. However, the temporal progression of glial activation and neurodegeneration in brain regions relevant to dementia remains unclear. To address this, we performed a longitudinal assessment of hippocampal pathology following intranasal infection with McMillan WEEV. Brain tissue was collected at 1, 2, and 4 weeks postinfection and analyzed using high-content fluorescence imaging, deep learning-based image analysis, and population-level cellular phenotyping. We observed a marked increase in gliosis peaking at 1-week postinfection, coinciding with fibrotic, immune cell-dense lesions that inversely correlated with eosinophilic neuronal density. Automated skeletonization analysis revealed increased astrocyte reactivity and a predominantly bushy microglial morphology at this time point. Heat map densitometry further demonstrated progressive amyloid-β accumulation across all time points. Together, these findings define a dynamic sequence of glial activation, lesion formation, and protein aggregation underlying WEEV-induced hippocampal neurotoxicity.},
}

@article {pmid42664423,
year = {2025},
author = {Gong, G and An, F and Wang, Y and Bian, M and Yu, LJ and Wei, C},
title = {Retraction: miR-15b represses BACE1 expression in sporadic Alzheimer's disease.},
journal = {Oncotarget},
volume = {16},
number = {1},
pages = {882},
doi = {10.18632/oncotarget.28814},
pmid = {42664423},
issn = {1949-2553},
}

@article {pmid42664430,
year = {2025},
author = {An, F and Gong, G and Wang, Y and Bian, M and Yu, L and Wei, C},
title = {Retraction: MiR-124 acts as a target for Alzheimer's disease by regulating BACE1.},
journal = {Oncotarget},
volume = {16},
number = {1},
pages = {883},
doi = {10.18632/oncotarget.28815},
pmid = {42664430},
issn = {1949-2553},
}

@article {pmid42664573,
year = {2026},
author = {Noguchi-Shinohara, M and Muramatsu, D and Shima, A and Sakashita, Y and Tada, Y and Yamaguchi, H and Komatsu, J and Ikeda, T and Ono, K},
title = {Real-world long-term continuation of lecanemab therapy and the clinical utility of phosphorylated tau 181.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100664},
doi = {10.1016/j.tjpad.2026.100664},
pmid = {42664573},
issn = {2426-0266},
abstract = {This real-world study evaluated the long-term feasibility of lecanemab treatment in 117 patients with early Alzheimer's disease at Kanazawa University Hospital. To assess treatment persistence over a full 18-month course, we focused on the 64 patients who initiated treatment between January and December 2024. Of these 64 patients, 78.1% completed the full 18-month course, and all 48 eligible patients elected to continue beyond 18 months. The overall discontinuation rate was 21.9%, with amyloid-related imaging abnormalities (ARIA) (27.7%), decreased motivation (22.2%), and cognitive decline (11.1%) as the primary reasons. Among all 117 patients, ARIA occurred in 12.9% and was significantly associated with apolipoprotein Eε4 carrier status, elevated baseline cerebrospinal fluid (CSF)-phosphorylated tau (ptau) 181 (ptau181; ≥78.6 pg/ml), ≥2 microbleeds, and Fazekas score≥2 deep white matter hyperintensity. Elevated CSF-ptau181 also independently predicted cognitive decline during treatment and ARIA-related discontinuation. These findings suggest that integrating CSF-ptau181 measurement and baseline MRI into clinical decision-making may support individualized risk stratification and the safe, sustained use of lecanemab in real-world practice.},
}

@article {pmid42664679,
year = {2026},
author = {Rodríguez-Callejas, JD and Mimenza-Alvarado, AJ and Lomas-Soria, C and Aguilar-Navarro, SG},
title = {Biomarkers of the blood-brain barrier and the neurovascular unit and their relationship with cognitive decline and cognitive frailty.},
journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion},
volume = {78},
number = {5},
pages = {100056},
doi = {10.1016/j.ric.2026.100056},
pmid = {42664679},
issn = {2564-8896},
abstract = {Aging is accompanied by an increasing prevalence of frailty and age-related cognitive decline (CD). Cognitive frailty (CF), characterized by physical frailty and cognitive impairment, has been associated with oxidative stress, neuroinflammation, mitochondrial dysfunction, and cardiovascular impairment. However, its biological foundations remain only partially understood. This review synthesizes evidence on biomarkers associated with the blood-brain barrier (BBB) and neurovascular unit (NVU) in CD and CF. These biomarkers are associated with endothelial injury, pericyte damage, BBB permeability, tight junction disruption, glial activation, and extracellular vesicles (EVs). They are assessed by analyzing cerebrospinal fluid (CSF), blood, neuroimaging (including DCE-MRI), and histology. The most frequently evaluated markers were CSF sPDGFRβ, the CSF/serum albumin ratio (QAlb), DCE-MRI permeability, and the adhesion molecules ICAM-1 and VCAM-1. Key convergent findings suggest that BBB breakdown (particularly pericyte injury, as indicated by elevated CSF sPDGFRβ) can precede or occur independently of classical amyloid-β and tau pathology, predict CD in APOE4 carriers over up to 4.5 years, and be associated with disrupted default mode network connectivity. Elevated QAlb demonstrated dose-response prognostic value for clinical deterioration, while DCE-MRI permeability was associated with poorer episodic memory and predicted white-matter injury, which mediated cognitive impairment. Endothelial activation markers were elevated early and predicted progression, whereas vWF exhibited a stage-dependent, potentially biphasic association. Overall, BBB/NVU biomarkers support vascular and neuroinflammatory mechanisms as early, partially Alzheimer's disease-independent contributors to CD and CF, with significant modification by APOE4 and metabolic comorbidities, and with distinct signatures across Alzheimer's disease and vascular cognitive impairment.},
}

@article {pmid42664828,
year = {2026},
author = {Hirlekar, R and Agnihotri, S and Sathe, S and Nagarsenkar, M},
title = {Exosomal innovations in neurodegenerative disorders: Emerging insights and intranasal route.},
journal = {Biochemical and biophysical research communications},
volume = {834},
number = {},
pages = {154474},
doi = {10.1016/j.bbrc.2026.154474},
pmid = {42664828},
issn = {1090-2104},
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple Sclerosis (MS), represent a substantial and growing global health burden, collectively accounting for millions of disability-adjusted life years (DALYs) worldwide and severely impacting cognition, mood, behavior, and motor function. Current therapies, particularly small-molecule drugs, are challenged by the blood-brain barrier (BBB), resulting in poor central nervous system (CNS) bioavailability, systemic adverse effects, and suboptimal patient adherence, underscoring the urgent need for novel delivery platforms. Exosomes, endogenous nanoscale extracellular vesicles (30-150 nm) derived from sources such as mesenchymal stem cells, neural stem cells, and immune cells, have emerged as highly promising biogenic drug carriers owing to their low immunogenicity, inherent biocompatibility, cargo versatility (proteins, mRNA, miRNA), and unique innate ability to cross the BBB, positioning them as superior alternatives to synthetic nanocarriers such as liposomes, niosomes, and solid lipid nanoparticles for targeted CNS delivery. This review provides a comprehensive overview of exosome biology and therapeutics for AD, PD, and MS, covering classification, isolation and characterization methods, drug-loading strategies and a comparative analysis of administration routes (intravenous, intracerebral, intrathecal, intra-arterial, and intranasal). Particular emphasis is placed on the intranasal route, which offers a non-invasive, direct nose-to-brain pathway via the olfactory and trigeminal nerves, effectively bypassing the BBB while minimizing systemic exposure. The review also examines the dual therapeutic and pathological roles of exosomes in BBB function, and emphasizes preclinical and early clinical evidence across AD, PD, and MS. Finally, the review outlines the major manufacturing, regulatory, and standardization hurdles that must be addressed including GMP-grade scale-up, consistent particle-based dosing benchmarks, and large placebo-controlled trials before intranasal exosome therapeutics can progress from promising preclinical candidates to approved disease-modifying treatments for neurodegenerative disorders.},
}

@article {pmid42665070,
year = {2026},
author = {Xu, LJ and Huang, LY and Tang, S and Zou, JJ and Tan, CC and Tan, L and Xu, W},
title = {Peripheral inflammation offers significant but limited explanation for the association between sleep and cognition health: evidence from two longitudinal studies.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106978},
doi = {10.1016/j.bbi.2026.106978},
pmid = {42665070},
issn = {1090-2139},
abstract = {Sleep disturbances can trigger peripheral inflammatory responses, and both poor sleep and inflammation have been linked to cognitive impairment. However, whether peripheral inflammation mediates the association between sleep quality and cognitive health remains insufficiently tested. We analyzed data from two independent cohorts: 259,817 non-demented participants (mean age 58 years, 55.39% female, mean follow-up 10.29 years) from the UK Biobank (UKB) and 1,107 participants (mean age 74 years, 56.82% female, mean follow-up 4.17 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At baseline, sleep quality was assessed using self-reported or caregiver-reported information. Peripheral blood lymphocyte count (LYM), neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), and serum C-reactive protein (CRP) were used as pragmatic peripheral inflammatory markers. Causal mediation analyses tested whether peripheral inflammation mediated the associations of sleep quality with cognitive performance and risk of incident dementia. In both cohorts, poor sleep quality was associated with higher levels of LYM, NEU, NLR and CRP (p < 0.001), and with lower cognitive function (p < 0.001). Poor sleep quality was also associated with an increased risk of incident dementia in UKB (p < 0.001), whereas this association was not significant in ADNI (p = 0.33). Higher NEU, NLR, and CRP levels were associated with lower cognitive function (UKB, p < 0.001; ADNI, p < 0.05) and increased risk of dementia (p < 0.001). In UKB, selected markers mediated the associations of sleep quality with fluid intelligence (p < 0.001), numeric memory score (p < 0.05), and risk of incident all-cause dementia and Alzheimer's disease (p < 0.001). However, the mediation proportions were limited (< 10%). In ADNI, no significant mediation was observed. These findings suggest that peripheral inflammation provides a statistically significant but quantitatively limited explanation for the association between sleep and cognitive health. Future studies should investigate additional mechanisms and potential intervention targets in more diverse cohorts.},
}

@article {pmid42665101,
year = {2026},
author = {Suk, K},
title = {Inflammatory-metabolic coupling in glia: LCN2-PDK axis as molecular mechanism and therapeutic paradigm.},
journal = {Biochemical pharmacology},
volume = {254},
number = {Pt 1},
pages = {118407},
doi = {10.1016/j.bcp.2026.118407},
pmid = {42665101},
issn = {1873-2968},
abstract = {Neuroinflammation and metabolic dysfunction converge in diverse neurological disorders, yet the molecular mechanisms linking these processes remain incompletely defined. This review integrates current evidence that the lipocalin-2 (LCN2) - pyruvate dehydrogenase kinase (PDK) axis represents a candidate mechanistic pathway, most directly established to date in diabetic peripheral neuropathy, coupling glial inflammatory activation to pathological metabolic reprogramming. LCN2, a pro-inflammatory mediator upregulated in reactive glia, drives PDK expression through two convergent mechanisms: PPARβ/δ-dependent transcription of PDK2/4, and iron-dependent HIF-1α stabilization inducing PDK1/3. PDK-mediated pyruvate dehydrogenase inhibition redirects metabolism from oxidative phosphorylation toward aerobic glycolysis, causing lactate accumulation whose functional consequences range from beneficial neuronal fuel support at physiological concentrations to potential neurotoxicity at higher, context-dependent levels (often cited around 5-10 mM), with the transition shaped by pH, tissue compartment, duration of exposure, and disease context rather than a single universal threshold. The axis operates across central and peripheral nervous system disorders with disease-specific patterns: in diabetic peripheral neuropathy, satellite glial cell LCN2 drives PPARβ/δ-PDK2-mediated lactate accumulation with Lcn2 knockout providing robust protection; in traumatic brain injury and stroke, acute astrocytic LCN2 surges are associated with secondary damage; and in Alzheimer disease, chronic microglial LCN2 elevation is associated with impaired metabolic function. Evidence for axis involvement is currently most direct and mechanistically established in diabetic peripheral neuropathy, whereas its role in traumatic brain injury, stroke, and Alzheimer disease is comparatively less characterized and remains largely correlative. Multi-level therapeutic opportunities include PDK inhibition with dichloroacetate, PPARβ/δ antagonism, LCN2 neutralization, and metabolic support strategies, although disease-specific dosing, timing, efficacy, and long-term safety (including the risk of peripheral neuropathy with dichloroacetate) require further clinical evaluation. Plasma LCN2 and hyperpolarized [13]C-pyruvate magnetic resonance imaging represent promising, though still emerging, candidate biomarkers for patient stratification and target engagement monitoring. This mechanistic convergence across disorders positions the LCN2-PDK axis as a promising candidate therapeutic target, with diabetic neuropathy - where supporting evidence is currently strongest - representing the lead indication for clinical translation.},
}

@article {pmid42665145,
year = {2026},
author = {Yu, X and Gao, P and Yao, Q and Yuan, F and Jing, W},
title = {Polysaccharides targeting organelle network dysfunction in Alzheimer's disease: A review.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154255},
doi = {10.1016/j.ijbiomac.2026.154255},
pmid = {42665145},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is driven by an interrelated pathological network, which to some extent explains the limited efficacy of single-target therapies and constitutes a significant challenge in current clinical treatment. Emerging evidence indicates that dysfunction and crosstalk among mitochondria, the endoplasmic reticulum, and lysosome-autophagy form a core organelle network that amplifies oxidative stress and exacerbates proteostatic imbalance, neuroinflammation, and synaptic failure. In this review, we summarize natural and engineered polysaccharides as potential multitarget modulators that may influence individual organelle-associated pathways involved in AD-related dysfunction. We discuss how the structural parameters of polysaccharides (e.g., molecular weight, monosaccharide composition, glycosidic linkages, branching, and charge density) are associated with bioactivities through receptor-related signaling pathways, redox and inflammatory regulation, proteostasis/autophagy modulation, and, when applicable, potential gut-brain axis involvement. Furthermore, we highlight rational design strategies (e.g., sulfation and carboxymethylation) and formulation/delivery considerations that may increase efficacy and translational readiness. Finally, key challenges, including heterogeneity, mechanism attribution, brain delivery, and standardization, are outlined to guide the development of polysaccharide-based strategies potentially addressing organelle-associated dysfunction in AD.},
}

@article {pmid42665238,
year = {2026},
author = {Abdelaziz, AM and Eltyar, FS},
title = {Clinical immunology lessons from failed α-Synuclein and Tau immunotherapies: A roadmap for combination strategies in Alzheimer's disease.},
journal = {Clinical immunology (Orlando, Fla.)},
volume = {288},
number = {},
pages = {110777},
doi = {10.1016/j.clim.2026.110777},
pmid = {42665238},
issn = {1521-7035},
abstract = {Anti-amyloid-β monoclonal antibodies have established immunotherapy as a viable approach for Alzheimer's disease, yet all α-synuclein and tau antibodies tested to date have failed clinically. These setbacks offer invaluable immunology lessons reshaping next-generation therapeutic development. Four key lessons emerge: epitope specificity determines outcomes, with mid-domain and microtubule-binding region antibodies showing promise over failed N-terminal approaches; biomarker-driven stratification using p-tau217 and AI algorithms can unmask efficacy in rapid progressors; most patients harbor mixed proteinopathies, rendering monotherapy insufficient and mandating combination immunotherapy; and neuroinflammation, particularly NLRP3 activation and microglial dysfunction, represents a convergent pathway targetable independently of upstream triggers. Emerging approaches include conformation-specific antibodies, protein-protein interaction inhibitors, and immune checkpoint targeting, such as anti-SIGLEC-10, to restore phagocytosis. These insights inform biomarker-enriched trials and combination regimens, although clinical evidence for specific combinations remains limited and requires validation. The systems framework targeting aggregation, neuroinflammation, and immunity offers a promising paradigm yet awaits empirical testing.},
}

@article {pmid42665355,
year = {2026},
author = {Afonso, AS and Schroeder, KM and Mitchell, L and Carragher, N and Casey, C and Patel, N},
title = {Characterising patients with Alzheimer's disease in England: a cohort study using data from Clinical Practice Research Datalink linked to Hospital Episode Statistics.},
journal = {BMJ open},
volume = {16},
number = {8},
pages = {e115438},
doi = {10.1136/bmjopen-2025-115438},
pmid = {42665355},
issn = {2044-6055},
mesh = {Humans ; Female ; *Alzheimer Disease/epidemiology/drug therapy ; England/epidemiology ; Aged, 80 and over ; Male ; Comorbidity ; Aged ; Databases, Factual ; Cohort Studies ; Algorithms ; Middle Aged ; Polypharmacy ; Hospitalization/statistics & numerical data ; },
abstract = {OBJECTIVES: To characterise demographics, comorbidities, co-medications and healthcare resource utilisation (HCRU) in patients newly diagnosed with Alzheimer's disease (AD) in England using published and validated AD algorithms.

DESIGN: Observational cohort study.

SETTING: Real-world data in England from the Clinical Practice Research Datalink Aurum primary care database linked to the Hospital Episode Statistics secondary care database.

PARTICIPANTS: Two disease-based algorithms (Imfeld et al and Douros et al) and one medication-based algorithm (Schroeder et al) were selected from the literature to identify patients with AD. The index period for patient selection was from 1 January to 31 December 2019. Patients were grouped into three non-mutually exclusive cohorts reflecting these algorithms (cohorts A-C), then patients aged ≥60 years were further grouped into three subcohorts (subcohorts 1-3). Subcohort 1 included 9826 patients, subcohort 2 included 10 265 patients and subcohort 3 included 7355 patients.

PRIMARY OUTCOME MEASURES: Demographics, comorbidities, co-medications and HCRU present up to and including the date of cohort qualification were described.

RESULTS: Across subcohorts 1-3, mean age at index ranged from 81 to 83 years, and most patients were female (59%-63%) and White (93%). Common comorbidities were hypertension (67%-71%), asthma and chronic obstructive pulmonary disease (60%-63%) and arthritis and osteoarthritis (51%-53%). Common co-medications were analgesics (87%-89%), systemic corticosteroids (83%-84%) and anti-inflammatory and anti-rheumatic agents (81%-82%). Up to 34% of patients had a specialist referral or visit, with up to 18% involving a neurologist. In the 12 months prior to and including the index date, up to 46% of patients had an emergency department visit or inpatient visit for any cause.

CONCLUSIONS: In England, most newly diagnosed patients with AD were White females in their early 80s with common comorbidities including hypertension, asthma, chronic obstructive pulmonary disease, arthritis and osteoarthritis. This study addresses a critical evidence gap by quantifying the England-specific burden of comorbidity, polypharmacy, and HCRU among patients with AD using multiple validated and published AD algorithms. Findings were broadly consistent across the three subcohorts identified using disease-based and medication-based algorithms, strengthening internal validity of the study and demonstrating that the findings are robust to the method of AD case definition. This study provides a novel insight into the real-world AD population in England, and findings may help healthcare professionals to identify patients living with AD, understand patients' needs and tailor treatment strategies.},
}

Humans
Female
*Alzheimer Disease/epidemiology/drug therapy
England/epidemiology
Aged, 80 and over
Male
Comorbidity
Aged
Databases, Factual
Cohort Studies
Algorithms
Middle Aged
Polypharmacy
Hospitalization/statistics & numerical data

@article {pmid42665452,
year = {2026},
author = {Huang, WL and Wang, LL and Shi, JR and Liu, Q},
title = {Acupuncture for Alzheimer's disease: A systematic review and meta-analysis integrating traditional insights and scientific evidence.},
journal = {Journal of integrative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.joim.2026.08.002},
pmid = {42665452},
issn = {2095-4964},
abstract = {BACKGROUND: Alzheimer's disease (AD), a leading cause of dementia in the elderly, is characterized by progressive cognitive impairment, and still lacks effective therapeutic interventions.

OBJECTIVE: This systematic review synthesizes the classical theoretical foundations, clinical evidence, and modern mechanistic insights for the use of acupuncture to treat AD.

SEARCH STRATEGY: A meta-analysis was conducted based on a comprehensive literature search of PubMed, Embase, the Cochrane Library, CNKI, VIP information, and Wanfang Data, covering the period from inception until September 2025.

INCLUSION CRITERIA: Eligible randomized controlled trials (RCTs) compared acupuncture (manual or electroacupuncture) with control interventions, including sham acupuncture, donepezil, placebo, or no treatment.

DATA EXTRACTION AND ANALYSIS: Data were extracted by two reviewers working independently and then analyzed using the meta and meta for packages in R (v4.3.2). Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated.

RESULTS: A total of 21 RCTs comprising 1354 participants met the inclusion criteria. Compared with no-treatment controls, acupuncture significantly improved cognitive performance, as measured by the Mini-Mental State Examination (MMSE) (WMD = 3.74, 95% CI: 1.34-6.14), and outperformed placebo controls (WMD = 2.13, 95% CI: 1.39-2.87). Acupuncture showed efficacy comparable to that of donepezil on MMSE and Activity of Daily Living (ADL), suggesting non-inferiority to standard pharmacotherapy. Frequently used acupoints included GV20, ST36, GB20, LR3, and ST40, often combining local (GV24, EX-HN1) and distal (SP10, KI3) points. Reported adverse events were mild and transient, with no significant difference from controls. Biomarker analyses indicated that acupuncture enhanced acetylcholine levels and reduced plasma Aβ1-40, Aβ1-42, and Tau levels, implying modulation of cholinergic transmission and AD-related pathology.

CONCLUSION: This review highlights acupuncture as a holistic, multi-targeted therapy with promising potential for managing AD. Future research should aim to standardize acupuncture protocols, integrate TCM syndrome differentiation, and adopt neurobiological and imaging techniques to explore mechanisms. Please cite this article as: Huang WL, Wang LL, Shi JR, Liu Q. Acupuncture for Alzheimer's disease: A systematic review and meta-analysis integrating traditional insights and scientific evidence. J Integr Med. 2026; Epub ahead of print.},
}

@article {pmid42665539,
year = {2026},
author = {Lu, H and Hu, C and Fu, Y},
title = {Fabrication of Mesoporous Manganese Nanoparticles Incorporated Aβ-Peptide Inhibits Aβ Aggregation and Alleviates Neuroinflammation Against Alzheimer's Disease.},
journal = {Journal of biomedical materials research. Part B, Applied biomaterials},
volume = {114},
number = {9},
pages = {e70131},
doi = {10.1002/jbm.b.70131},
pmid = {42665539},
issn = {1552-4981},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/chemistry/metabolism ; Mice ; *Manganese/chemistry/pharmacology ; Humans ; Porosity ; *Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; *Neuroinflammatory Diseases/metabolism/drug therapy/pathology ; Protein Aggregation, Pathological ; tau Proteins/metabolism ; Protein Aggregates/drug effects ; },
abstract = {Extracellular amyloid plaques from Aβ accumulation and intracellular neurofibrillary tangles (NFTs) from hyperphosphorylated Tau (p-Tau), both leading to neuronal dysfunction, synapse loss, and cognitive decline. Nonetheless, achieving an effective therapeutic outcome is challenging due to the limited drug bioavailability through the blood-brain barrier (BBB) and the complex microenvironment within the brain. This study proposes MM-TA for the synergistic treatment of AD, utilizing mesoporous manganese (MM) as a nanocarrier to deliver a LK7 (Aβ-inhibiting peptide) and a DAA (amino acid-peptide) that inhibits Tau-related fibrils formation. A biomimetic nanocarrier (MM-LD@4CM termed as MLDC) encapsulated with 4T1 cell membranes (4CM) was developed, inspired by 4T1 cells' ability to facilitate BBB penetration. Following traversal of the BBB, MLDC concurrently prevented Tau phosphorylation and suppressed Aβ aggregation. Furthermore, by leveraging MM's catalase-mimetic properties, MLDC mitigated oxidative stress and altered the microenvironment associated with AD progression. In contrast to the singular therapeutic agent, MLDC ameliorated nerve damage and enhanced cognitive function in AD mice by reducing Aβ oligomers, phosphorylated Tau, and inflammation, thereby providing a synergistic therapeutic approach with significant potential for effective AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Amyloid beta-Peptides/chemistry/metabolism
Mice
*Manganese/chemistry/pharmacology
Humans
Porosity
*Nanoparticles/chemistry
Blood-Brain Barrier/metabolism
*Neuroinflammatory Diseases/metabolism/drug therapy/pathology
Protein Aggregation, Pathological
tau Proteins/metabolism
Protein Aggregates/drug effects

@article {pmid42665582,
year = {2026},
author = {Ghandian, S and Albarghouthi, L and Nava, K and Sharma, SRR and Minaud, L and Beckett, L and Saito, N and DeCarli, C and Rissman, RA and Teich, AF and Jin, LW and Dugger, BN and Keiser, MJ},
title = {Learning precise segmentation of neurofibrillary tangles from rapid manual point annotations.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42665582},
issn = {2045-2322},
support = {P30AG072972/AG/NIA NIH HHS/United States ; P50AG008702/AG/NIA NIH HHS/United States ; R01AG062517/AG/NIA NIH HHS/United States ; DAF2018-191905 (https://doi.org/10.37921/550142lkcjzw)//Chan Zuckerberg Initiative/ ; },
mesh = {Humans ; *Neurofibrillary Tangles/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; tau Proteins/metabolism ; *Deep Learning ; *Image Processing, Computer-Assisted/methods ; Brain/pathology ; },
abstract = {Accumulation of abnormal tau protein into neurofibrillary tangles (NFTs) is a pathologic hallmark of Alzheimer disease (AD). Accurate detection of NFTs in tissue samples can reveal relationships with clinical, demographic, and genetic features through deep phenotyping. However, expert manual analysis is time-consuming, subject to observer variability, and cannot handle the data amounts generated by modern imaging. We present a scalable, open-source, deep-learning approach to quantify NFT burden in digital whole slide images (WSIs) of post-mortem human brain tissue. To achieve this, we developed a method to generate detailed NFT boundaries directly from single-point-per-NFT annotations. We then trained a semantic segmentation model on 45 annotated 2400 μm by 1200 μm regions of interest (ROIs) selected from 15 unique temporal cortex WSIs of AD cases from three institutions (University of California (UC)-Davis, UC-San Diego, and Columbia University). Segmenting NFTs at the single-pixel level, the model achieved an area under the receiver operating characteristic of 0.832 and an F1 of 0.527 (196-fold over random) on a held-out test set of 664 NFTs from 20 ROIs (7 WSIs). We compared this to deep object detection, which achieved comparable but coarser-grained performance that was 60% faster. The segmentation and object detection models correlated well with expert semi-quantitative scores at the whole-slide level (Spearman's rho ρ = 0.654 (p = 6.50e-5) and ρ = 0.513 (p = 3.18e-3), respectively). We openly release this multi-institution deep-learning pipeline to provide detailed NFT spatial distribution and morphology analysis capability at a scale otherwise infeasible by manual assessment.},
}

Humans
*Neurofibrillary Tangles/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
tau Proteins/metabolism
*Deep Learning
*Image Processing, Computer-Assisted/methods
Brain/pathology

@article {pmid42665661,
year = {2026},
author = {Abtahi, Y and Ghadiminia, N and Nasiri, H and Ladani, AJ and Khanghah, KN and Shamspour, M and Jamaloei, DD and Meybodi, FS and Rahimi, S and Hashemi, D and Saleh, M and Ashoori, N and Shakeri, S},
title = {Plasma p-tau217 as a two-cutoff approach to improve tau-PET screening and trial recruitment in Alzheimer's disease.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42665661},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/diagnostic imaging ; *tau Proteins/blood ; *Positron-Emission Tomography/methods ; Female ; Biomarkers/blood ; Male ; Aged ; Amyloid beta-Peptides/blood ; Cognitive Dysfunction/blood/diagnosis ; Aged, 80 and over ; ROC Curve ; },
abstract = {Blood-based biomarkers could broaden access to Alzheimer's disease diagnostics, but their ability to approximate tau PET, and to address gray-zone results, remains uncertain. We evaluated plasma p-tau217 against tau PET using a harmonized ADNI baseline cohort and an independently derived temporal meta-ROI tau-PET threshold. We included participants with complete baseline plasma biomarkers (p-tau217, Aβ42, Aβ40, NfL, GFAP), tau PET, and demographics, including: cognitively normal = 229, mild cognitive impairment = 149, and Alzheimer's disease dementia = 41. ROC analyses assessed discrimination of tau-PET positivity overall and by diagnostic group. A two-cutoff strategy was implemented to minimize indeterminate classifications. Across the pooled cohort, p-tau217 demonstrated the strongest ability to discriminate tau-PET status (AUC 0.671, 95% CI 0.597-0.746), outperforming Aβ42, Aβ40, and Aβ42/Aβ40; Though overall accuracy remained moderate and performance differed based on diagnosis, with AUCs of 0.785 for Alzheimer's disease dementia and lower values for cognitively normal and mild cognitive impairment. The two-cutoff approach substantially reduced intermediate classifications compared with conventional markers. In ADNI, plasma p-tau217 showed the highest discriminative performance among the single blood biomarker for detecting tau-PET positivity, showing moderate accuracy overall and its strongest performance in Alzheimer's disease dementia. A two-cutoff approach substantially reduces gray-zone classifications, supporting p-tau217 as a primary screening tool before confirmatory imaging. Further work and validation are needed across different groups.},
}

Humans
*Alzheimer Disease/blood/diagnosis/diagnostic imaging
*tau Proteins/blood
*Positron-Emission Tomography/methods
Female
Biomarkers/blood
Male
Aged
Amyloid beta-Peptides/blood
Cognitive Dysfunction/blood/diagnosis
Aged, 80 and over
ROC Curve

@article {pmid42665752,
year = {2026},
author = {McHugh, CP and Buckley, RF and Clement, MHS and Hohman, TJ and Kivipelto, M and Pa, J and Sindi, S and Bose, N},
title = {Closing the gap in Alzheimer's disease research through the Sex | Gender in Neurodegeneration Consortium.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43587-026-01214-y},
pmid = {42665752},
issn = {2662-8465},
support = {DP2AG082342//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG079142//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG088811//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
}

@article {pmid42665768,
year = {2026},
author = {Quattrini, G and Bocchetta, M and Bagattini, C and Saglia, S and Bertazzoli, G and Ferrari, E and Delai, M and Bulgari, M and Brignani, D and Canu, E and Agosta, F and Festari, C and Filippi, M and Gasparotti, R and Pievani, M and Cattaneo, A and Bortoletto, M and Marizzoni, M},
title = {Different hypothalamic regions in late-onset Alzheimer's disease and aging: involvement and links with cognitive and non-cognitive features.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42665768},
issn = {2509-2723},
abstract = {Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) have different clinical and neuroimaging characteristics, and non-cognitive deficits usually observed are suggestive of hypothalamic dysfunctions. Here, we assessed in vivo the hypothalamic volumetry in EOAD and LOAD and explored its association with cognitive and non-cognitive features. The hypothalamus and its subunits were segmented on T1-weighted MRIs from 14 younger and 23 elderly controls (EC), 14 EOAD, and 28 LOAD. Amyloid or fluid biomarker confirmation was not available for all participants, and diagnostic classification was primarily based on clinical criteria. Volumes were correlated with cognitive (global cognition, memory) and non-cognitive (mood, body mass index) features. Lower bilateral volumes of the whole and posterior hypothalamus were observed in LOAD compared with EC (p < 0.010), while lower right anterior-inferior subunit was a common feature in patients than in controls (p = 0.007). These alterations were associated with abnormal cognition (rho ranging from -0.35 to -0.30, p < 0.041), as well as with memory (rho = 0.30, p = 0.041) and depressive mood (rho ranging from -0.82 to -0.68, p < 0.031) in the LOAD-EC pooled group. Our study provided a valuable insight into the heterogeneity of EOAD and LOAD, extending current understanding of the differential involvement of brain regions and highlighting the importance of hypothalamic involvement as a potential target for further investigation in conjunction with clinical assessment.},
}

@article {pmid42665946,
year = {2026},
author = {Le, N and Anne, N and Shen, C and Pallapothu, R and Liu, Y and Park, C},
title = {Dementias in Older Women With Early-Stage HER2-Negative Breast Cancer Treated With Anthracycline Plus Taxane Versus Taxane-Based Chemotherapy Regimens.},
journal = {Pharmacoepidemiology and drug safety},
volume = {35},
number = {9},
pages = {e70457},
doi = {10.1002/pds.70457},
pmid = {42665946},
issn = {1099-1557},
mesh = {Humans ; Female ; *Taxoids/adverse effects/administration & dosage ; Aged ; *Anthracyclines/adverse effects/administration & dosage ; SEER Program/statistics & numerical data ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/administration & dosage ; *Breast Neoplasms/drug therapy/pathology ; Erb-b2 Receptor Tyrosine Kinases ; *Dementia/epidemiology/chemically induced ; United States/epidemiology ; Aged, 80 and over ; Bridged-Ring Compounds/adverse effects/administration & dosage ; Medicare/statistics & numerical data ; Incidence ; Neoplasm Staging ; Longitudinal Studies ; Alzheimer Disease/epidemiology/chemically induced ; },
abstract = {BACKGROUND: Anthracycline plus taxane (ATAX) regimens are associated with improved survival in HER2-negative breast cancer (HBC) compared to taxane-based (TAX) regimens. However, anthracyclines are known for their cardiotoxicity, which could increase the risk of neurocognitive deficits, raising concerns about neurocognitive safety, particularly in older adults. Limited evidence exists comparing neurocognitive outcomes between these two regimens.

OBJECTIVE: To compare the incidence of Alzheimer's disease and related dementias (ADRD) between ATAX and TAX regimens in neoadjuvant (Trial #1) and adjuvant (Trial #2) settings among older women with early-stage HBC.

METHODS: Using SEER-Medicare data (2010-2021), we identified women aged ≥ 66 years with newly diagnosed HBC and no prior neurocognitive conditions between 2011 and 2021. Patients were longitudinally tracked, and their eligibility for each regimen was evaluated. We applied the clone-censor-weight method and used weighted pooled logistic regression to estimate the 10-year risks of ADRD, Alzheimer's disease (AD), and vascular dementia (VD).

RESULTS: We identified 14 079 and 9321 eligible individuals in Trial #1 and Trial #2, respectively. For ADRD outcome, the 10-year risk difference (RD) was -6.91% (95% CI: -15.60% to 0.91%) for HR+/HER2- cohort and -2.14% (95% CI: -9.57% to 5.46%) for TNBC cohort in Trial #1. The 10-year RD was -1.42% (95% CI: -9.33% to 6.98%) for HR+/HER2- cohort and -2.91% (95% CI: -9.54% to 7.86%) for TNBC cohort in Trial #2.

CONCLUSION: Our findings suggest that ATAX regimens were not associated with increased risks of ADRD, AD, and VD compared to TAX regimens in older women with HBC. However, the risks of AD and VD should be interpreted with caution due to sparse events. These findings may support the continued use of ATAX regimens in this population, while also informing more personalized, risk-adapted treatment strategies.},
}

Humans
Female
*Taxoids/adverse effects/administration & dosage
Aged
*Anthracyclines/adverse effects/administration & dosage
SEER Program/statistics & numerical data
*Antineoplastic Combined Chemotherapy Protocols/adverse effects/administration & dosage
*Breast Neoplasms/drug therapy/pathology
Erb-b2 Receptor Tyrosine Kinases
*Dementia/epidemiology/chemically induced
United States/epidemiology
Aged, 80 and over
Bridged-Ring Compounds/adverse effects/administration & dosage
Medicare/statistics & numerical data
Incidence
Neoplasm Staging
Longitudinal Studies
Alzheimer Disease/epidemiology/chemically induced

@article {pmid42666058,
year = {2026},
author = {Khan, AU and Abdullah, A and Naqvi, SF and Tahir, H and Khalid, H and Sarfraz, H and Khan, Y},
title = {Multitargeted drug strategies for Alzheimer's and Parkinson's diseases.},
journal = {Zeitschrift fur Naturforschung. C, Journal of biosciences},
volume = {},
number = {},
pages = {},
pmid = {42666058},
issn = {1865-7125},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are multifactorial diseases that are characterized by several interconnected pathological mechanisms, such as the aggregation of amyloid-beta (Aβ), hyperphosphorylation of tau, accumulation of α-synuclein, oxidative stress, mitochondrial dysfunction, neuroinflammation, and neurotransmitter imbalance. Conventional single-target therapies failed to produce significant clinical effects due to the fact that they target only individual disease pathways. Thus, the multitarget-directed ligand (MTDL) strategy has become an attractive therapeutic option, and MTDLs can act on several pathological targets simultaneously. Recent advances in multitarget drug development for AD and PD targeting compounds targeting Aβ, BACE1, MAO-B, cholinesterases, metal-ion dyshomeostasis, oxidative stress, and inflammatory pathways are reviewed. A few potential candidates, such as GV-971, Prasinezumab, Huperzine A, curcumin derivatives, and hybrids of MAO-B inhibitors, have shown neuroprotective and cognitive effects in preclinical and clinical studies. There are significant advances in the clinical pipeline, with over 180 clinical trials for AD and over 130 clinical trials for PD testing multitarget or disease-modifying strategies. The review also highlights the growing importance of computer-aided drug design (CADD), artificial intelligence (AI), and machine learning (ML) in speeding up the discovery of MTDL, optimizing their pharmacokinetic profiles, and predicting multitarget interactions. However, there are still major obstacles to be overcome, such as the ability to cross the blood-brain barrier, optimizing the pharmacokinetics, the difficulties of transferring from the animal to the human model, and the complexity of the regulatory process. New strategies based on nanomedicine, biomarker-driven trials, personalized medicine, and drug repurposing will enhance therapeutic precision and clinical success.},
}

@article {pmid42666080,
year = {2026},
author = {Rentsendorj, A and Vit, JP and Hutton, A and Koronyo, Y and Shahin, S and Robinson, E and Barron, E and Rodriguez, A and Jallow, O and Sheyn, J and Gaire, BP and Subedi, L and Davis, MR and Gnanabharathi, B and Ljubimov, AV and Graham, SL and Gupta, VK and Mirzaei, M and Hawes, D and Silm, K and Black, KL and Schneider, LS and Sadun, AA and Meyer, JG and Fuchs, DT and Koronyo-Hamaoui, M},
title = {Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e00020},
doi = {10.1002/advs.202600020},
pmid = {42666080},
issn = {2198-3844},
support = {/NH/NIH HHS/United States ; R35GM142502/GM/NIGMS NIH HHS/United States ; R01AG056478/AG/NIA NIH HHS/United States ; R01AG055865/AG/NIA NIH HHS/United States ; AG056478-04S1/AG/NIA NIH HHS/United States ; //the Hertz Innovation Funds/ ; //the Gordon Foundation/ ; //the Wilstein Foundation/ ; //the Saban Foundation/ ; //the Ray Charles Foundation/ ; },
abstract = {Synaptic dysfunction is a major driver of cognitive decline in Alzheimer's disease (AD), yet its extent and molecular basis in the retina remain poorly defined. We integrated postmortem retinal and matched brain histopathology with ultrastructural, proteomic, biochemical, and machine-learning analyses across cognitively normal, mild cognitive impairment, and AD cohorts. Retinal glutamatergic synapses exhibited early, progressive degeneration, marked by loss of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), along with ribbon synapse ultrastructural disruption. Synaptic deficits correlated with amyloid-β42 (Aβ42), pathogenic tau, oxidative stress, the Aβ-binding p75 neurotrophin receptor, and glial activation that paralleled disease progression. Proteomics revealed widespread synaptic remodeling accompanied by disease-associated microglia, astrocyte-mediated excitotoxicity, and pyroptotic pathways. The synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) was dysregulated early, particularly in horizontal and bipolar interneurons, and strongly associated with synaptic loss and neuroinflammation. Mechanistically, fibrillar Aβ42 induced rapid UCHL1 and synaptic depletion in human and murine neurons before overt neurodegeneration. Machine-learning models identified retinal UCHL1 as the strongest predictor of Braak stage and cognitive impairment. These findings establish the retina as an early site of AD synaptopathy and position UCHL1 as a candidate biomarker and mechanistic mediator linking amyloid pathology, neuroinflammation, and synaptic vulnerability.},
}

@article {pmid42666234,
year = {2026},
author = {Mandal, S and Dipa, P and Neha, and Chatterjee, D and Maparu, K},
title = {Environmental determinants of neurotoxicity: role of heavy metals in neurological disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1867856},
pmid = {42666234},
issn = {1664-2295},
mesh = {Humans ; *Metals, Heavy/toxicity/adverse effects ; *Environmental Exposure/adverse effects ; Animals ; *Nervous System Diseases/chemically induced ; *Neurotoxicity Syndromes/etiology ; },
abstract = {Neurodevelopmental and neurodegenerative disorders are related disorders lying on a spectrum of neural dysfunction with overlapping molecular and cellular mechanisms. Early-life diseases like autism spectrum disorder and attention-deficit/hyperactivity disorder are the result of disturbed neurodevelopment, while late-onset diseases such as Alzheimer's disease and Parkinson's disease are defined by progressive neuronal loss and loss of function. Emerging evidence shows that environmental exposures are important, modifiable factors that affect brain health throughout the lifespan. Factors such as air pollution, heavy metals, pesticides, and endocrine-disrupting chemicals act in combination with genetic susceptibility to disrupt neurogenesis, synaptic plasticity, and neuro-immune signaling. These exposures cause persistent epigenetic modifications, oxidative stress, mitochondrial dysfunction, and chronic neuro-inflammation, linking early developmental insults to neurodegenerative processes later in life. The concepts of the exposome and the developmental origins of health and disease provide additional support for the cumulative, lifelong impact of environmental interactions. Mechanistically, the recurrent process of neuronal damage is caused by impaired proteostasis, microglial stimulation, and blood-brain barrier dysfunction. Furthermore, the gut-brain axis is a hyperactive system in which immune responses and microbial metabolites trigger neurobiological responses to external stimuli. This review integrates multidisciplinary evidence to elucidate the mechanism and emphasizes environmental risk mitigation and translational strategies to reduce disease burden and promote lifelong brain resilience.},
}

Humans
*Metals, Heavy/toxicity/adverse effects
*Environmental Exposure/adverse effects
Animals
*Nervous System Diseases/chemically induced
*Neurotoxicity Syndromes/etiology

@article {pmid42657128,
year = {2026},
author = {Alnounou, A and Alabbas, M and Machchhar, R and Ibrahim, EA and Alali, M and Alhusen, A and Jafri, SM and Njei, B},
title = {Incident Cognitive Impairment in Nonobese Versus Obese Adults Aged 50 Years or Older With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Propensity Score-Matched Cohort Study.},
journal = {International journal of hepatology},
volume = {2026},
number = {},
pages = {7550224},
pmid = {42657128},
issn = {2090-3448},
abstract = {AIMS: Nonobese metabolic dysfunction-associated steatotic liver disease (MASLD) may carry disproportionate neurodegenerative risk, but whether body habitus modifies cognitive risk within MASLD remains unresolved. We compared cognitive impairment between nonobese and obese adults aged 50 years or older with MASLD.

METHODS AND RESULTS: Retrospective cohort study with 1:1 propensity score matching in the TriNetX Research Network, a federated electronic health record network. Adults with a first MASLD diagnosis (2016-2022) meeting a metabolic-risk criterion were classified by index body mass index as nonobese (18.50-29.99 kg/m[2]) or obese (≥ 30.00 kg/m[2]); underweight patients were excluded. The primary outcome was a composite of incident cognitive impairment (mild cognitive impairment [MCI] through dementia) over Days 366-1825. Hazard ratios (HRs) were estimated with Kaplan-Meier and log-rank methods; a negative control (acute appendicitis) and an E-value assessed bias. Matching yielded 36,021 patients per group (mean age 64.3 years; 57% women; all standardized mean differences < 0.10). Nonobese MASLD was associated with a higher risk of the composite cognitive outcome (2.9% vs 2.6%; HR 1.126, 95% confidence interval [CI] 1.031-1.230; p = 0.008; E-value 1.50), driven by MCI (HR 1.221, 95% CI 1.078-1.384; p = 0.002). Estimates were null for incident Alzheimer disease, all-cause dementia, vascular dementia, all-cause mortality, and the negative control.

CONCLUSION: Among adults aged 50 years or older with MASLD, nonobese status was associated with a modestly higher risk of incident cognitive impairment. Prospective validation in imaging- or biomarker-confirmed MASLD cohorts is warranted.},
}

@article {pmid42657170,
year = {2026},
author = {Bossa, NA and Busatto, G and Nitrini, R and Brucki, SMD and Miotto, EC},
title = {Cognitive training effects in mild cognitive impairment with and without amyloid pathology.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250398},
pmid = {42657170},
issn = {1980-5764},
abstract = {UNLABELLED: Imagery-based cognitive training (CT) is a promising strategy for individuals with amnestic mild cognitive impairment (aMCI). However, there is a lack of studies investigating its differential impact in aMCI with and without amyloid pathology.

OBJECTIVE: To investigate the effects of CT based on mental imagery on episodic memory in individuals with amyloid-positive aMCI (Aβ+), amyloid-negative aMCI (Aβ-), and healthy controls (HC).

METHODS: Fifty-five participants were included: Aβ+aMCI (n=19), Aβ-aMCI (n=20), and HC (n=16), aged 51-89 years, with more than 6 years of education. Amyloid status was confirmed by 11C-PiB PET. All participants completed pre- and post-training neuropsychological assessments and attended six individual online CT sessions. Performance was assessed using the logical memory test (LM), Rey Auditory Verbal Learning Test (RAVLT), and generalization tasks (GT I-II).

RESULTS: Data were analyzed using the Shapiro-Wilk, Levene, Wilcoxon, ANOVA, Kruskal-Wallis, and Bonferroni tests. Significant improvements in immediate episodic memory (LM I, RAVLT A1-A5) were observed in the Aβ+ and Aβ-groups, particularly in the Aβ-aMCI group. Delayed recall (LM II, RAVLT A7) increased, although without statistical significance. All groups showed gains in generalization tasks, supporting the benefit of CT.

CONCLUSION: Unimodal CT based on mental imagery promoted gains in immediate episodic memory across all groups. Although delayed recall gains were not statistically significant, the strategy was internalized and generalized. Similar responsiveness in Aβ+ and Aβ-groups suggest preserved compensatory mechanisms despite amyloid pathology. These findings suggest more robust effects at the level of encoding than consolidation, which may vary according to task characteristics and underlying neural integrity.},
}

@article {pmid42657236,
year = {2026},
author = {Pulze, M and Garbarino, S and Lorenzini, L and Cirone, A and Ali, S and Gualco, L and Massa, F and Arnaldi, D and Orso, B and Losa, M and Kreshpa, W and Caneva, S and Parodi, M and Sofia, L and Raffa, S and Sambuceti, G and Caulo, M and Pravatà, E and Levrero, F and Bozzali, M and Morbelli, S and Piana, M and Uccelli, A and Roccatagliata, L and Chincarini, A and Pardini, M and , },
title = {Structural MRI signature predicts tau staging in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70451},
pmid = {42657236},
issn = {2352-8729},
abstract = {INTRODUCTION: Tau positron emission tomography (PET) probes Alzheimer's disease (AD) severity via regional tau spread but is not widely available. We tested whether multiregion structural magnetic resonance imaging (MRI) could approximate individual tau burden.

METHODS: We studied 378 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with mild cognitive impairment (MCI)-AD or AD dementia with paired T1-MRI and [18F]flortaucipir tau-PET (≤6 months apart). Regional cortical thickness and volume were extracted with FreeSurfer. Principal component analysis and multivariable linear regression yielded MRI signatures of tau-PET standardized uptake value ratio (SUVR) in Braak composite regions (I, III-IV, V-VI), a meta-temporal region of interest (ROI), and a global neocortical meta-ROI. Performance and high/low tau classification were evaluated by leave-one-out cross-validation against published cut-offs.

RESULTS: MRI signatures were significantly associated with tau-PET burden across all regions (p < 0.001). High-versus-low tau discrimination varied: AUC ≈ 0.70 in Braak I, ≈0.89 in Braak V-VI, and ≈0.90 globally.

DISCUSSION: Here we provide proof-of-concept evidence that multiregion T1-MRI patterns can inform on tau-PET burden in AD and may support approximate tau staging when tau-PET is unavailable, especially in subjects with more advanced tau burden.},
}

@article {pmid42657250,
year = {2026},
author = {Napoleon, T and Akinrinde, D and Femi-Lawal, VO and Adebajo, GO and Yokolo, H and Okei, FU and Alabi, G and Ifeoluwa, OI and Lawal, SO and Abati, SO and Duru, CN and Oluwatosin, O and Sanusi, IO and Solomon, AO and Clement, A and Bello, T and Egwu, EO and Chukwuemeka, EK},
title = {Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease Cognitive Impairment: A Narrative Review of Clinical Trials.},
journal = {Health science reports},
volume = {9},
number = {9},
pages = {e73104},
pmid = {42657250},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Alzheimer's disease (AD), primarily characterized by cognitive impairment, places an immense burden on patients and caregivers. Non-invasive neuromodulation with repetitive transcranial magnetic stimulation has been proposed to improve cognition in mild to moderate AD. This narrative review aimed to summarize clinical trial evidence on the effects, safety, and tolerability of rTMS for AD-related cognitive impairment and to identify research gaps.

METHODS: A narrative review of clinical trials was performed. PubMed/MEDLINE, Embase, Cochrane Google scholar, and Scopus were searched from inception to January 25, 2025, using terms for "repetitive transcranial magnetic stimulation", "Alzheimer's disease", "cognitive impairment", "clinical trials", and "randomized controlled trial". Clinical trials of active rTMS versus sham or treatment-as-usual in adults with mild to moderate AD that reported validated cognitive outcomes were included. Data on rTMS protocols, cognitive measures, adverse effects, and follow-up were extracted and synthesized narratively without statistical pooling.

RESULTS: 14 trials were included. Across most studies, rTMS delivered at 5-20 Hz for 4 to 12 weeks, at least 5 days per week, was associated with improved cognitive function. Improvements were reported on tools such as the MMSE, CDR-SB, SIB, and ADAS-Cog, with statistically significant differences versus sham in most trials [p < 0.05], and some evidence of sustained benefit at follow-up. rTMS was generally safe and tolerable. Reported adverse effects were mild to moderate and included transient headache, scalp or skin discomfort, pain, and fatigue. Preliminary evidence also suggested potential neuropsychiatric benefits. However, substantial heterogeneity in duration, frequency, treatment plan, targets, and outcome measures limited definitive conclusions.

CONCLUSION: rTMS appears safe in the short term and may be linked to short-term cognitive and neuropsychiatric gains in mild to moderate AD. However, marked protocol heterogeneity, small sample sizes, short follow-up, and risk of bias limit certainty and prevent identification of optimal parameters. rTMS is not ready for routine AD care. Larger, sham-controlled trials with standardized protocols and biomarker or long-term outcomes are needed.},
}

@article {pmid42657258,
year = {2026},
author = {Wang, X and Albin, RL and Giordani, B and Mukherjee, B and Paulson, HL and Bakulski, KM},
title = {Associations between essential trace elements and Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70467},
pmid = {42657258},
issn = {2352-8729},
abstract = {INTRODUCTION: Dysregulation of essential trace elements has been implicated in Alzheimer's disease (AD) pathogenesis, yet comprehensive epidemiologic evidence remains limited. We investigated associations of seven plasma essential trace elements, including manganese, iron, cobalt, copper, zinc, selenium, and molybdenum, with AD and all-cause dementia risk.

METHODS: We analyzed 1,737 participants from the National Alzheimer's Coordinating Center. Cross-sectional analyses assessed prevalent disease; longitudinal analyses evaluated incident cases among 1,101 initially dementia-free participants (median follow-up: 2.05 years). Multivariable logistic regression, Cox proportional hazards models, and quantile-based g-computation evaluated individual and mixture effects.

RESULTS: A simultaneous one-quartile increase in the seven-element mixture was associated with lower prevalent AD (odds ratio [OR] = 0.69; 95% confidence interval [CI]: 0.52-0.91). Longitudinally, higher plasma iron was associated with lower incident AD (hazard ratio [HR] = 0.41; 95% CI: 0.19-0.92, Q4 vs. Q1), while selenium predicted higher incident AD risk (HR = 2.42; 95% CI: 1.11-5.27, Q4 vs. Q1).

DISCUSSION: Lower plasma iron and higher plasma selenium were each associated with greater dementia risk, identifying iron and selenium as potentially modifiable factors for dementia prevention, especially in selenium-replete populations.},
}

@article {pmid42657316,
year = {2026},
author = {Mounié, A and Sato, K and Nakashima, S and Kurihara, M and Ihara, R and Niimi, Y and Iwata, A and Iwatsubo, T},
title = {MMSE-CDR-SB residual as an exploratory indicator of deviation from an Alzheimer's disease-typical cognitive-functional pattern.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70460},
pmid = {42657316},
issn = {2352-8729},
abstract = {INTRODUCTION: In clinical practice, patients with Alzheimer's disease (AD) often present with cognitive and functional profiles that diverge from what is expected. We tested whether the Mini-Mental State Examination Clinical Dementia Rating Sum of Boxes (MMSE-CDR-SB) residual, defined as observed minus expected CDR-SB from a published MMSE-CDR-SB reference equation, reflects clinically meaningful deviation from the expected cognitive-functional relationship.

METHODS: Using National Alzheimer's Coordinating Center data, we analyzed an autopsy cohort (n = 1981) and a separate clinical diagnosis cohort (n = 3184). Negative residual values indicated less functional impairment than expected for a given cognitive score, and positive values indicated greater functional impairment than expected. Associations were examined using multivariable logistic regression adjusted for MMSE score range, age, sex, and education.

RESULTS: Lower residual values were associated with lower odds of amyloid and AD-type tau pathology. Higher residual values showed a directional association with transactive response DNA binding protein 43 kDa; vascular burden was also associated with the residual index but across a broader range. In the clinical cohort, higher residual values were enriched in progressive supranuclear palsy and frontotemporal lobar degeneration (other), whereas AD cases clustered near the reference pattern.

DISCUSSION: The MMSE-CDR-SB residual may help flag less AD-typical presentations for further etiologic evaluation, but cannot be interpreted as a pathology-specific marker due to substantial overlap across diagnostic groups.},
}

@article {pmid42657501,
year = {2026},
author = {Hill, C and Morgan, H and Michopoulou, S and Niranjan, M and Kipps, CM},
title = {Dynamic imaging markers of incident microhemorrhages and superficial siderosis in the A4 study: A longitudinal person-interval analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71792},
pmid = {42657501},
issn = {1552-5279},
support = {//UKRI Engineering and Physical Sciences Research Council Doctoral Landscape Award/ ; //National Institute for Health and Care Research/ ; },
mesh = {Humans ; Female ; *Magnetic Resonance Imaging ; Longitudinal Studies ; Male ; Aged ; *Siderosis/diagnostic imaging/epidemiology ; *Cerebral Hemorrhage/diagnostic imaging/epidemiology ; Incidence ; *Brain/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging ; },
abstract = {INTRODUCTION: Incident microhemorrhages and superficial siderosis are hemorrhagic magnetic resonance imaging (MRI) abnormalities relevant to amyloid-related imaging abnormalities with hemosiderin deposition (ARIA-H) risk stratification, but evidence exploring their short-term dynamic predictors remains limited.

METHODS: We analyzed longitudinal MRI data from the A4 study, constructing a discrete person-interval dataset for modeling the short-term risk of incident hemorrhagic MRI abnormalities. Models incorporated baseline covariates, alongside dynamic variables of recent microhemorrhage accumulation and current microhemorrhage burden. The outcome was defined as two or more new microhemorrhages or one or more new superficial siderosis between consecutive MRI scans.

RESULTS: Among 1069 participants (3647 intervals), 171 hemorrhagic events occurred. Both current burden (time-to-event: odds ratio [OR] 1.37, 95% confidence interval [CI] 1.09-1.73; all-event: OR 1.24, 95% CI: 1.04-1.49) and recent microhemorrhage accumulation were independently associated with an increased risk of hemorrhagic events (time-to-event: OR 1.83, 95% CI 1.01-3.30; all-event: OR 1.43, 95% CI: 1.00-2.04).

DISCUSSION: Temporal imaging variables may provide independent prognostic information beyond baseline risk, supporting a dynamic model of hemorrhagic risk in Alzheimer's disease.

CLINICAL TRIAL REGISTRATION: Clinical trial of Solanezumab for older individuals who may be at risk for memory loss (A4) (NCT02008357).},
}

Humans
Female
*Magnetic Resonance Imaging
Longitudinal Studies
Male
Aged
*Siderosis/diagnostic imaging/epidemiology
*Cerebral Hemorrhage/diagnostic imaging/epidemiology
Incidence
*Brain/diagnostic imaging
*Alzheimer Disease/diagnostic imaging

@article {pmid42657581,
year = {2026},
author = {Junior, WSC and Bezerra, KS and Matias, EGC and Oliveira, JIN and Fulco, UL},
title = {DFT analysis of gamma-secretase interactions with potential inhibitors: therapeutic for Alzheimer's disease.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp02037b},
pmid = {42657581},
issn = {1463-9084},
abstract = {Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to cognitive decline. The enzyme γ-secretase (γS) plays a central role in Aβ production and is therefore an important therapeutic target. In this study, interaction energies were evaluated using the Molecular Fragmentation with Conjugated Caps (MFCC) method combined with Density Functional Theory (DFT) calculations to investigate the interactions between γS and the inhibitors Semagacestat (SEM) and Avagacestat (AVA). The SEM-γS complex exhibited a more favorable total interaction energy, primarily driven by interactions with residues such as Ala431, Lys380, and Leu425. In contrast, the AVA-γS complex showed prominent interactions involving key residues, including Leu381, Leu425, and Leu432, which participate in substrate recognition and stabilization within the enzymes binding pocket. Overall, both ligands highlight the combined importance of hydrophobic and hydrophilic interactions in stabilizing the complexes. This study provides molecular-level insights into the interaction mechanisms of γ-secretase inhibitors, contributing to a better understanding of structure-energy relationships that are essential for the rational design of more selective and effective therapeutic agents for Alzheimers disease.},
}

@article {pmid42657604,
year = {2026},
author = {Almeida, MM and Fernandes, CS and Campos Ferreira, M},
title = {Co-Design and Development of Digital Health Solution for Informal Alzheimer's Caregivers.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {42657604},
issn = {1546-4156},
abstract = {INTRODUCTION: Alzheimer disease (AD) imposes significant cognitive, emotional, and practical challenges on individuals and their caregivers. Informal caregivers, often family members, assume a central role in managing complex care routines, frequently with limited support. Digital tools offer promising avenues for addressing these challenges, yet existing solutions often lack integration, personalization, or user-centered design.

METHODS: This study presents the design, development, and validation of AlzCare, a digital health solution developed using a user-centered design (UCD) methodology. The needs assessment involved 52 survey respondents and 6 in-depth interviews with caregivers and healthcare professionals. Based on this, a prototype was developed integrating modules for health monitoring, cognitive stimulation, task management, and caregiver support. Usability and functionality were evaluated through testing with 25 participants using task-based interaction, semistructured interviews, and the System Usability Scale (SUS).

RESULTS: The solution received highly positive feedback regarding usability, relevance, and emotional resonance. The SUS yielded a mean score of 90.9, indicating "Best Imaginable" usability. Users valued features such as daily health tracking, the "Who Am I?" reminiscence tool, and the caregiver support section. Suggestions included automating data entry and integrating wearables.

DISCUSSION: AlzCare demonstrates how digital technologies developed through participatory approaches can support informal dementia caregiving across practical and emotional dimensions. Future work will focus on broader clinical integration, automation, and longitudinal validation in real-world settings. The findings reinforce the value of accessible, holistic digital tools in advancing dementia care within telemedicine ecosystems.},
}

@article {pmid42657615,
year = {2026},
author = {Berto, M and Manco Urbina, PA and Paradisi, A and Sensi, M and Iacovino, N and Carbone, C and Bedin, R and Pinti, M and Biscarini, F and Zamboni, G and Bortolotti, CA},
title = {Quantification of Phosphorylated Tau Protein in Alzheimer's Disease Patients' Fluids With Electrolyte-Gated Organic Transistor Biosensors.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e71634},
doi = {10.1002/adhm.71634},
pmid = {42657615},
issn = {2192-2659},
support = {//European Union-NextGenerationEU/ ; //University of Modena and Reggio Emilia/ ; //Fondo Italiano per la Scienza - FIS 3/ ; },
abstract = {Dementia is a syndrome that affects millions of people in the world, and Alzheimer's disease (AD) is the most common cause. The diagnosis of AD begins with cognitive symptoms such as mild cognitive impairment (MCI) but requires the demonstration and quantification of the underlying neuropathological processes through the measurement of specific biomarkers. Among these, the phosphorylated tau protein at threonine 181 (p-tau 181) is considered specific for AD diagnosis in people with MCI. In this work, we report the detection of p-tau 181 spanning from physiological to pathological concentrations in cerebrospinal fluids from patients with MCI. The proposed sensor is based on an electrolyte-gated organic transistor functionalized with specific anti-p-tau 181 antibodies. We analyzed the multiparametric sensor response using a Langmuir model to extract the thermodynamic affinity constant, resulting in values between 10[12] and 10[13]. The sensor response is then correlated with the gray matter volume of the same patients from Magnetic Resonance Imaging: the resulting maps show areas in the brain where the gray matter density decreases with increasing levels of p-tau in CSF.},
}

@article {pmid42657669,
year = {2026},
author = {Romano, CD and Bratlee-Whitaker, E and Hartry, A and Taylor, J and Callahan, LF and Monks, D and Kremer, I and Lappin, D and Frangiosa, T and Sangodkar, S and Lee, J and Shirneshan, E and Slowiejko, D and DiBenedetti, D and Herring, WL and Bussberg, C and Dardis, GJ and Goss, D and Edwards, T and McLeod, L and Poulos, C and Paulsen, R},
title = {Priorities of people living with Alzheimer's and care partners: What Matters Most?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71554},
pmid = {42657669},
issn = {1552-5279},
support = {//UsAgainstAlzheimer's/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology ; Female ; Male ; *Caregivers/psychology ; Cross-Sectional Studies ; Aged ; Aged, 80 and over ; Qualitative Research ; Activities of Daily Living ; Middle Aged ; Surveys and Questionnaires ; },
abstract = {INTRODUCTION: Understanding the experience of people living with Alzheimer's disease (PLWAD) and care partners is central to defining meaningful treatment outcomes. The What Matters Most (WMM) research program seeks to identify and measure treatment-related needs, preferences, and priorities across the disease continuum.

METHODS: This mixed-methods, observational, US-based study included qualitative interviews and a cross-sectional, web-based quantitative survey assessing priorities among WMM model concepts and domains.

RESULTS: Racially and ethnically diverse participants represented the full spectrum of disease severity. Qualitative interviews (N = 64) supported a WMM conceptual model of disease comprising 50 concepts across six domains: General Independence, Thought Processing, Communication, Daily Activities, Emotions, and Social Life/Activities. All WMM concepts were deemed important, but the quantitative survey priority ranking (N = 640) identified differences in prioritization among PLWAD and care partners.

DISCUSSION: These findings provide novel, critical insights into the lived experience of Alzheimer's disease (AD) and the identification of meaningful treatment outcomes.},
}

Humans
*Alzheimer Disease/psychology
Female
Male
*Caregivers/psychology
Cross-Sectional Studies
Aged
Aged, 80 and over
Qualitative Research
Activities of Daily Living
Middle Aged
Surveys and Questionnaires

@article {pmid42657790,
year = {2026},
author = {Tittelmeier, J and Sandhof, CA and Martin, N and El-Kabarity, D and Ngonza-Nito, SB and Melki, R and Nussbaum-Krammer, C},
title = {Disruption of sphingolipid metabolism promotes tau seeding through endolysosomal membrane rigidification and rupture.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
pmid = {42657790},
issn = {2050-084X},
support = {ALZ201912009776//Fondation pour la Recherche Médicale/ ; 21053//Alzheimer Forschung Initiative/ ; },
mesh = {Animals ; *Sphingolipids/metabolism ; *tau Proteins/metabolism ; Caenorhabditis elegans/metabolism ; Humans ; *Lysosomes/metabolism ; *Endosomes/metabolism ; *Membrane Fluidity ; *Intracellular Membranes/metabolism ; },
abstract = {Endolysosomal dysfunction is a hallmark of Alzheimer's disease and related tauopathies, yet underlying mechanisms remain poorly understood. This study investigates the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau aggregation and toxicity in Caenorhabditis elegans and human cell culture models. Fluorescence recovery after photobleaching and C-Laurdan dye imaging revealed that silencing sphingolipid metabolism genes reduced endolysosomal vesicle membrane fluidity, increasing their rupture. The accumulation of aggregated tau in endolysosomal vesicles further aggravated endomembrane rigidification and damage, and promoted seeded tau aggregation, potentially by facilitating the escape of tau seeds from the endolysosomal system. Supplementation with unsaturated fatty acids improved membrane fluidity, suppressing endolysosomal rupture and seeded tau aggregation in cell models, and alleviating tau-associated neurotoxicity in C. elegans. Together, this study provides mechanistic insight into how perturbation of sphingolipid metabolism promotes endolysosomal membrane damage and contributes to the escape of aggregated tau from this compartment, suggesting that restoration of membrane fluidity may represent a strategy to limit tau propagation and toxicity.},
}

Animals
*Sphingolipids/metabolism
*tau Proteins/metabolism
Caenorhabditis elegans/metabolism
Humans
*Lysosomes/metabolism
*Endosomes/metabolism
*Membrane Fluidity
*Intracellular Membranes/metabolism

@article {pmid42658010,
year = {2026},
author = {Lim, D and Tapella, L},
title = {From Proteinopathy to Immunopathy in Alzheimer's Disease-A Role for Astrocytic Calcineurin?.},
journal = {Journal of neurochemistry},
volume = {170},
number = {9},
pages = {e70543},
pmid = {42658010},
issn = {1471-4159},
support = {PNRR-MCNT2-2023-12377363//Ministero della Salute/ ; },
}

@article {pmid42658042,
year = {2026},
author = {Hashimoto, Y and Bao, W and Yamaguchi, S and Watanabe, M and Hashimoto, M and Ohno, S and Yamaguchi, Y and Matsuzawa, K and Tokoro, Y and Kizuka, Y},
title = {Bisecting GlcNAc in N-glycan regulates synaptic maturation.},
journal = {The Biochemical journal},
volume = {},
number = {},
pages = {},
doi = {10.1042/BCJ20260379},
pmid = {42658042},
issn = {1470-8728},
abstract = {Bisecting GlcNAc, a central branch in N-glycans synthesized by the N-acetylglucosaminyltransferase III (MGAT3; also known as GnT-III), is highly expressed in neurons. Although pathological roles of MGAT3 and bisecting GlcNAc have been demonstrated in Alzheimer's disease, their physiological functions in neurons remain unclear. To identify their physiological functions, here we examine the morphology of neurons in knockout (Mgat3-/-) mouse brains and investigate the expression and localization of bisecting GlcNAc-bearing glycoproteins involved in neuronal activity and morphogenesis. We found impaired neurite extension and spine maturation in cultured cortical neurons of Mgat3-/- mice, along with reduced stimulus-induced in vivo neuronal activity. Moreover, key glycoproteins for these processes (specifically α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]-type glutamate receptors) showed reduced accumulation in postsynaptic density membrane fractions and a weakened interaction with transmembrane AMPA receptor regulatory protein 8 (TARP8) in Mgat3-/- mouse brain. These results suggest that bisecting GlcNAc plays important roles in synaptic maturation, highlighting a new mechanism for neuronal activity regulated by specific N-glycans.},
}

@article {pmid42658064,
year = {2026},
author = {Wu, X and Zu, Y and Lu, Y and Zhao, Y and Crosslin, D and Fonseca, V and Maraganore, D and Yoshida, Y},
title = {The Joint Effects of Life's Essential 8 and Genetics on Mild Cognitive Impairment and Dementia Risk in People With Diabetes: Findings From the UK Biobank and All of Us.},
journal = {Diabetes care},
volume = {},
number = {},
pages = {},
doi = {10.2337/dc25-3126},
pmid = {42658064},
issn = {1935-5548},
support = {1P20GM152305//Foundation for the National Institutes of Health/ ; 7-23-JDFWH-10//Foundation for the National Institutes of Health/ ; U54 GM104940//Foundation for the National Institutes of Health/ ; },
abstract = {OBJECTIVE: We examined how cardiovascular health (CVH), measured by Life's Essential 8 (LE8), and genetic risk are jointly associated with risks of mild cognitive impairment (MCI), dementia, and related cognitive outcomes in people with diabetes.

RESEARCH DESIGN AND METHODS: We analyzed 41,374 participants without dementia from the UK Biobank (UKB) and 9,766 from All of Us (AoU). LE8, comprising diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure, was scored from 0 to 100 and categorized as low, moderate, or high. Genetic risk was assessed using APOE ε4 alleles and polygenic risk scores (PRS) for Alzheimer disease. We used Cox regression to examine associations of LE8 with MCI and dementia and linear regression to assess MRI-based brain functional measures and cognitive test outcomes, adjusting for covariates. Interactions between LE8 and genetic risk were tested on multiplicative and additive scales.

RESULTS: Over 15 years of follow-up (UKB), moderate or high CVH versus low CVH was associated with a lower risk of MCI (hazard ratio 0.82 [95% CI 0.71, 0.95], P < 0.05) but not with risk of all-cause dementia (0.97 [0.84, 1.11], P = 0.63). In participants at high genetic risk (high PRS), moderate or high CVH was associated with a lower risk of MCI (0.78 [0.62, 0.98], P for additive interaction < 0.05). AoU results were consistent.

CONCLUSIONS: Better CVH was significantly associated with a lower risk of MCI in people with diabetes, accounting for genetic risk. The association between CVH and MCI and dementia was stronger among individuals with low or moderate genetic risk and appeared attenuated among those with high genetic risk.},
}

@article {pmid42658102,
year = {2026},
author = {Basalim, AA and Lu, EM},
title = {From Periodontal Pocket to Systemic Diseases: Mechanistic Insights Into the Role of Porphyromonas gingivalis in Host Pathology.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {16},
pages = {e71327},
pmid = {42658102},
issn = {1582-4934},
mesh = {Humans ; *Porphyromonas gingivalis/pathogenicity/physiology ; *Host-Pathogen Interactions ; Animals ; Alzheimer Disease/microbiology/pathology ; *Periodontitis/microbiology/pathology ; *Bacteroidaceae Infections/microbiology/pathology/complications ; Cardiovascular Diseases/microbiology/pathology ; },
abstract = {Porphyromonas gingivalis (P. gingivalis), a keystone pathogen in periodontitis, has been increasingly recognised as a mechanistic bridge linking periodontal infection to pathological destruction in distant organs. P. gingivalis virulence factors, including gingipains, lipopolysaccharides (LPS), and outer membrane vesicles (OMVs), mediate complex host-pathogen interactions. In this review, we critically evaluated recent experimental studies which demonstrate the effects of P. gingivalis oral infection on systemic diseases, including cardiovascular disease (CVD), diabetes mellitus (DM), adverse pregnancy outcomes (APOs), colorectal cancer (CRC), and Alzheimer's disease (AD). In CVD, DM, and AD, P. gingivalis gingipains exert proteolytic activity that disrupts key cellular targets, including endothelial adhesion molecules, insulin receptors in insulin-responsive tissues, and neuronal proteins. In AD, P. gingivalis LPS contributes to neuronal damage by inducing tau hyperphosphorylation and synaptic dysfunction. In APO and AD, P. gingivalis OMVs play a central role in compromising barrier integrity. These processes converge on five principal pathogenic pathways: (1) barrier and structural disruption, (2) immune activation and subversion, (3) mitochondrial dysfunction and oxidative stress induction, (4) systemic inflammation, and (5) metabolism-mediated effects. Understanding these shared pathways underscores the importance of controlling periodontal disease in promoting systemic health.},
}

Humans
*Porphyromonas gingivalis/pathogenicity/physiology
*Host-Pathogen Interactions
Animals
Alzheimer Disease/microbiology/pathology
*Periodontitis/microbiology/pathology
*Bacteroidaceae Infections/microbiology/pathology/complications
Cardiovascular Diseases/microbiology/pathology

@article {pmid42658406,
year = {2026},
author = {Uçar, M},
title = {A comparative study of vision transformer architectures for the detection of Alzheimer's disease using magnetic resonance images.},
journal = {Physical and engineering sciences in medicine},
volume = {},
number = {},
pages = {},
pmid = {42658406},
issn = {2662-4737},
abstract = {Alzheimer's disease is a neurodegenerative disease that affects millions of people worldwide. With the increasing global elderly population, early and accurate diagnosis of the disease is becoming increasingly important to slow its progression and improve patient outcomes. This study aims to present a comprehensive vision transformer-based solution proposal for the accurate and rapid detection of Alzheimer's disease using magnetic resonance images. Nine different transformer-based models, namely Vision Transformer, Pooling-based Vision Transformer, Convolutional Vision Transformer, Crossformer, Cross-attention Vision Transformer, Nested Transformers, Multi-Axis Vision Transformer, Separable Vision Transformer, and MobileViT, were used to analyse their effectiveness in diagnosing the disease in detail. Experimental results have shown that transformer-based architectures exhibit high performance in the detection of Alzheimer's disease. In binary classification results, the Multi-Axis Vision Transformer model stood out from other models by achieving the most successful performance in accuracy, sensitivity, specificity, precision, and f1-score metrics. In multi-class classification results, the Crossformer model provided the highest results in terms of sensitivity, specificity, precision, and f1-score, while the Separable Vision Transformer model was the most successful model in the accuracy metric. Furthermore, it was observed that the Mobile Vision Transformer model produced competitive results, especially in sensitivity and specificity metrics. In conclusion, this study provides a promising framework for the use of vision transformers in neuroimaging, providing an innovative solution for the early diagnosis of Alzheimer's disease.},
}

@article {pmid42658568,
year = {2026},
author = {Tremblay, C and Freiburghaus, T and Pawlik, D and Hauer, KO and Serrano, GE and Zeighami, Y and Dadar, M and Intorcia, AJ and Ossenkoppele, R and Pontecorvo, MJ and Hansson, O and Smith, R and Beach, TG},
title = {Comparison of quantitative digital and semiquantitative assessments of tau pathology in relation to regional in vivo tau PET.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag093},
pmid = {42658568},
issn = {1554-6578},
support = {//Avid Radiopharmaceuticals/ ; //Eli Lilly and Company/ ; U24 NS072026//National Institute of Neurological Disorders and Stroke (NINDS)/ ; //National Brain and Tissue Resource for Parkinson's Disease and Related Disorders/ ; P30 AG019610//National Institute on Aging (NIA)/ ; P30AG072980//National Institute on Aging (NIA)/ ; //Arizona Alzheimer's Disease Center/ ; //Arizona Department of Health Services/ ; //Arizona Alzheimer's Research Center/ ; //Arizona Biomedical Research Commission/ ; //Arizona Parkinson's Disease Consortium/ ; //The Michael J. Fox Foundation (MJFF) for Parkinson's Research/ ; ADG-101096455/ERC_/European Research Council/International ; ZEN24-1069572/ALZ/Alzheimer's Association/United States ; SG-23-1061717/ALZ/Alzheimer's Association/United States ; //GHR Foundation/ ; 2022-00775//Swedish Research Council/ ; ERAPERMED2021-184//ERA PerMed/ ; //Knut and Alice Wallenberg foundation/ ; //Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University/ ; AF-980907//Swedish Alzheimer Foundation/ ; AF-939981//Swedish Alzheimer Foundation/ ; FO2021-0293//Swedish Brain Foundation/ ; 1412/22//Parkinson foundation of Sweden/ ; //Cure Alzheimer's fund/ ; //Rönström Family Foundation/ ; 2020-O000028//Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Skåne University Hospital Foundation/ ; 2022-1259//Regionalt Forskningsstöd/ ; 2021-1013//Regionalt Forskningsstöd/ ; //Bundy Academy/ ; //Kockska Foundation/ ; 2022-Projekt0080//Swedish federal government under the ALF agreement/ ; 2020-YF0020//Swedish federal government under the ALF agreement/ ; },
abstract = {Quantitative digital image analysis has emerged as a powerful tool for assessing neuropathological burden. Although previous studies have compared quantitative digital and semiquantitative pathology measures, their respective relationships with regionally corresponding in vivo tau PET measures remain poorly characterized. We compared quantitative digital pathology quantification and semiquantitative regional gradings of phosphorylated tau (ptau) immunohistochemical staining and assessed their correlations with regional in vivo [18F]flortaucipir standardized uptake value ratios (SUVRs) in 52 cases from the AVID A16 end-of-life study. Digital pathology quantification and semiquantitative gradings of ptau were strongly correlated across all 19 cortical and mesial temporal regions examined (Spearman's rho range: 0.6-0.9; all P < .0001). Both approaches showed similarly robust associations with regionally corresponding tau PET SUVRs. Direct comparison of matched correlation coefficients revealed stronger PET-pathology associations for the digital quantification in the left amygdala and the inferior parietal lobule. Overall, digital pathology quantification and semiquantitative assessments of ptau pathology yielded highly comparable results, both in the quantification of regional pathology burden and in their relationships with tau PET measures. These findings support the use of digital pathology quantification methods and suggest that semiquantitative pathology gradings remain a valid and informative approach for clinicopathological correlation studies.},
}

@article {pmid42658656,
year = {2026},
author = {Moored, KD and Sekhon, VK and Xue, QL and Parisi, JM and Amjad, H and Rebok, GW and Eldreth, DA and Carlson, MC},
title = {Lifestyle activities and risk of incident dementia from linked insurance claims in the Baltimore Experience Corps Study.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag177},
pmid = {42658656},
issn = {1758-5368},
abstract = {OBJECTIVES: Lifestyle activity engagement in later life may protect against dementia, but studies have often been limited to short follow-up periods and predominantly White samples. We examined activity variety and frequency as predictors of incident dementia, leveraging 15 years of linked longitudinal insurance claims data in the Baltimore Experience Corps Study (BECS).

METHODS: Participants were 482 individuals from BECS (2006-2013) with linked insurance claims (mean age=68.2, 84% women, 95% Black/African American). Participants self-reported baseline engagement in 28 activities. We calculated the number of unique activities (activity variety) and average frequency of engagement across reported activities (activity frequency). Incident dementia (2008-2022) was ascertained from CMS and private claims using the Bynum-EM algorithm. We used Cox proportional hazards models, adjusting for age and intervention group, and tested multiple follow-up periods (5-year, 15-year).

RESULTS: The average baseline variety was 18.8 activities (SD = 3.3) and frequency was 13.1 days/month (SD = 3.2). For the 15-year follow-up only, higher activity variety was associated with lower risk of incident dementia (HR=.94, 95% CI: 0.89-0.99), equivalent to about a 6-month delay in diagnosis per additional activity. This association was attenuated after adjusting for additional demographics (e.g., sex, education), prevalent health conditions, and depression (HR=.96, 95% CI: 0.90-1.01). Activity frequency was not significant in any model.

DISCUSSION: Higher activity variety, but not frequency, modestly predicted lower dementia risk over 15 years in a sample of primarily Black older adults. Findings suggest that engagement in a range of activities, rather than more frequent engagement in limited activities, may elicit greater cognitive benefits.},
}

@article {pmid42658881,
year = {2026},
author = {Guo, H and Wu, T and Wang, W and Jiang, Y and Li, G and Nie, L and Jia, Y and Quan, L and Huang, M and Lyu, Q},
title = {iDCF: Interpretable deconvolution of cell fractions via biologically-informed deep learning using scRNA-seq data.},
journal = {PLoS computational biology},
volume = {22},
number = {8},
pages = {e1014727},
doi = {10.1371/journal.pcbi.1014727},
pmid = {42658881},
issn = {1553-7358},
abstract = {Precise resolution of cellular heterogeneity within complex tissues is fundamental to deciphering disease etiologies from bulk transcriptomic profiles. While computational deconvolution offers a scalable alternative, current deep learning methods predominantly operate as "black boxes," neglecting the structural constraints of biological laws. This reliance on purely data-driven feature extraction often yields biologically incoherent predictions and limited mechanistic interpretability. iDCF (Interpretable Deconvolution of Cell Fractions) is a novel framework that enforces biological topology onto deep neural networks. The iDCF architecture employs a dual-stream design, synergizing a standard deep network with a knowledge-based sparse neural network (KSNN) explicitly masked by pathway definitions and protein-protein interaction (PPI) networks. In comprehensive benchmarks, iDCF achieves top-tier performance, consistently ranking among state-of-the-art methods in accuracy and robustness. iDCF integrates the SHapley Additive exPlanations (SHAP) framework, bridging the gap between computational inference and biological intuition. The model's decision logic is governed by established biological mechanisms rather than spurious statistical correlations, validating its reliability. Validations across clinical contexts, including Alzheimer's disease, ovarian cancer, and diabetes, demonstrate iDCF's ability to recover disease-relevant cellular dynamics. iDCF offers a high-performance, interpretable, and biologically grounded tool for deconvolving cell-type proportions, facilitating deeper insights into tissue heterogeneity in health and disease.},
}

@article {pmid42659615,
year = {2026},
author = {Gonzalez-Gomez, R and Tagliazuchi, E and Campo, CG and Medel, V and Bennett, DA and Iturria-Medina, Y},
title = {Lesion-Level Subtypes of White Matter Hyperintensity Evolution Beyond Spatial Location.},
journal = {Neurology},
volume = {107},
number = {6},
pages = {e218472},
doi = {10.1212/WNL.0000000000218472},
pmid = {42659615},
issn = {1526-632X},
mesh = {Humans ; Female ; *White Matter/pathology/diagnostic imaging ; Male ; Longitudinal Studies ; Aged ; *Aging/pathology ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/diagnostic imaging/pathology ; *Brain/pathology/diagnostic imaging ; *Parkinson Disease/diagnostic imaging/pathology ; *Alzheimer Disease/diagnostic imaging/pathology ; Aged, 80 and over ; },
abstract = {BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMHs) are common neuroimaging markers of cerebrovascular pathology in aging and neurodegeneration. Despite their clinical relevance, WMH are typically quantified using global burden measures that assume a relatively homogeneous pathologic process. However, growing evidence suggests substantial biological heterogeneity across lesions. We aimed to identify lesion-level WMH subtypes beyond anatomic location and evaluate their associations with neurodegeneration and vascular risk.

METHODS: We conducted a longitudinal observational study analyzing 3224 MRI scans from 403 participants spanning cognitively normal aging, mild cognitive impairment, Alzheimer, and Parkinson disease. Imaging at baseline and 2-year follow-up included structural, diffusion, and resting-state MRI. A total of 2107 WMH lesions were identified, and lesion-wise longitudinal changes were used to derive subtypes using unsupervised clustering. Associations with neurodegeneration and vascular risk factors were assessed using multivariable models with false discovery rate correction.

RESULTS: Three lesion subtypes (L1-L3) were identified, frequently coexisting within the same individual. L1 lesions were the most prevalent (48.1%), predominated in cognitively normal individuals, and exhibited relatively stable trajectories without association with brain atrophy. L2 lesions represented a less frequent (11.3%) unstable subtype associated with weight gain (odds ratio [OR] 1.33, 95% CI 1.22-1.45; pFDR ≤ 0.001), suggesting metabolic vulnerability. L3 lesions (40.6%) represented an unstable subtype associated with brain atrophy (β = -0.11, 95% CI -0.16 to -0.05; pFDR < 0.001), older age (OR 1.15, 95% CI 1.07-1.23; pFDR < 0.001), and vascular risk reflected by pulse pressure changes (OR 1.09, 95% CI 1.03-1.15; pFDR = 0.006). Global WMH burden was no longer associated with brain atrophy after accounting for L3 lesion burden. Clustering robustness was supported by sensitivity analyses excluding anatomical location and by external validation in an independent cohort reproducing the main atrophy-related findings.

DISCUSSION: WMH are not a homogeneous entity but comprise biologically distinct lesion subtypes with differential neurobiological and clinical significance. Lesion composition may therefore offer a more informative framework than global WMH burden for understanding cerebrovascular contributions to aging and neurodegeneration, with potential implications for risk stratification, clinical interpretation, and targeted interventions.},
}

Humans
Female
*White Matter/pathology/diagnostic imaging
Male
Longitudinal Studies
Aged
*Aging/pathology
Magnetic Resonance Imaging
*Cognitive Dysfunction/diagnostic imaging/pathology
*Brain/pathology/diagnostic imaging
*Parkinson Disease/diagnostic imaging/pathology
*Alzheimer Disease/diagnostic imaging/pathology
Aged, 80 and over

@article {pmid42659841,
year = {2026},
author = {Cho, JH and Passera, B and Bertazzoli, G and Ozdemir, RA and Gomaa, B and Ferry, E and Pascual-Leone, A and Sperling, RA and Press, DZ and Shafi, MM and Fried, PJ and Buss, SS},
title = {Input-output curves demonstrate motor cortex hyperexcitability associated with cognitive impairment in Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {147-158},
doi = {10.1016/j.neurobiolaging.2026.08.002},
pmid = {42659841},
issn = {1558-1497},
abstract = {Recent studies suggest that cortical hyperexcitability in Alzheimer's disease (AD) may accelerate disease progression. However, the field lacks validated non-invasive methods to assay excitability in humans. In this study we used transcranial magnetic stimulation with electromyography to investigate mechanisms of motor cortical excitability in 63 biomarker-positive early-AD (ranging from mild cognitive impairment to mild dementia) participants and 72 cognitively unimpaired age-matched adults (CU). Single-pulse stimulation was applied to motor cortex to record resting motor thresholds (rMT) and motor-evoked potentials. An Input-Output curve was generated by delivering 10 pulses each at eight different intensities of maximum stimulator output (%MSO). Linear models or equivalent non-parametric tests 1) compared excitability metrics between groups, 2) tested correlations with cognition (mini-mental state exam, MMSE; Alzheimer's disease assessment scale-cognitive, ADAS-Cog), and 3) tested the impact of APOE4. Results show that early-AD participants have increased motor cortical excitability than CU, with lower rMT (p < 0.001), lower Input-Output curve Inflection Point (p = 0.007), and higher Dynamic Range (p = 0.035). An analysis of the Input-Output curve adjusting for rMT showed larger responses in AD specifically in the 135-150% rMT range (p = 0.023). In AD, higher excitability was related to worse cognition (rMT: MMSE p = 0.008, Inflection Point: MMSE p = 0.030 and ADAS-Cog p = 0.041). There was no relationship between APOE4 and excitability. In conclusion, AD participants have increased motor cortical excitability, related to cognition. This is evident both at lower and higher stimulation intensities. TMS may provide a useful measure of target engagement for therapies aimed at preserving cognition or slowing decline in early-AD.},
}

@article {pmid42659862,
year = {2026},
author = {Hosseini, MS and Saheli, M and RajiZadeh, MA and Nematollahi-Mahani, SN and Joushi, S and Gaeini, A and Khoramipour, K and Sheibani, V},
title = {High-intensity interval training versus mesenchymal stem cells in amyloid-β-induced Alzheimer's disease: comparative effects on cognitive function,hippocampal inflammation, oxidative balance, and BDNF.},
journal = {Biochemical and biophysical research communications},
volume = {834},
number = {},
pages = {154463},
doi = {10.1016/j.bbrc.2026.154463},
pmid = {42659862},
issn = {1090-2104},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Although high-intensity interval training (HIIT) and mesenchymal stem cells (MSCs) have demonstrated neuroprotective effects, their comparative efficacy has not been compared. Male Wistar rats were assigned to five groups: Control, Vehicle, AD, AD + HIIT, and AD + MSCs. AD was induced by intracerebroventricular (ICV) injection of amyloid-beta (Aβ1-42). HIIT was performed for six weeks, and MSCs were injected via ICV. Learning and memory were evaluated using the Morris water maze (MWM), and CA1 cell number was assessed by Nissl staining. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), and brain-derived neurotrophic factor (BDNF) were measured in the hippocampus. Aβ1-42 impaired learning and memory and decreased CA1 cell number, whereas MSCs increased CA1 cell number compared with the AD group (P < 0.05). Aβ1-42 injection increased TNF-α and MDA (both P < 0.001) and decreased IL-10, BDNF (P < 0.01), SOD, and TAC (both P < 0.001). Both HIIT and MSCs improved cognitive performance and modulated biochemical markers compared with AD (P < 0.05). Compared with HIIT, MSCs produced greater reductions in TNF-α (P < 0.01) and greater increases in SOD and TAC (both P < 0.05). Despite these biochemical differences, no significant cognitive function difference was observed between HIIT and MSCs (P > 0.05). These findings suggest that, within the conditions of this study, both HIIT and MSCs administration were associated with improved cognitive performance, with no significant difference in effectiveness between the two treatments. HIIT may therefore be a promising non-pharmacological intervention, but further research is needed to confirm its benefits.},
}

@article {pmid42659873,
year = {2026},
author = {López-Aviña, YI and Ríos-Castro, E and Rodríguez-Cruz, F and Mendoza-Franco, G and Vega, BC and Boucard, AA and Luna-Arias, JP and Basurto-Islas, G and García-Sierra, F},
title = {The truncated Tau fragment 315-441 produced by Caspase-2 translocates to the nucleus and alters the proteome of neuroblastoma cells.},
journal = {European journal of cell biology},
volume = {105},
number = {4},
pages = {151567},
doi = {10.1016/j.ejcb.2026.151567},
pmid = {42659873},
issn = {1618-1298},
abstract = {Alzheimer's disease (AD) symptoms arise from significant loss of neurons in the hippocampal region and the entorhinal cortex. This neuronal death is primarily caused by the abnormal aggregation of Tau protein into paired helical filaments within the somatodendritic compartment. However, the molecular mechanisms underlying this toxicity remain unclear. One contributing factor is the proteolysis of Tau, mainly mediated by Caspase-3. This abnormal post-translational modification promotes Tau aggregation and neuronal toxicity in the brains affected by AD, as well as in vitro cultured cells. Additionally, a new proteolytic site at Asp[314], produced by Caspase-2, has been identified in AD. However, little is known about the pathological role of the Tau fragments generated by Caspase-2, specifically Tau 1-314 and Tau 315-441. In this study, we transiently transfected neuroblastoma cells with plasmids encoding either Tau 1-314 or Tau 315-441 and analyzed changes in cell morphology as well as toxicity using immunofluorescence and confocal microscopy. Furthermore, we aimed to examine the physiological effects of truncated Tau expression on the overall proteome of the transfected neuroblastoma cells through mass spectrometry analysis. Our findings indicate that the Caspase-2-generated truncated Tau fragments exhibit distinct intracellular distributions, leading to the abnormal transport of Tau 315-441 into the nuclear compartment accompanied by the abnormal downregulation of functional and structural nuclear proteins. The generation of Caspase-2-derived truncated Tau fragments may represent an additional mechanism of neuronal toxicity occurring at early stages of the disease, prior to the filamentous aggregation of the Tau protein.},
}

@article {pmid42659996,
year = {2026},
author = {Han, S and Zhu, C and Ding, Y and Kudelati, Z and Wang, H},
title = {The relationship between positive psychological capital, self-care ability, and quality of life in patients with mild cognitive impairment: A cross-sectional study.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {73},
number = {},
pages = {104314},
doi = {10.1016/j.gerinurse.2026.104314},
pmid = {42659996},
issn = {1528-3984},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) severely impairs elders' quality of life. Positive psychological capital (PsyCap) and self-care ability are key protective factors, but most existing studies merely conduct linear analyses using total scale scores, ignoring multi-dimensional interactions. This study explored their internal associations to guide targeted clinical interventions.

METHOD: This cross-sectional observational study was carried out from November 2025 to January 2026 at a Chinese tertiary hospital. We recruited elderly outpatients with MCI through convenience sampling, and collected data via on-site face-to-face questionnaires. Three standardized scales were applied: the Positive Psychological Capital Scale (PPC), Self-care Ability Scale for the Elderly (SASE), and Quality of Life in Alzheimer's Disease (QOL-AD). No family members were enrolled. Network analysis was used to detect central and bridge nodes and their links with quality of life.

RESULTS: A total of 210 valid questionnaires were collected, with a mean score of 109.33 ± 16.57 on the PsyCap scale and a mean score of 59.88 ± 5.20 on the SASE scale. "Hope" acted as the top core node. "Hope" and "environment" serve as cross-scale bridge nodes. "Hope" correlated most strongly with life satisfaction, and stability tests proved the network's good reliability.

CONCLUSION: This study revealed multi-level psychological mechanisms in MCI patients and identified hope and environment as key bridge nodes boosting PsyCap and self-care simultaneously. Customised interventions can improve MCI patients' well-being. At the same time, this study provides clinical staff with a framework for dual-track interventions aimed at fostering hope and optimising the home environment.},
}

@article {pmid42659997,
year = {2026},
author = {DiLeone, C and Maruca, AT},
title = {Evaluating the virtual dementia tour with undergraduate nursing students using the RE-AIM framework.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {73},
number = {},
pages = {104298},
doi = {10.1016/j.gerinurse.2026.104298},
pmid = {42659997},
issn = {1528-3984},
abstract = {BACKGROUND: As the U.S. population ages, the incidence of Alzheimer's and dementia is expected to increase to more than nine million Americans by 2030. The virtual dementia tour (VDT®) simulation program is an innovative educational strategy used to improve nursing students' perception of dementia experience thereby enhancing patient centered care.

SAMPLE: 143 Nursing students in an accelerated BSN program.

METHODS: Conducted as a pilot, VDT was delivered to undergraduate nursing students using the RE-AIM Framework. A pre/post survey examines student's experience of the care needs of patients with Dementia.

RESULTS: The results indicated a significant difference from pre-to-post response ranging (p-value <2,2e-16 to 5.84e-16) and the median difference estimated to be 2.99, with 95% confidence interval.

CONCLUSION: This feasibility study highlights VDT® is a valuable training method to support dementia care education. Results inform phase 2 of the future delivery of the VDT® in community and public health agencies.},
}

@article {pmid42660275,
year = {2026},
author = {Mastroeni, DF and Nolz, J and Zhang, Y and Griffiths, DR and Louangprasert, KA and Emerson, H and Karamanova, N and Law, LM and Park, J and Migrino, RQ and Lifshitz, J},
title = {Microtubule and cytoskeletal Destabilization gene expression in the brain vasculature after experimental diffuse traumatic brain Injury, Implications for neurodegenerative disease later in life.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138711},
doi = {10.1016/j.neulet.2026.138711},
pmid = {42660275},
issn = {1872-7972},
abstract = {Neurodegenerative disease risk following traumatic brain injury (TBI) has been associated with vascular abnormalities and brain inflammation. However, the extent to which diffuse TBI with at least one persistent neurological deficit contributes to chronic neurodegeneration is not well understood. In this study, we investigated the impact of experimental diffuse TBI on the cerebral vasculature in the CA1 region of the hippocampus, which is vulnerable to multiple cognitive-associated neurodegenerative diseases. At the 6-month post-injury timepoint, a timepoint with known cognitive impairment, we employed laser capture microdissection (LCM) to isolate parenchymal blood vessels from the CA1 subregion of the hippocampus in Sprague-Dawley rats subjected to either sham or midline fluid percussion injury. LCM vessels were processed for RNA sequencing and differentially expressed gene (DEG) analyses (DESeq2) were performed, followed by pathway enrichment analysis using genes with a log2FC > 0 and p-value < 0.05. A subset of differentially expressed genes (9%) were associated with microtubule/cytoskeletal organization, including Plectin (PLEC) gene (Log2FC=+9.5, p < 0.0001), a cytoskeletal protein that maintains tissue integrity and whose overexpression was recently identified as a risk factor for Alzheimer's disease (AD). Pathway analyses showed the most upregulated and downregulated biological pathways were involved in neurodegeneration-multiple-diseases (Gene count 11, p-adjusted < 0.01) and AD (Gene count 8, p-adjusted < 0.04). Understanding the complex interplay between TBI, the cerebral vasculature, and neurodegeneration risk is critical for prognosis and interventions that mitigate the long-term effects of brain injury and improve outcomes for patients.},
}

@article {pmid42660456,
year = {2026},
author = {Nurmakova, K and Gomes, GW and Levine, ZA},
title = {Apolipoprotein E lipidation, rather than isoform identity, determines amyloid-β binding and astrocyte clearance.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113494},
doi = {10.1016/j.jbc.2026.113494},
pmid = {42660456},
issn = {1083-351X},
abstract = {Inherited variations in the Apolipoprotein E (APOE) gene are the largest genetic determinant for late-onset Alzheimer's disease, with the APOEε4 allele conferring the highest risk. While APOE was shown to modulate amyloid beta (Aβ) pathology in a genotype-specific manner (APOEε4>APOEε3>APOEε2), it remains an open question whether these differences are due directly to isoform-specific interactions between ApoE and Aβ or indirect effects on Aβ clearance. To disentangle how single ApoE mutations confer vastly different effects on Aβ pathology, we investigated how both the ApoE isoform and lipidation modulate its binding to Aβ species, and its effect on Aβ uptake and cytotoxicity in human astrocytes. We found that ApoE lipidation, not isoform, has the biggest impact on its interaction with Aβ, on the uptake of Aβ by astrocytes, and on Aβ-induced cytotoxicity. Specifically, unlipidated ApoE preferentially interacts with Aβ oligomers and fibrils, which substantially inhibits their uptake by astrocytes. Conversely, lipidated ApoE showed no interaction with Aβ oligomers and had a reduced ability to inhibit Aβ uptake. Our observations suggest that previously reported ApoE isoform-specific differences in Aβ oligomer levels are not driven by intrinsic sequence-specific differences in the affinity between ApoE and Aβ, but potentially by isoform-specific differences in ApoE lipidation in the brain. We propose that the impaired lipidation of ApoE4 in the brain increases levels of unlipidated ApoE, which then bind toxic Aβ oligomers and reduce their clearance by astrocytes. Such a mechanism underscores the therapeutic potential of interventions aimed at increasing ApoE lipidation.},
}

@article {pmid42660657,
year = {2026},
author = {Nguyen, AM and Lo, H and Fields, J and Cramer, KS and Zeng, FG and Dong, W and Xu, X},
title = {Temporal progression of auditory brainstem dysfunction and behavioral phenotypes in mouse models of tauopathy.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.0511-26.2026},
pmid = {42660657},
issn = {1529-2401},
abstract = {Cognitive decline in Alzheimer's disease and related dementias (AD/ADRD) frequently co-occurs with motor and sensory processing impairments. While auditory abnormalities were reported in beta-amyloid-based models before cognitive decline, the effects of tau pathology on auditory circuit function remain poorly understood. The PS19 mouse model expressing the P301S tau mutation exhibits tau pathology associated with frontotemporal dementia. When combined with the humanized ApoE ɛ4 allele, these mice show accelerated tau accumulation and neurodegeneration. We investigated the temporal progression of auditory and behavioral deficits in PS19 and ApoE4/PS19 mice of either sex at 3 and 7 months. Auditory processing was assessed using auditory brainstem response (ABR) recordings, while anxiety-like and motor behaviors were evaluated using the elevated plus maze (EPM) and rotarod assays. PS19 mice exhibited auditory pathway dysfunction at 3 months, characterized by reduced and delayed neural responses to acoustic stimuli. These auditory deficits occurred without detectable behavioral changes in anxiety- or motor-related measures. By 7 months, cochlear-nucleus-derived ABR activity shifted from an initial reduction to elevation relative to controls, suggesting compensatory hyperexcitability. In contrast, ApoE4/PS19 mice showed reduced ABR amplitudes and shortened response latencies that persisted with age, accompanied by altered anxiety-like behavior and motor performance. Together, these results demonstrate that auditory pathway dysfunction may represent an early marker of tau pathology preceding behavioral impairment. The divergent temporal patterns of ABR alterations across genotypes suggest that genetic context, particularly ApoE4, modulates the progression of tau-driven circuit dysfunction, highlighting ABR as a potential noninvasive biomarker for early tau-related neurodegenerative disease.Significance Statement Early detection of Alzheimer's disease and related dementias remains a major clinical challenge. This study identifies auditory pathway dysfunction as an early, measurable marker of tau pathology, preceding detectable behavioral impairments in mouse models with abnormal auditory brainstem responses (ABRs) appeared months before anxiety or motor behavioral changes. Genetic background also significantly influenced disease progression, with the ApoE4 allele altering both the timing and nature of auditory and behavioral phenotypes. Together, these findings demonstrate that tau pathology disrupts auditory processing at early disease stages and suggest that ABR-based measures as sensitive, non-invasive approach for early detection and monitoring of tau-related neurodegeneration.},
}

@article {pmid42660828,
year = {2026},
author = {Yang, T and Ma, JR and Liang, SY and Zhang, YM and Guo, L and Li, WJ and Lü, YH},
title = {Traditional Chinese Herbal Formula YA3D3 Ameliorates Alzheimer's Disease-Like Pathology and Cognitive Impairment in APP/PS1 Transgenic Mice.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {4},
pages = {602-614},
doi = {10.3881/j.issn.1000-503X.17127},
pmid = {42660828},
issn = {1000-503X},
mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology ; *Alzheimer Disease/drug therapy/pathology ; Mice, Transgenic ; Mice ; Male ; *Cognitive Dysfunction/drug therapy ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Amyloid beta-Protein Precursor ; },
abstract = {Objective To evaluate the effects of the traditional Chinese herbal formula YA3D3 on cognitive impairment and cerebral β-amyloid （Aβ） deposition in APP/PS1 transgenic mice and to determine whether these effects are mediated by up-regulation of the autophagy-related gene 14 （ATG14）. Methods Network pharmacology was employed to predict YA3D3 targets.Total antioxidant capacity and hydroxyl free radical scavenging activity were measured in vitro.BV2 microglial cells were infected with short hairpin RNA （shRNA） lentivirus targeting ATG14 （designated as sh-ATG14） and then treated with 0.5 mg/mL of either water-extract （YA3D3-HF） or fermented （YA3D3-MHF） preparation for 24 h.The expression levels of ATG14 and downstream ATG16L1 were assessed by qPCR and Western blot.Sixty-four 3-month-old male APP/PS1 mice were randomly allocated to eight groups （n=8）：APP/PS1 model，donepezil，low-，medium-，and high-dose YA3D3-HF，and low-，medium-，and high-dose YA3D3-MHF.All the drugs were administered ad libitum in drinking water for 90 days.Spatial learning and memory were evaluated through the Morris water maze.Cerebral Aβ deposition was quantified by immunofluorescence.Autophagy-related gene expression in the brain tissue was analyzed by qPCR. Results Network pharmacology indicated significant enrichment of YA3D3 targets in autophagy and phosphatidylinositol 3-kinase/protein kinase B signaling pathways.YA3D3-MHF showed stronger antioxidant activity than YA3D3-HF in vitro （P<0.001）.In BV2 cells，both preparations reversed ATG14 knock-down-induced down-regulation in the expression of ATG14 and ATG16L1，with YA3D3-MHF being more potent （P=0.003）.The animal experiment showed that all the YA3D3 groups exhibited shorter escape latency and more platform crossings than the APP/PS1 model group （all P<0.05），along with reduced Aβ fluorescence intensity （all P<0.001）.The efficacy of high-dose YA3D3-MHF was similar to that of donepezil.qPCR confirmed that YA3D3 up-regulated the expression of ATG14 and modulated the expression of downstream autophagy-related genes in the brain tissue （all P<0.05）. Conclusions The traditional Chinese herbal formula YA3D3 may up-regulate the expression of ATG14 to slow down Aβ deposition and ameliorate cognitive impairment in APP/PS1 mice，serving as a potential candidate for Alzheimer's disease intervention.It should be noted that this study has not directly verified the necessity of ATG14 in vivo，and the causal relationship between the in vivo therapeutic efficacy of YA3D3 and the up-regulation of ATG14 requires further confirmation.In addition，this study only verifies the expression regulation of autophagy-related molecules and does not confirm the enhancement of autophagy flux.},
}

Animals
*Drugs, Chinese Herbal/pharmacology
*Alzheimer Disease/drug therapy/pathology
Mice, Transgenic
Mice
Male
*Cognitive Dysfunction/drug therapy
Amyloid beta-Peptides/metabolism
Disease Models, Animal
Amyloid beta-Protein Precursor

@article {pmid42661000,
year = {2026},
author = {Echeveste, B and Guillén, EF and Prieto, E and Hirschmüller, KCE and Riverol, M and Arbizu, J},
title = {Prognostic value of Amyloid PET in Real-World Amnestic MCI: Influence of reader experience and interpretation method.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42661000},
issn = {1619-7089},
abstract = {PURPOSE: This study assessed the prognostic value and inter-/intra-observer reliability of three amyloid PET interpretation methods-conventional visual reading, assisted visual interpretation and standardized uptake value ratio (SUVR)-based quantification-for predicting conversion to Alzheimer's disease (AD).

METHODS: This retrospective longitudinal study included 145 patients with amnestic mild cognitive impairment who underwent amyloid PET and were followed for up to 8 years at a single memory clinic. Two certified nuclear medicine physicians performed structured visual reads and assisted visual interpretations. Semiquantitative SUVR thresholds validated in prior studies were applied as a third method. Inter- and intra-observer agreement was assessed using Cohen's kappa (κ). Cox regression models estimated the association of conversion to AD in PET-positive versus PET-negative patients for each method, adjusting for age, sex and education.

RESULTS: Inter-observer agreement was excellent for structured visual reading (κ = 0.877) and assisted visual interpretation (κ = 0.904). Intra-observer reliability was also high (κ = 0.891 for Reader 1; κ = 0.859 for Reader 2). Consensus agreement for the assisted method reached κ = 0.936. Amyloid PET positivity was strongly associated with progression to AD across all methods. Hazard ratios were highest for assisted visual interpretation (HR = 3.23, 95% CI 1.94-5.38, p < 0.0001), followed by SUVR quantification (HR = 2.19, 95% CI 1.55-3.10, p < 0.0001) and structured visual reading (HR = 1.83, 95% CI 1.10-3.06, p = 0.02).

CONCLUSION: Amyloid PET positivity consistently predicted conversion to AD regardless of interpretation method. Assisted visual and semiquantitative approaches showed numerically higher prognostic discrimination, while expert structured visual reading remained clinically reliable.},
}

@article {pmid42661061,
year = {2026},
author = {Lantero-Rodriguez, J and Janelidze, S and Palmqvist, S and Braun-Wohlfahrt, LS and Vavra, J and Bali, D and Orduña Dolado, A and Mattsson-Carlgren, N and Stomrud, E and Zetterberg, H and Blennow, K and Hansson, O and Montoliu-Gaya, L and Salvadó, G},
title = {CSF p-tau205: a biomarker of Alzheimer's disease progression and biological staging.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42661061},
issn = {1476-5578},
abstract = {Among soluble tau biomarkers, tau phosphorylation at position T205 (p-tau205) has been suggested to distinctly emergence across Alzheimer's disease (AD) continuum compared to other p-tau and non-phosphorylated tau forms, and a moderate relationship with both amyloid-β and tau aggregated pathologies. To evaluate this and further expand the characterization of this biomarker, we measured cerebrospinal fluid (CSF) p-tau205 using an in-house developed immunoassay in a total of 2069 samples from the BioFINDER-2 (n = 1364) and BioFINDER-1 (n = 705) cohorts. These two cohorts spanned the full AD continuum and were analyzed to assess cross-sectional and longitudinal associations with imaging and clinical measures. CSF p-tau205 levels were elevated in both biologically and clinically advanced disease stages. In Aβ-positive individuals, baseline p-tau205 levels correlated with Aβ-PET (R[2] = 0.28), tau-PET (medial temporal: R[2] = 0.35, neocortical: R[2] = 0.29), cortical atrophy (R[2] = 0.15) and cognition (MMSE, R[2] = 0.15). Baseline p-tau205 predicted subsequent Aβ accumulation (R[2] = 0.44) and tau-accumulation measured by PET (R[2] = 0.33). Longitudinal p-tau205 levels increased more steeply longitudinally in Aβ-positive than Aβ-negative participants (β[95%CI] = 0.16[0.12-0.21], p < 0.001). Longitudinal p-tau205 changes were associated with cortical thinning (R[2] = 0.32) and cognitive decline (R[2] ≥ 0.41). When incorporating Aβ42/40, p-tau217 and p-tau205 into a conceptual CSF-based staging model, the final p-tau205-positive stage showed the strongest association with cortical atrophy, cognitive impairment, and risk of progression to dementia (HR = 6.40[4.28-9.59]). These findings support CSF p-tau205 as a biomarker of Alzheimer's disease pathology and progression with potential value for biological staging.},
}

@article {pmid42661068,
year = {2026},
author = {Kurniansyah, N and Tasaki, S and Rehman, H and Zhu, C and Farrell, J and Sherva, R and Hauger, R and Merritt, VC and Panizzon, M and Zhang, R and Gaziano, JM and Gim, J and Lee, K and Lee, DY and Nho, K and Vialle, RA and Mukherjee, S and Trittschuh, EH and Lee, AJ and Brickman, AM and Cruchaga, C and Risacher, S and Greve, DN and Crane, P and Martin, E and Bush, WS and Mayeux, R and Haines, JL and Pericak-Vance, MA and Logue, M and Bennett, DA and Barnes, LL and Saykin, A and Hohman, T and Wang, LS and Schellenberg, GD and Ang, TFA and Au, R and Mez, J and Lunetta, KL and Zhang, X and Farrer, LA},
title = {A multiancestry polygenic risk score for Alzheimer's disease is associated with cognitive decline and neuropathological hallmarks in diverse populations.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42661068},
issn = {1546-1718},
support = {R01-AG048927//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01-AG058654//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01-AG062602//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19-AG068753//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01-AG072577//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01-AG080810//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01-AG082665//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; T32-GM150533//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; },
abstract = {Previously derived polygenic risk scores (PRSs) for Alzheimer's disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated with AD in European ancestry, African American, Caribbean Hispanic and Native American Hispanic groups with adjusted odds ratios between 1.14 and 1.52 per PRS standard deviation. PRS performance was validated in the replication cohorts (odds ratios: 1.21-1.65). The PRS was also associated with poorer memory, executive function and language performance, greater AD-related neuropathological burden, reduced hippocampal volume, lower cerebrospinal fluid amyloid-β42 and elevated total tau and phosphorylated tau, with stronger phosphorylated tau associations observed in women. Our findings support the value of ancestry-aware PRSs as a component of broader multimodal risk stratification frameworks.},
}

@article {pmid42661114,
year = {2026},
author = {Sharma, K and Vikram, V and Jamwal, P and Bhaumik, S and Prasad, N and Rohit, and Juneja, R},
title = {Quercetin as a Hypothesized Involvement of VMAT2 in Neurodegenerative Diseases-Mechanistic Insight and Therapeutic Applications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42661114},
issn = {1559-1182},
mesh = {*Vesicular Monoamine Transport Proteins/metabolism ; Humans ; Animals ; *Quercetin/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; Antioxidants/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease and Huntington's disease are characterized by progressive neuronal loss driven by complex mechanisms such as oxidative stress, neuroinflammation, protein aggregation, neurotransmitter imbalance, and synaptic dysfunction. Among these, Alzheimer's disease remains the most prevalent and challenging disorder, lacking effective disease-modifying therapies. Quercetin, a naturally occurring flavonoid abundant in fruits and vegetables, has attracted considerable attention due to its potent antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective properties, along with its ability to cross the blood-brain barrier. This review critically examines the potential role of quercetin in modulating key pathological pathways in neurological disease, with a special focus on its interaction with the vesicular monoamine transporter 2 (VMAT2). Vesicular monoamine transporter 2 plays a crucial role in maintaining monoamine neurotransmitter homeostasis and protecting neurons from oxidative damage caused by cytosolic monoamine degradation. Increasing data indicates that VMAT2-mediated dysfunction represents one of multiple processes that lead to neurotoxicity by altering monoamine synthesis, increasing oxidative damage, and leading to synaptic damage, especially in neuronal pathways. Quercetin, as a potential monoamine oxidase inhibitor and reactive oxygen species scavenger, may indirectly preserve vesicular monoamine transporter 2 function and mitigate downstream neurotoxic events. Overall, the multitargeted actions of quercetin, combined with its potential influence on vesicular monoamine transporter 2-mediated pathways, highlight its promise as a complementary therapeutic candidate for further neurodegenerative disorders. An increasing number of studies demonstrates that quercetin may indirectly regulate VMAT2 function by eliminating reactive oxygen compounds, decreasing neuroinflammation, inhibiting monoamine oxidase activity, improving mitochondrial activity, and maintaining monoaminergic neuronal function, although there remains limited direct evidence connecting quercetin to VMAT2 regulation. The substance quercetin can reduce oxidative neuronal damage and decrease subsequent neurodegenerative events through several connected methods. Although direct experimental verification of the quercetin-VMAT2 connection is still lacking, the data that is now accessible suggests that VMAT2 may be a suitable target for further research. Therefore, the suggested quercetin-VMAT2 connection should be seen as a hypothetical and mechanistic approach.},
}

*Vesicular Monoamine Transport Proteins/metabolism
Humans
Animals
*Quercetin/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism
Oxidative Stress/drug effects
Neuroprotective Agents/therapeutic use/pharmacology
Antioxidants/therapeutic use/pharmacology

@article {pmid42661118,
year = {2026},
author = {Vora, C and Saini, V and Shevtsov, M and Trivedi, P and Sonawane, A and Jha, HC},
title = {From viral epigenetic reprogramming to neuroinflammation: Mechanisms driving neurodegeneration.},
journal = {Journal of neurovirology},
volume = {32},
number = {5},
pages = {},
pmid = {42661118},
issn = {1538-2443},
support = {R44AR079960//Technische Universität München/ ; PRIN2022//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; IG2025//Associazione Italiana per la Ricerca sul Cancro/ ; 37(1693)/17/EMR-II//Council of Scientific and Industrial Research, India/ ; ANRF/PAIR/2025/000018/PAIR-A(G)).//ANRF (IN)/ ; },
mesh = {Humans ; *Epigenesis, Genetic ; DNA Methylation ; Animals ; Host-Pathogen Interactions/genetics ; Herpesvirus 4, Human/genetics/pathogenicity/metabolism ; Histones/metabolism/genetics ; *Neuroinflammatory Diseases/virology/genetics/pathology ; Neurons/virology/pathology/metabolism ; Simplexvirus/genetics/pathogenicity ; *Alzheimer Disease/virology/genetics/pathology ; Parkinson Disease/virology/genetics/pathology ; Neurodegenerative Diseases/virology/genetics ; HIV-1/genetics/pathogenicity ; Virus Diseases/genetics ; },
abstract = {Viruses exploit host genetic machinery to establish chronic infections and contribute to chronic neurodegenerative and immune disorders. By manipulating DNA methylation, histone modifications, and non-coding RNA networks, viruses such as Epstein-Barr virus (EBV), Herpes Simplex virus (HSV), Zika virus (ZIKV), and Human immunodeficiency virus (HIV) induce epigenetic changes that silence or delay the host antiviral defenses and reprogram host gene expression. For instance, EBV recruits DNA methyltransferases (DNMTs) to hypermethylate genes such as SOCS1 while ZIKV disrupts neuronal DNA methylation via heterochromatinization. Concurrently, HIV-1 encoded Tat protein disrupts H3K27 acetylation in astrocytes that potently triggers glutamate excitotoxicity. Viruses also subvert the chromatin architecture to modulate 3D interactions and reader protein recruitment, thus rewiring transcriptional programs. Such epigenetic alterations correlate with neuropathologies wherein global hypomethylation and histone acetylation contribute to Alzheimer's or Parkinson's disease. Although several mechanisms are known, the field of viral control in neuroepigenetics is underexplored. Emerging therapies that target viral-host epigenetic crosstalk through DNMT or HDAC inhibitors are promising. This review highlights how neurotropic viruses co-opt epigenetic pathways to drive neurodegeneration. We also explore biomarker-driven strategies for personalized interventions in neurodegenerative disorders thus emphasizing potential epigenetic editing tools to restore neuronal homeostasis.},
}

Humans
*Epigenesis, Genetic
DNA Methylation
Animals
Host-Pathogen Interactions/genetics
Herpesvirus 4, Human/genetics/pathogenicity/metabolism
Histones/metabolism/genetics
*Neuroinflammatory Diseases/virology/genetics/pathology
Neurons/virology/pathology/metabolism
Simplexvirus/genetics/pathogenicity
*Alzheimer Disease/virology/genetics/pathology
Parkinson Disease/virology/genetics/pathology
Neurodegenerative Diseases/virology/genetics
HIV-1/genetics/pathogenicity
Virus Diseases/genetics

@article {pmid42661181,
year = {2026},
author = {Sayed, MA and Said, A and Meselhy, M},
title = {Nutritional modulation of neuroinflammation in Alzheimer's disease and mild cognitive impairment: a systematic review of clinical and preclinical evidence.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {42661181},
issn = {1471-2318},
mesh = {Humans ; *Alzheimer Disease/diet therapy/metabolism ; *Cognitive Dysfunction/diet therapy/metabolism ; *Neuroinflammatory Diseases/diet therapy ; Animals ; Fatty Acids, Omega-3/administration & dosage ; Dietary Supplements ; Diet, Ketogenic/methods ; Vitamin D/administration & dosage ; Randomized Controlled Trials as Topic/methods ; },
abstract = {BACKGROUND: Neuroinflammationis a key contributor to the pathogenesis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Nutritional interventions have been proposed as potential modulators of neuroinflammatory pathways; however, the consistency and strength of the available evidence remain uncertain. This systematic review evaluated the clinical and preclinical evidence regarding the effects of nutritional interventions on neuroinflammatory mechanisms relevant to AD and MCI.

METHODS: PubMed/MEDLINE, Embase, Scopus, and Web of Science were systematically searched for studies investigating nutritional interventions and neuroinflammatory outcomes. Eligible studies included randomized controlled trials and preclinical experimental investigations evaluating omega-3 fatty acids, ketogenic dietary interventions, B-vitamin supplementation, vitamin D, and microbiota-targeted strategies. Primary outcomes included inflammatory cytokines, neuroinflammatory signaling pathways, oxidative stress biomarkers, and glial activation. Methodological quality and risk of bias were assessed using study design-specific appraisal tools.

RESULTS: Twenty-two studies met the eligibility criteria, including ten clinical studies and twelve preclinical investigations. Overall, nutritional interventions were associated with modulation of neuroinflammatory biomarkers, including TNF-α, IL-1β, and IL-6, together with alterations in NF-κB and NLRP3 signaling, microglial activation, and oxidative stress pathways. The most consistent evidence supported omega-3 fatty acids and ketogenic dietary interventions, although evidence for ketogenic strategies was derived predominantly from preclinical studies. Evidence for B-vitamin supplementation, vitamin D, and microbiota-targeted interventions was limited because relatively few eligible studies were available. Considerable heterogeneity was observed across intervention protocols, outcome measures, and study populations.

CONCLUSIONS: Nutritional interventions may modulate biological pathways involved in neuroinflammation; however, the strength and certainty of the evidence vary across intervention categories. Larger, well-designed randomized controlled trials incorporating standardized neuroinflammatory biomarkers are required to clarify the therapeutic potential of nutritional strategies for AD and MCI.},
}

Humans
*Alzheimer Disease/diet therapy/metabolism
*Cognitive Dysfunction/diet therapy/metabolism
*Neuroinflammatory Diseases/diet therapy
Animals
Fatty Acids, Omega-3/administration & dosage
Dietary Supplements
Diet, Ketogenic/methods
Vitamin D/administration & dosage
Randomized Controlled Trials as Topic/methods

@article {pmid42661225,
year = {2026},
author = {Xu, B and Guo, Z and Chen, J and Xie, Y and Wang, P and Xiong, X and Yu, J and Xu, Z and Fu, Y and Lan, Z and Peng, G and Zhang, J},
title = {HSPA8 orchestrates SNARE complex assembly to drive extracellular vesicle-mediated spread of p-tau217 in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42661225},
issn = {2047-9158},
support = {LY24H090006//Natural Science Foundation of Zhejiang Province/ ; 2025C01120//Key Research and Development Program of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 82571348//National Natural Science Foundation of China/ ; 32530027//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Animals ; Humans ; *tau Proteins/metabolism ; *Extracellular Vesicles/metabolism ; *HSC70 Heat-Shock Proteins/metabolism ; *SNARE Proteins/metabolism ; Mice ; Hippocampus/metabolism ; Male ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Dysregulation of multivesicular bodies (MVBs) in Alzheimer's disease (AD) contributes to aberrant tau secretion via extracellular vesicles (EVs). This may potentially explain our previous paradoxical observation of elevated free-form p-tau217 alongside reduced p-tau217[+] EVs in plasma. This study aimed to investigate the mechanisms underlying the reduction of p-tau217[+] EVs to uncover AD therapeutic targets.

METHODS: By integrating hippocampal spatial transcriptomics of human brain with EV proteomics of cerebrospinal fluid, we identified key regulators of p-tau217[+] EV release. Subsequently, we investigated the mechanisms underlying the synthesis and secretion of p-tau217[+] EVs. The regulatory roles of these candidate proteins were systematically evaluated through shRNA knockdown and interference with a synthetic peptide in both Aβ42-treated cells and AD model mice.

RESULTS: Heat shock protein family A member 8 (HSPA8) was identified as a crucial regulator of EV biogenesis and release, mediating the Aβ-SNAP29 interaction to disrupt SNARE complex assembly and impair p-tau217[+] EV secretion. In AD models, HSPA8 inhibition with shRNA rescued p-tau217[+] EVs and improved cognitive function. Additionally, blocking the Aβ-SNAP29 interaction with a selective peptide inhibitor for HSPA8 reversed the decline in p-tau217[+] EV and cognitive deficits.

CONCLUSIONS: These findings reveal a role of HSPA8 in regulating the MVB-mediated EV release and tau propagation, and highlight HSPA8 as a promising therapeutic target for modifying AD progression.},
}

*Alzheimer Disease/metabolism/pathology
Animals
Humans
*tau Proteins/metabolism
*Extracellular Vesicles/metabolism
*HSC70 Heat-Shock Proteins/metabolism
*SNARE Proteins/metabolism
Mice
Hippocampus/metabolism
Male
Amyloid beta-Peptides/metabolism

@article {pmid42661318,
year = {2026},
author = {Kiyota, M and Jin, Y and Nemoto, N and Kakikawa, M},
title = {Low-frequency magnetic fields can improve behavioral abnormalities and suppress Aβ accumulation detected by thioflavin T in Caenorhabditis elegans models of Alzheimer's disease.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/15368378.2026.2722639},
pmid = {42661318},
issn = {1536-8386},
abstract = {Amyloid β (Aβ) accumulation and Aβ-related senile plaques, the pathological hallmarks of Alzheimer's disease (AD), damage neurons and impair cognitive functions in patients. Previous studies have shown that low‑field magnetic stimulation attenuates Aβ and enhances cognitive performance. In this study, AD models of Caenorhabditis elegans expressing Aβ in the nerves were placed in a low-frequency magnetic field (LFMF) and then subjected to a chemotaxis assay to evaluate attractive behavior. In control C. elegans (CL2122), which do not express Aβ but carried only the vector, the chemotactic behavior was normal and unaffected by LFMF. In contrast, in the AD model expressing Aβ within the nervous system, abnormalities in chemotactic behavior were observed; however, these were improved in a manner dependent on LFMF strength. In addition, the AD model expressing Aβ in the muscle exhibited paralysis, which was significantly attenuated by LFMF. Thioflavin T staining revealed that, in the AD model expressing in muscles, Aβ accumulation declined in the LFMF-treated group compared to that of the non-LFMF group. These results suggest that LFMF can improve abnormal chemotactic behavior and attenuate Aβ-induced paralysis by suppressing the accumulation and aggregation of Aβ in a C. elegans model of AD.},
}

@article {pmid42661397,
year = {2026},
author = {Noorani, AA and Islam, S and Filip, E and Catalfano, K and Paswan, S and Nagarajan, V and Wilkins, HM and Blagg, BSJ and Zou, K and Wolfe, MS},
title = {AHA1 Regulates Aβ Production via Modulation of APP Abundance and γ-Secretase Assembly.},
journal = {Journal of neurochemistry},
volume = {170},
number = {9},
pages = {e70544},
doi = {10.1111/jnc.70544},
pmid = {42661397},
issn = {1471-4159},
support = {AG066986//National Institute on Aging (NIA), National Institutes of Health/ ; },
mesh = {Humans ; *Amyloid Precursor Protein Secretases/metabolism ; Animals ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Cricetulus ; *Amyloid beta-Peptides/biosynthesis/metabolism ; CHO Cells ; HEK293 Cells ; Mice ; HSP90 Heat-Shock Proteins/metabolism ; *Molecular Chaperones/metabolism/genetics ; Mice, Knockout ; Presenilin-1/genetics ; },
abstract = {Deposition of amyloid β-protein (Aβ) is a hallmark of Alzheimer's disease (AD), produced by γ-secretase-mediated cleavage of amyloid precursor protein (APP). The 90-kDa heat shock protein (Hsp90) co-chaperone, activator of Hsp90 ATPase homolog 1 (AHA1), is known to promote the accumulation of toxic tau species; however, its effects on Aβ production remain unclear. Using cellular models-including human embryonic kidney 293 T (HEK293T) cells, stable HEK-APP cells, presenilin 1/2 double-knockout mouse embryonic fibroblasts (PS-DKO MEFs), and Chinese hamster ovary (CHO) cells-in which AHA1 was experimentally manipulated, together with observational analyses of human iPSC-derived neurons carrying an FAD-linked APP mutation, we demonstrate that AHA1 regulates Aβ generation through two mechanisms: regulation of APP protein abundance through pathways that are at least partially independent of Hsp90 interaction and Hsp90-dependent promotion of γ-secretase assembly. Knockdown of endogenous AHA1 reduces Aβ production and decreases APP and γ-secretase component levels, whereas AHA1 overexpression elevates Aβ generation and increases the expression of these proteins. The AHA1-E67K mutant, which has impaired Hsp90 binding, lowers Aβ production and the levels of APP and γ-secretase components compared with wild-type AHA1. AHA1 associates with APP and APH1, an immature γ-secretase component, indicating its role in APP proteolysis and Aβ production. Disruption of the AHA1/Hsp90 complex-through AHA1 knockdown, the E67K mutant, or a small-molecule inhibitor-reduces γ-secretase assembly. Notably, Familial AD mutations (APP-C99-I45F, PS1-L286V) upregulate AHA1/Hsp90, elevating APP/APH1 and Aβ42 production. AHA1 knockdown rescues FAD-linked Aβ42 overproduction in a mutant cell model, while AHA1 overexpression exacerbates PS1 mutant Aβ production. Collectively, these findings reveal that AHA1 regulates Aβ production by modulating APP abundance and γ-secretase assembly, establishing AHA1 as a potential target for therapeutic intervention in AD.},
}

Humans
*Amyloid Precursor Protein Secretases/metabolism
Animals
*Amyloid beta-Protein Precursor/metabolism/genetics
Cricetulus
*Amyloid beta-Peptides/biosynthesis/metabolism
CHO Cells
HEK293 Cells
Mice
HSP90 Heat-Shock Proteins/metabolism
*Molecular Chaperones/metabolism/genetics
Mice, Knockout
Presenilin-1/genetics

@article {pmid42661656,
year = {2026},
author = {Praharaj, S and Chakraborty, E and Mahalingam, G},
title = {Ultraviolet radiation and neurodegeneration: molecular mechanisms underlying dual neuroprotective and neurotoxic effects.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1909393},
pmid = {42661656},
issn = {1662-5102},
abstract = {Ultraviolet radiation exhibits a complex, often contradictory link to neurodegeneration risk/progression, spanning clinically diagnosed diseases [Parkinson's Disease (PD), Alzheimer's Disease (AD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS)] or intermediate phenotypes (decreased neurogenesis, loss of hippocampal volume). The aim of this review is to highlight the dual impact of UV radiation by collecting and synthesizing experimental (preclinical and translational) evidence as well as epidemiological evidence. Current literature exhibits a clear dichotomy: while Vitamin D is capable of exerting a potent neuroprotective effect via anti-oxidant and anti-inflammatory pathways, chronic and intense UV radiation exposure actually hastens the progression or even drives neurodegeneration via a variety of mechanisms. UV radiation exerts its effects through various interconnected pathways: DNA damage pathways, ROS mediated pathways, vitamin D signaling and the skin-brain axis, which unifies both protective and degenerative effects of UV radiation. Owing to the increasing occurrence of neurodegenerative diseases in the general population, these pathways and mechanisms must be leveraged in future research to develop novel therapeutic and preventive strategies. Investigation of biomarkers linked to certain genetic and environmental factors that could provide a link to predisposition toward neurodegeneration and standardization of UV radiation dosimetry (exposure dose/duration) across experimental or pre-clinical studies must also be prioritized.},
}

@article {pmid42661679,
year = {2026},
author = {Liu, L and Zhao, Y},
title = {Redox-exercise crosstalk in neurodegenerative diseases: mechanistic perspectives on antioxidant interactions with Nrf2-BDNF signaling, autophagy, and mitochondrial plasticity.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1850414},
pmid = {42661679},
issn = {2296-861X},
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease and Parkinson's disease, are characterized by progressive neuronal loss driven by oxidative stress, mitochondrial dysfunction, and impaired cellular homeostasis. Emerging research highlights a complex interplay between physical exercise and antioxidant mechanisms in the regulation of redox balance and neuroprotection. This review evaluates the integrative effects of exercise and antioxidant interventions on molecular pathways involved in NDDs, emphasizing mechanistic and translational findings from both preclinical and clinical studies. This narrative review was informed by a structured literature search conducted in PubMed, Scopus, and Web of Science, focusing on studies investigating exercise, antioxidants, and NDDs. Current studies indicate that vitamins, trace elements (particularly selenium and zinc), endogenous antioxidant systems, and flavonoids may interact with exercise through partially overlapping mechanisms that may influence neurodegenerative processes. These interventions influence several interconnected molecular pathways, including redox-sensitive Nrf2 signaling, BDNF-mediated neuroplasticity, autophagy, mitochondrial plasticity, and gut-brain axis communication. Exercise-induced activation of redox-sensitive pathways enhances endogenous antioxidant defenses. Under appropriate conditions, antioxidant supplementation may complement these adaptations by limiting excessive oxidative stress and supporting cellular metabolism. Available data suggest that combined exercise-antioxidant interventions may provide additional neuroprotective benefits in some experimental settings; however, these effects are highly context-dependent and are not consistently superior to exercise alone. Furthermore, exercise-antioxidant interactions may influence epigenetic regulation and neurotrophic signaling, thereby contributing to neuroprotection. However, the literature remains limited by substantial heterogeneity in intervention protocols, antioxidant type, dosage and timing, exercise characteristics, disease stage, and the scarcity of large-scale clinical trials. Future research should prioritize clinical validation and clarify how antioxidant type, dosage, timing, and exercise parameters influence adaptive redox signaling, hormetic responses, and neuroprotective outcomes.},
}

@article {pmid42661704,
year = {2026},
author = {Fukuchi, KI and Yang, J and Williams, J},
title = {Editorial: Exploring miRNA roles in neuroinflammation and brain aging: mechanisms and therapeutic potential.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1959643},
pmid = {42661704},
issn = {1664-3224},
}

@article {pmid42661728,
year = {2026},
author = {Hakim, R and Harris, K and Merrill, L and Falk-Vargas, A and Whalen, E and Xia, T and Ochoa, O and Hunter, D and Schulz, PE},
title = {Real-world evidence for amyloid-targeted therapies: Lecanemab and donanemab.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70404},
pmid = {42661728},
issn = {2352-8729},
abstract = {INTRODUCTION: Real-world safety data on amyloid-targeted therapies in early Alzheimer's disease remain limited, particularly for modified donanemab titration and direct lecanemab-donanemab comparisons.

METHODS: Retrospective review of 172 amyloid-positive patients treated with lecanemab (n = 89) or donanemab (original titration n = 21; modified n = 62). The cohort included patients with ≥2 chronic comorbidities (72.7%), systemic autoimmune or hematologic disorders, and concurrent immunomodulators.

RESULTS: Amyloid-related imaging abnormalities (ARIA) occurred in 11.2% (10/89) with lecanemab and 13.3% (11/83) with donanemab-less than in pivotal trials. Modified donanemab titration reduced ARIA versus the original protocol (8.1% vs 28.6%; p = 0.03) and TRAILBLAZER-ALZ 6 (23.6%). No anaphylaxis occurred. Surveillance magnetic resonance imaging captured 95.2% of ARIA events. Within-center comparison showed comparable safety between lecanemab and modified-titration donanemab (all p's > 0.40). IRRs occurred in 12.0% (donanemab) and 9.0% (lecanemab).

DISCUSSION: In a real-world cohort representing patients excluded from trials, ARIA and IRR rates matched or improved upon pivotal trials, supporting safe ATT use under FDA-approved MRI intervals.},
}

@article {pmid42661899,
year = {2026},
author = {Ma, L and Wang, J and Xu, Z and Huang, Z and Chen, K and Teng, X and Chen, M and Lin, S and Zhou, R},
title = {The molecular mechanisms of Guizhi Fuling Pills in ameliorating Alzheimer's disease-like cognitive impairment: insights from transcriptomics, metabolomics, and gut microbiome.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1839445},
pmid = {42661899},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD)-like cognitive impairment, as a major type of cognitive disorder, has witnessed a sharp rise in prevalence. Therefore, there is an urgent need to develop effective therapeutic intervention measures. Guizhi Fuling Pills (GFP), a classical Traditional Chinese Medicine (TCM) formula, has been shown to exert protective effects on cognitive function. However, its underlying mechanisms remain unclear.

OBJECTIVE: To investigate the effects of GFP on AD-like cognitive impairment and elucidate its underlying mechanisms.

METHODS: D-galactose (D-gal)-induced aged mice were used as the model. Mice were administered via gavage for 4 weeks with 0.9% normal saline (0.1 mL/10 g/d), low-dose GFP (12.56 g/kg/d), medium-dose GFP (25.11 g/kg/d), high-dose GFP (50.22 g/kg/d), and donepezil (5 mg/kg/d). A behavioral test was conducted using the Morris water maze. Histopathological changes were observed via H&E staining and immunohistochemistry (IHC). In addition, various methods such as transcriptomics, metabolomics, network pharmacology, and analysis of gut microbiota were utilized to elucidate the possible mechanisms.

RESULTS: Guizhi Fuling Pills improved learning and memory function in aged mice, ameliorated hippocampal neuronal morphology, and reduced p-Tau protein deposition. Network pharmacology and hippocampal transcriptomic analyses suggested that the active components in GFP may ameliorate cognitive impairment through multiple mechanisms. It included regulation of the VEGF and PI3K/AKT signaling pathways, attenuation of inflammatory responses, inhibition of apoptosis, and repair of the blood-brain barrier (BBB). Gut microbiota analysis revealed that GFP modulated the compositional structure of the gut microbiota, including increasing the abundance of Lactobacillales and decreasing Desulfovibrionia and Tannerellaceae. Metabolomics suggested that GFP may ameliorate metabolic disorders in aged mice by modulating the synthesis of lipids and lipid-like molecules.

CONCLUSION: The findings of this study suggest that GFP may ameliorate cognitive dysfunction in AD-like cognitive impairment mice through multiple mechanisms, including repair of the BBB, attenuation of inflammatory responses, and modulation of the gut microbiota and metabolic disorders.},
}

@article {pmid42661952,
year = {2026},
author = {Bhatti, MHR and Aly, A and Khan, A and Awan, S},
title = {A Scoping Review of Machine Learning-Based Prediction of Alzheimer's Disease Using Blood Biomarkers.},
journal = {Biomedical engineering and computational biology},
volume = {17},
number = {},
pages = {11795972261481838},
pmid = {42661952},
issn = {1179-5972},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder of late life that causes cognitive and functional decline and substantial mortality. Machine learning (ML) is increasingly used to discover patterns in clinical and biomarker data that support earlier and more accurate AD detection.

OBJECTIVES: This scoping review addresses three core research questions. First, we investigate recent trends in using machine-learning techniques to detect Alzheimer's disease using blood biomarkers. Second, we identify the blood biomarkers involved in Alzheimer's detection and evaluate how machine learning has been applied to improve the diagnostic capabilities of these biomarkers. Third, we highlight significant challenges associated with using machine learning for blood biomarker data in Alzheimer's detection and examine proposed advancements or solutions to handle these problems.

METHODS: In June 2025, we searched six academic databases to identify relevant papers on blood biomarkers and ML methods for Alzheimer's Disease. Search queries were developed based on our predefined research questions. Papers were then screened using defined inclusion and exclusion criteria, where titles, abstracts, and full texts of articles were systematically reviewed.

RESULTS: Following the screening approach, we selected 36 papers that fulfilled our inclusion and exclusion criteria. Through careful examination, we classified blood biomarkers into four types: transcriptomics, proteomics, multi-omic biomarkers, and general elemental blood biomarkers. Across these studies, proteomic blood biomarkers consistently emerged as significant indicators for Alzheimer's disease, including Alpha-2-Macroglobulin (A2M), Apolipoprotein E (ApoE), Eotaxin-3 (EOT3), plasma phosphorylated tau (p-tau 181), and neurofilament light chain (NfL). Furthermore, we explored challenges such as small sample sizes, lack of standardization, heterogeneity, and data imbalance.

CONCLUSIONS: This review provides insights into how combining blood biomarkers with ML can enhance AD prediction. The review summarizes key challenges and identifies critical gaps for future research.},
}

@article {pmid42662146,
year = {2026},
author = {Kumar, N and Khan, I and Singh, J and Kumar, K and Kushwaha, VK and Kumar, S and Ojha, S and Dash, AK and Shankar, G},
title = {Benzothiazole-driven molecular probes and therapeutics for neurodegenerative diseases: focus on amyloid-beta (Aβ), tau, and α-synuclein.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42662146},
issn = {2632-8682},
abstract = {Neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), represent a rapidly growing global health challenge characterized by progressive neuronal loss, irreversible cognitive decline, and the absence of effective disease-modifying therapies. A major obstacle in the clinical management of these disorders is the inability to accurately diagnose pathological changes at early stages, when therapeutic intervention is most likely to be effective. The pathological aggregation of amyloid-β (Aβ), hyperphosphorylated tau, and α-synuclein (α-syn) constitutes a central molecular hallmark of neurodegeneration and has therefore emerged as a critical target for both diagnostic imaging and therapeutic intervention. Among the numerous heterocyclic scaffolds investigated for central nervous system drug discovery, benzothiazole (BZT) has attracted exceptional attention owing to its favorable blood-brain barrier permeability, synthetic versatility, and intrinsic affinity toward β-sheet-rich protein aggregates. The clinical success of Pittsburgh compound-B (PiB) established BZT as a privileged molecular recognition motif for in vivo visualization of amyloid pathology and stimulated extensive medicinal chemistry efforts toward the development of next-generation imaging probes. More recently, advances in structure-guided design and multitarget-directed ligand (MTDL) strategies have transformed BZT from a purely diagnostic scaffold into a versatile theranostic platform capable of simultaneously recognizing and modulating neurodegenerative proteinopathies. Between 2020 and 2026, a wide range of structurally diverse BZT-based derivatives and hybrid molecules have been reported with improved affinity, selectivity, and sensitivity toward Aβ plaques, tau fibrils, and α-synuclein aggregates, while also exhibiting therapeutic activities such as inhibition of protein aggregation, fibril destabilization, cholinesterase inhibition, monoamine oxidase modulation, antioxidant activity, metal chelation, mitochondrial protection, and neuroinflammation suppression. This review provides a comprehensive overview of recent advances (2020-2026) in the design, synthesis, structure-activity relationships, molecular mechanisms, diagnostic applications, and therapeutic potential of BZT-based agents for neurodegenerative disorders. Particular emphasis is placed on the molecular basis of BZT recognition of amyloidogenic proteins, the evolution of diagnostic probes into multifunctional therapeutic hybrids, and emerging theranostic strategies targeting interconnected pathological pathways associated with AD, PD, and related proteinopathies. Furthermore, key trends in medicinal chemistry, translational challenges, and future opportunities for the development of next-generation BZT-derived diagnostics and therapeutics are critically discussed. Collectively, the evidence highlights BZT as one of the most promising privileged scaffolds for integrating early diagnosis, disease monitoring, and disease-modifying intervention within a unified molecular framework for neurodegenerative disorders.},
}

@article {pmid42662336,
year = {2026},
author = {Reinapu, A and Kirss, S and Tõugu, V and Palumaa, P},
title = {Distinct Effects of Copper Ionophores on Intracellular Copper and Cell Viability in Wild-Type and CTR1-Deficient SH-SY5Y Cells.},
journal = {ACS omega},
volume = {11},
number = {33},
pages = {49807-49814},
pmid = {42662336},
issn = {2470-1343},
abstract = {Copper homeostasis is essential for neuronal function, and its dysregulation has been implicated in neurodegenerative disorders. In particular, reduced intracellular copper levels alongside with elevated extracellular copper concentrations have been associated with Alzheimer's disease (AD). Therefore, strategies aimed at restoring intracellular copper levels represent a potential therapeutic approach. In this study, we investigated the effects of selected copper-binding compounds(?)α-lipoic acid (LA), elesclomol (ES), disulfiram (DSF), thiourea (TU), and triapine (3-AP)(?)on copper uptake and cytotoxicity in SH-SY5Y wild-type (WT) and CTR1-deficient (CTR1[-/-]) cells. Intracellular copper levels were quantified using inductively coupled plasma mass spectrometry (ICP-MS), and cell viability was assessed by using propidium iodide assay under various treatment conditions. Among the tested compounds, LA, ES, and DSF significantly increased intracellular copper levels in both WT and CTR1[-/-] cells, whereas TU and 3-AP did not enhance copper accumulation beyond copper-only treatment. Notably, CTR1[-/-] cells exhibited reduced sensitivity to copper-associated toxicity compared to WT cells. Under copper-supplemented conditions, DSF and ES displayed concentration-dependent cytotoxicity, while LA and TU induced only mild effects. In contrast, 3-AP toxicity was abolished in the presence of copper. Furthermore, cotreatment with LA and copper increased cell proliferation and promoted differentiation-associated morphological changes in CTR1[-/-] cells. Overall, our results demonstrate that copper ionophores can enhance intracellular copper levels dependently and independently of CTR1, with distinct effects on cell viability. Among the tested compounds, LA and DSF showed a favorable profile by increasing copper levels while maintaining low cytotoxicity, highlighting their potential for modulating cellular copper homeostasis.},
}

@article {pmid42662502,
year = {2026},
author = {Chou, CJ and Chuang, YF and Chiu, YL and Wu, SC and Fan, YM and Liu, YC},
title = {Clinical impact of amyloid PET in memory clinic: A 2-year longitudinal real-world study in Taiwan.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70454},
pmid = {42662502},
issn = {2352-8729},
abstract = {INTRODUCTION: Longitudinal evidence on amyloid positron emission tomography (PET) for Alzheimer's disease (AD) diagnosis in Taiwan and Asian memory clinics remains limited. This study evaluated the diagnostic and prognostic impact of florbetaben PET in a Taiwanese cohort.

METHODS: This prospective cohort study enrolled 206 memory clinic participants who underwent florbetaben amyloid PET, volumetric magnetic resonance imaging, apolipoprotein E genotyping, and neuropsychological assessment, with 2-year longitudinal follow-up.

RESULTS: Amyloid positivity was present in 48% of participants and drove diagnostic reclassification in 49.5% of the cohort. Receiver operating characteristic curve analysis identified an optimal Centiloid (CL) threshold of 21.60 (sensitivity 91.18%, specificity 99.04%, area under the curve [AUC] = 0.98). Amygdala, inferior parietal, and superior temporal atrophy were strong structural predictors of amyloid positivity (AUC = 0.79).

DISCUSSION: These findings establish a locally validated amyloid threshold and provide actionable diagnostic and prognostic stratification in a real-world Asian memory clinic.},
}

@article {pmid42662738,
year = {2026},
author = {Sermkaew, N and Songnaka, N and Masraksa, W and Jaisi, A and Yongyuen, Y and Buntha, P and Nor Azman, NS and Jomrit, J and Boonruamkaew, P},
title = {Self-Emulsifying Formulation of Huperzia carinata Extract to Improve Huperzine A Solubility for Therapeutic Efficacy Enhancement in Parkinsonian Mice.},
journal = {ACS omega},
volume = {11},
number = {33},
pages = {49717-49732},
pmid = {42662738},
issn = {2470-1343},
abstract = {Huperzine A (HupA), a sesquiterpene alkaloid isolated from Huperzia serrata, is clinically applied in China for Alzheimer's disease and in the United States as a dietary supplement. In Thailand, Huperzia carinata (H. carinata) is an alternative and the richest natural source of HupA. However, poor solubility and low oral bioavailability restrict its therapeutic application. This study aimed to develop a self-emulsifying drug delivery system (SEDDS) to improve the solubility, dissolution, and efficacy of HupA from H. carinata extract in a mouse model of Parkinson's disease (PD). The optimized SEDDS consisted of oleic acid (20%), polyethylene glycol-40 hydrogenated castor oil (70%), and propylene glycol (10%), containing 10% H. carinata extract. The HupA-loaded SEDDS displayed efficient self-emulsification, producing droplet sizes of 175.2 ± 8.3 nm to 253.4 ± 2.8 nm upon dilution in water. The SEDDS promoted rapid dissolution, achieving approximately 70% HupA release within 5 min and near-complete dissolution (100%) by 120 min in both gastric and intestinal media. In vitro, the SEDDS displayed significantly superior antioxidant and anti-inflammatory activities compared with the unformulated extract (p < 0.001). In vivo, MPTP-induced Parkinsonian mice receiving SEDDS containing HupA (0.75 and 1.00 μmol/kg body weight) showed significant improvements in locomotor function and motor coordination compared with both vehicle- and blank-SEDDS-treated groups (p < 0.001) at days 3 and 7 after MPTP induction. Biochemical assessments revealed declined malondialdehyde and nitrite levels in cortical and striatal brain tissues compared with the vehicle- and blank-SEDDS-treated groups (p < 0.05). Molecular studies confirmed that HupA-loaded SEDDS increased tyrosine hydroxylase and decreased tumor necrosis factor-α expression compared with the vehicle-treated group (p < 0.001) while protecting dopaminergic neurons in immunohistochemistry, indicating neuroprotective and antineuroinflammatory effects. The SEDDS formulation may represent a promising drug delivery system for the clinical application of HupA in PD and potentially other neurodegenerative disorders. This study contributes to Sustainable Development Goal 3 (good health and well-being) by developing neuroprotective formulations for neurodegenerative diseases.},
}

@article {pmid42662868,
year = {2026},
author = {Ho, V and Tjondropurnomo, R and Nguyen, J and Balkó, E and Depew, S and Chen, X and Singh, R and van Veen, JE and Rácz, B and Golshani, P},
title = {Single-nucleus transcriptomics reveals cell type-specific remodeling and epilepsy-associated microglia.},
journal = {iScience},
volume = {29},
number = {9},
pages = {117228},
pmid = {42662868},
issn = {2589-0042},
abstract = {Temporal lobe epilepsy (TLE) is the most common acquired epilepsy, causing refractory seizures and cognitive deficits. We performed single-nucleus RNA sequencing on hippocampal tissue from mice 3 and 6 weeks following pilocarpine-induced status epilepticus, a robust model of TLE. Epilepsy samples showed reductions in Cck and Lamp5-Lhx6 interneuron subclusters, alongside increases in Cajal-Retzius cells, dentate granule (DG) cell precursors, and a mature DG cell subcluster. Among glia, an astrocyte subcluster and a markedly expanded microglia sublcuster were increased. We term this microglia population epilepsy-associated microglia (EAM). The transcriptomic profile of EAM overlaps with microglia described in models of Alzheimer's disease and traumatic brain injury, including enrichment of Myo1e and Igf1. EAM display amoeboid morphology, can be found in clumps around pyramidal and granule cell body layers, and exhibit enlarged vesicles and mitochondria. Cell-cell interaction analysis predicts DG cells as their primary interaction partners. This dataset defines transcriptomic programs underlying key cellular alterations in TLE, enabling mechanistic dissection of epileptogenesis.},
}

@article {pmid42662874,
year = {2026},
author = {Hsu, CH and Jallow, AW and Saleem, F and Chau Vu, TM and Lin, YF},
title = {Transcriptomic analysis reveals and validates lipid raft-associated biomarkers and functional networks in Alzheimer's disease.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {625-638},
pmid = {42662874},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) involves complex changes, including synaptic dysfunction, neuroinflammation, and metabolic impairment, yet the role of lipid raft-associated gene networks in these processes remains unclear. In this study, we performed an integrative transcriptomic analysis using the GSE5281 dataset and validated the findings in an independent cohort (GSE33000). By combining differential expression analysis with weighted gene co-expression network analysis, we identified 72 lipid raft-associated genes linked to mitochondrial, synaptic, and immune-related pathways. Using network analysis and machine learning approaches (LASSO and SHAP), we further identified eight key biomarkers (CBL, CD44, EZR, FAS, FYN, ITGB1, MAPK1, and TGFBR1) that showed strong diagnostic performance and consistent results across datasets. Functional analysis revealed increased inflammatory signaling, including pyroptosis and cytokine pathways, alongside reduced oxidative phosphorylation and synaptic activity. Interestingly, immune profiling showed only minor differences in immune cell infiltration, but clear activation of multiple immune pathways, such as Th2 and Treg signaling, CD8[+] T-cell signatures, and IL-6/IL-10-mediated inflammation. These immune changes were strongly associated with lipid raft-related biomarkers. Overall, our findings suggest that lipid raft dysregulation may act as a key link between immune activation, mitochondrial dysfunction, and synaptic impairment in AD.},
}

@article {pmid42662931,
year = {2025},
author = {Davis, L and Obisesan, T},
title = {The Shifting Treatment Landscape for Alzheimer's Disease in Primary Care.},
journal = {Federal practitioner : for the health care professionals of the VA, DoD, and PHS},
volume = {42},
number = {Suppl5},
pages = {S37-S42},
pmid = {42662931},
issn = {1078-4497},
}

@article {pmid42663119,
year = {2026},
author = {Kong, Y and Li, X and Guan, R and Wang, X and Chen, A and Zhang, H},
title = {Age-Dependent and APOE-Modified Associations Between Vascular Risk Factor Patterns and Cognitive Function: A Latent Class Analysis of 44,879 NACC Participants.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {42663119},
issn = {1546-4156},
abstract = {INTRODUCTION: Vascular risk factors (VRFs) are established contributors to cognitive decline, yet they often co-occur in distinct patterns. Whether VRF pattern-cognition associations are modified by age or apolipoprotein E (APOE) genotype remains unclear.

METHODS: We analyzed 44,879 participants aged 60 to 90 years from the National Alzheimer's Coordinating Center (NACC) with normal cognition or mild cognitive impairment (MCI). Latent class analysis (LCA) identified VRF patterns from 7 indicators: hypertension, diabetes, hypercholesterolemia, myocardial infarction, atrial fibrillation, heart failure, and stroke. Multivariable linear regression examined associations between VRF patterns and Mini-Mental State Examination (MMSE) scores, with stratification by age and APOE ε4 status.

RESULTS: Five VRF patterns were identified: Low Risk (38.4%), Metabolic Predominant (40.5%), Hypertension Predominant (16.0%), Arrhythmia-Cardiac (2.7%), and High Multimorbidity (2.4%). Each additional VRF was associated with 0.056-point lower MMSE (β=-0.056, 95% CI: -0.072 to -0.039, P<0.001). Significant age × pattern (P=0.0015) and APOE × pattern (P=0.0016) interactions emerged. In younger-old adults (60 to 74 y), Metabolic Predominant was associated with lower MMSE (β=-0.171, P<0.001), but not in older-old adults (75 to 90 y; β=0.020, P=0.53). Among APOE ε4 carriers, the Metabolic Predominant association was substantially stronger (β=-0.228, P<0.001) compared with noncarriers (β=-0.053, P=0.025), a 4.3-fold difference in magnitude.

CONCLUSIONS: VRF-cognition associations show significant heterogeneity by age and APOE genotype. Attenuated associations in older-old adults may reflect survivor bias, while stronger associations in APOE ε4 carriers are consistent with gene-environment interactions.},
}

@article {pmid42663296,
year = {2026},
author = {Li, S and Liu, X and Zhang, Z and Yang, L and Li, Y and Hu, Q},
title = {Research progress on BTG2 in non‑tumor diseases (Review).},
journal = {International journal of molecular medicine},
volume = {58},
number = {5},
pages = {},
doi = {10.3892/ijmm.2026.5970},
pmid = {42663296},
issn = {1791-244X},
mesh = {Humans ; *Tumor Suppressor Proteins/metabolism/genetics ; *Immediate-Early Proteins/metabolism/genetics ; Animals ; },
abstract = {The B‑cell translocation gene 2 (BTG2), originally identified as a tumor suppressor, has been extensively studied in oncology research. However, its multifaceted functions in non‑tumor diseases are still being recognized but not entirely understood. This review systematically synthesizes advances in the pivotal, context‑dependent roles of BTG2 in non‑tumor pathologies, including fibrotic, neurological, cardiovascular, inflammatory, metabolic and other systemic diseases. BTG2 is not merely a binary regulator but a context‑sensitive molecular hub. Specific disease microenvironments, cell types and pathological stages contribute to its biological impact, whether protective or pathogenic. For instance, BTG2 promotes protective microglial activation in Alzheimer's disease while exacerbating neuronal death in acute spinal cord injury. Mechanistically, BTG2 influences cell fate decisions involving apoptosis, senescence, inflammation and metabolism by integrating signals from various pathways at the intersection of major regulatory networks, such as the neuro‑immune‑epigenetic axis and the metabolic‑epigenetic‑fibrosis network. It has emerged as a promising dual‑purpose biomarker for disease diagnosis and prognosis, as well as a potential therapeutic target, owing to its dose‑sensitive expression and regulatory position. However, because of its functional duality, therapeutic targeting necessitates precise, context‑specific strategies. This review offers a novel, integrative perspective on BTG2 in non‑tumor biology, underscoring its implication as a key regulatory node with extensive translational potential.},
}

Humans
*Tumor Suppressor Proteins/metabolism/genetics
*Immediate-Early Proteins/metabolism/genetics
Animals

@article {pmid42663379,
year = {2026},
author = {Kume, K and Kurashige, T and Itabashi, T and Akagi, A and Ando, T and Nakamura, M and Kikumoto, M and Tamada, A and Kamada, M and Ayaki, T and Izumi, Y and Yabe, I and Muguruma, K and Miyamoto, T and Iwasaki, Y and Kawakami, H},
title = {AGG repeat expansion and aggregation of BIN1 in multiple system atrophy.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag194},
pmid = {42663379},
issn = {1460-2156},
abstract = {Multiple system atrophy is a fatal, sporadic α-synucleinopathy characterized by glial cytoplasmic inclusions in oligodendrocytes. No causative gene for multiple system atrophy has been identified to date. Whole-genome sequencing was performed for a patient with familial multiple system atrophy, in whom an AGG repeat expansion in BIN1 was identified. Based on this finding, we screened for the AGG repeat expansion in BIN1 in a cohort comprising 224 patients with clinically diagnosed multiple system atrophy, 67 patients with pathologically confirmed multiple system atrophy, and control groups including 574 blood samples and 65 brain samples from neurologically healthy individuals. The pathological analysis was performed for four cases with the repeat expansion and five cases without the repeat expansion. The biochemical analysis was performed for nine control subjects, ten cases without the repeat expansion, and eight cases with the repeat expansion. Long-read sequencing identified an AGG repeat expansion in the first intron of BIN1 in the proband. Patients with multiple system atrophy carried a higher frequency of repeat expansions exceeding 80 repeats in the pathological multiple system atrophy group compared to the brain control group (frequency: 13.4% vs. 0%; odds ratio: infinity; 95% confidence interval [CI], 2.1 to infinity; P = 0.003, Fisher's exact test). In contrast, the difference of frequency did not reach statistical significance in the clinical multiple system atrophy group compared to the blood control group (frequency: 4.5% vs 2.4%; odds ratio: 1.87; 95% CI, 0.8 to 4.5; P = 0.16, Fisher's exact test). Neuropathological analysis revealed BIN1-positive glial cytoplasmic inclusions more frequently in the brains of patients with repeat expansions. In immunoblot analysis, insoluble BIN1 were increased in the brains of multiple system atrophy irrespective of repeat status. Our findings indicate that the AGG repeat expansion in BIN1 and BIN1 protein aggregation plays an important role in the pathogenesis of multiple system atrophy.},
}

@article {pmid42663443,
year = {2026},
author = {Oh, DJ and Han, JW and Kim, TH and Kwak, KP and Kim, BJ and Kim, SG and Kim, JL and Moon, SW and Park, JH and Ryu, SH and Lee, DW and Lee, SB and Lee, JJ and Jhoo, JH and Kim, KW},
title = {APOE ε4 and peripheral metabolic network architecture in older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476718},
doi = {10.1177/13872877261476718},
pmid = {42663443},
issn = {1875-8908},
abstract = {BackgroundWhether apolipoprotein E (APOE) ε4 status shapes the organization of modifiable peripheral metabolic risk pathways for dementia prevention remains unclear. Most prior studies have focused on individual APOE-by-biomarker interactions rather than the broader conditional dependency structure among metabolic variables.ObjectiveWe aimed to examine whether APOE ε4 is conditionally connected to metabolic factors and whether network architecture differs by genotype.MethodsIn 2454 participants from the Korean Longitudinal Study on Cognitive Aging and Dementia with complete data on 13 variables, conditional dependency networks were estimated using graphical least absolute shrinkage and selection operator models and mixed graphical models. Network Comparison Tests were used to compare 12-node metabolic networks between ε4 carriers and non-carriers. Cox proportional hazards models evaluated whether hub biomarkers predicted incident cognitive impairment over a median follow-up of 7.4 years and whether associations differed by APOE genotype.ResultsAPOE ε4 showed negligible conditional connectivity, with near-zero partial correlations in GLASSO (maximum |r| = 0.0114) and zero edge weights in mixed graphical models. The 12-node metabolic network did not differ significantly between carriers and non-carriers in either network structure (M = 0.1671, p = 0.45) or global strength (S = 2.3662, p = 0.46). Among 1922 baseline cognitively normal participants, 504 developed cognitive impairment during follow-up. Neither the APOE × homocysteine interaction (p = 0.921) nor the APOE × creatinine interaction (p = 0.402) was significant.ConclusionsAPOE ε4 was conditionally independent of the peripheral metabolic variables examined, with no major genotype-specific differences in network architecture. These findings highlight the importance of metabolic dementia prevention regardless of genotype, although interventional confirmation is warranted.},
}

@article {pmid42663447,
year = {2026},
author = {Sakurai, K and Kaneda, D and Uchida, Y and Shibata, H and Morimoto, S and Hashizume, Y},
title = {Network-based statistical mapping of structural covariance alterations in pathologically confirmed argyrophilic grain disease and Alzheimer's disease: An exploratory pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480673},
doi = {10.1177/13872877261480673},
pmid = {42663447},
issn = {1875-8908},
abstract = {BackgroundAlthough neuroimaging differences from Alzheimer's disease (AD) in argyrophilic grain disease (AGD), a limbic-predominant 4-repeat tauopathy, have been evaluated, edge-wise alterations in structural similarity remain unexamined.ObjectiveAs an exploratory pilot study, to apply network-based statistics (NBS) to individualized structural covariance (ISC) matrices to identify morphological-similarity alterations in AGD and AD.MethodsWe analyzed 3D T1-weighted MRI from 13 pathologically confirmed AGD, 17 AD, and 18 healthy controls (HC). Gray-matter volumes from a 170-region atlas were used to compute ISC matrices. Between-group differences were assessed using NBS (threshold t = 3.5; 5000 permutations). Component strength was the sum of ISC edge weights within the significant component. Stability was assessed via leave-one-out analyses and bootstrap confidence intervals. Significant edges were mapped to Yeo 7 resting-state networks.ResultsAll three comparisons yielded a single significant component (HC versus AD: 340 edges; HC versus AGD: 80 edges; AGD versus AD: 39 edges). Component strength was higher in the group with less widespread morphological disruption (HC > AD; HC > AGD; AGD > AD), with non-overlapping bootstrap confidence intervals. Mapping to resting-state networks revealed widespread posterior cortico-limbic involvement in AD and a limbic-predominant pattern in AGD. In the AGD versus AD comparison, AD showed greater disruption within frontoparietal, somatomotor, and ventral attention systems. Component strength correlated positively with Mini-Mental State Examination scores (r = 0.48, p = 0.01).ConclusionsNBS applied to ISC matrices provides preliminary evidence of altered morphological similarity in AGD and AD, with AGD showing a limbic-predominant subnetwork and AD demonstrating broader posterior cortico-limbic involvement.},
}

@article {pmid42646579,
year = {2026},
author = {Calabrò, RS and Calderone, A and Ravi, D and Galipò, C and Crupi, MF and Quartarone, A},
title = {Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
pmid = {42646579},
issn = {2076-3271},
mesh = {Humans ; *Nervous System Diseases/therapy ; *Transitional Care ; Multiple Sclerosis ; Hospitalization ; Chronic Disease ; Amyotrophic Lateral Sclerosis ; },
abstract = {BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.

RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.

CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.},
}

Humans
*Nervous System Diseases/therapy
*Transitional Care
Multiple Sclerosis
Hospitalization
Chronic Disease
Amyotrophic Lateral Sclerosis

@article {pmid42646820,
year = {2026},
author = {Liu, Y and Lu, J and Zhang, Z and Yao, D and Xia, Y and Chen, K},
title = {The Visual System in Alzheimer's Disease: A Multilevel Review of Pathology, Monitoring, and Intervention.},
journal = {Vision (Basel, Switzerland)},
volume = {10},
number = {3},
pages = {},
pmid = {42646820},
issn = {2411-5150},
support = {2022ZD0208500//National Science and Technology Major Project/ ; 2024YFHZ0359//Sichuan Science and Technology Program/ ; },
abstract = {Alzheimer's disease (AD) extends beyond the brain to the visual system, offering a promising window for pathology, monitoring, and intervention. This review synthesizes evidence on AD-related visual impairments across molecular, cellular, circuit, and cortical levels. We examine the eye-brain pathological relationship as a working framework, noting experimental evidence for brain-to-eye amyloid-β (Aβ) transport in mouse models and associations between retinal and cerebral pathology in humans, while emphasizing that bidirectional pathological transport has not been established. Structural and functional changes in the retina, optic nerve, and visual cortex are reviewed, alongside white matter damage and posterior cortical atrophy patterns. We evaluate emerging multimodal tools (OCTA, ERG, and hyperspectral imaging) that shift diagnosis toward an integrated "structure-vessel-function" assessment. We critically examine non-pharmacological interventions, including 40 Hz gamma stimulation and photobiomodulation, discussing their mechanisms, translational challenges, and the dissociation between structural and cognitive outcomes. We propose the visual system as a candidate pathological window, a quantitative monitoring platform, and an investigational intervention entry point in Alzheimer's disease. However, clinical translation of these applications requires standardized acquisition protocols, prospective longitudinal validation, and robust mechanistic evidence. To advance this agenda, we identify three priorities: multimodal data integration, closed-loop neuromodulation strategies, and methodologically rigorous validation frameworks.},
}

@article {pmid42646836,
year = {2026},
author = {Yang, HW and Han, JW and Oh, DJ and Kim, BJ and Lee, DW and Kim, JL and Jhoo, JH and Park, JH and Lee, JJ and Kwak, KP and Lee, SB and Moon, SW and Ryu, SH and Kim, SG and Kim, KW},
title = {Domain-Specific Cognitive Concordance in Older Married Couples.},
journal = {JAMA network open},
volume = {9},
number = {8},
pages = {e2631017},
pmid = {42646836},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; Cross-Sectional Studies ; Republic of Korea ; Aged ; *Spouses/psychology/statistics & numerical data ; *Cognition/physiology ; Longitudinal Studies ; Aged, 80 and over ; Neuropsychological Tests ; *Marriage/psychology ; },
abstract = {IMPORTANCE: Spousal similarity in late-life cognition has been reported, but whether concordance differs across cognitive domains remains unclear.

OBJECTIVE: To examine whether cognitive concordance among older married couples is domain specific by comparing real couples with demographically and genetically matched control pairs.

This nationwide, multicenter, community-based cross-sectional study was conducted from January 2019 to December 2020 and included married couples from the Korean Longitudinal Study of Cognitive Aging and Dementia. Each spouse was individually matched to an unrelated control based on sex, cognitive diagnosis, apolipoprotein E ε4 status, age, and education. Data were analyzed from March to April 2026.

EXPOSURE: Marital pairing within a 4-group matched design (real couples, spouse-control pairs, and matched null couples).

MAIN OUTCOMES AND MEASURES: For 9 subtests from the Korean version of the Consortium to Establish a Registry for Alzheimer Disease Assessment Packet, intraclass correlation coefficients (ICCs) were calculated within each group, and the spousal concordance (ICC difference) was defined as the difference between the ICC of real couples and that of matched null couples. Significance was assessed with 2-sided permutation tests and Benjamini-Hochberg false discovery rate correction.

RESULTS: The sample included 783 married couples (1566 individuals; 783 [50.0%] female and 783 [50.0%] male; mean [SD] age, 74.0 [5.5] years) and 783 matched control couples. Among the 783 married couples, 4 of 9 subtests showed significant ICC differences after false discovery rate correction in unadjusted analyses: Verbal Fluency (ICC difference, 0.232; 95% CI, 0.138-0.324), Constructional Praxis (ICC difference, 0.145; 95% CI, 0.039-0.252), Boston Naming Test (ICC difference, 0.134; 95% CI, 0.038-0.231), and Constructional Recall (ICC difference, 0.110; 95% CI, 0.017-0.200); all remained significant after covariate adjustment. In contrast, the Mini-Mental State Examination and verbal memory recall and recognition showed little concordance beyond demographically matched null pairs.

CONCLUSIONS AND RELEVANCE: In this cross-sectional study of 783 older married couples, spousal cognitive concordance was domain specific, with the greatest effect size estimates in language and visuospatial function rather than global cognition. These findings suggest that spousal cognitive similarity may be missed when analyses rely only on global screening measures, highlighting the need for longitudinal study of within-couple concordance.},
}

Humans
Female
Male
Cross-Sectional Studies
Republic of Korea
Aged
*Spouses/psychology/statistics & numerical data
*Cognition/physiology
Longitudinal Studies
Aged, 80 and over
Neuropsychological Tests
*Marriage/psychology

@article {pmid42646944,
year = {2026},
author = {Guo, B and Chang, J and Liu, A and Li, M and Guo, L and Cheng, S and Wang, H and Ba, Q},
title = {Environmental Cadmium Exposure Exacerbates Alzheimer's-like Pathology in a Gut Microbiota-Involved Manner.},
journal = {Toxics},
volume = {14},
number = {8},
pages = {},
pmid = {42646944},
issn = {2305-6304},
support = {2022YFF0606703//National Key R&D Program of China/ ; KF202330//the Open Foundation of Shaanxi University of Chinese Medi-cine Key Laboratory of Research & Development of Characteristic Qin Medicine Re-sources/ ; },
abstract = {Cadmium (Cd), a ubiquitous environmental toxicant, poses substantial health risks even at low-dose chronic exposures. In this study, we developed a mouse model with chronic low-dose dietary Cd exposure (100 nM CdCl2 in drinking water for eight months) to investigate its impacts on cognitive and neuropathological alterations. Behavioral assessments demonstrated that Cd-exposed mice exhibited pronounced deficits in spatial learning, memory retention, and working memory compared with control mice. Histopathological analyses of hippocampus uncovered accelerated Alzheimer's-like neuropathology, marked by elevated β-amyloid plaque immunoreactivity and tau hyperphosphorylation. Concurrently, neuroinflammatory responses were markedly upregulated, shown as astrocytes activation and pro-inflammatory Th17 cell signatures in parenchyma. Brain transcriptomic profiling revealed extracerebral prostaglandin signaling following Cd exposure, a finding consistent with elevated prostaglandins detected in the gut. Crucially, these outcomes were gut microbiota-involved: antibiotic-mediated microbiota depletion attenuated dietary Cd-enhanced cognitive impairments, neuroinflammation, and prostaglandin upregulation, underscoring the critical role of intestinal microbes in mediating Cd neurotoxicity. Furthermore, in vitro co-culture experiments demonstrated that Cd potentiated prostaglandin production in intestinal epithelial cells-an effect amplified by gut bacterial stimuli. This observation suggests a mechanism under which peripheral prostaglandins may contribute to central inflammatory cascades. Together, these findings support a gut-brain mechanism underlying dietary Cd-exacerbated neurodegeneration and highlight gut homeostasis and prostaglandin signaling as promising therapeutic targets for mitigating Cd-associated neurodegenerative disorders.},
}

@article {pmid42647155,
year = {2026},
author = {Ohara, K and Zhang, H and Shibata, H and Hasegawa, Y},
title = {Long-Term Dietary Supplementation with Pearl Oyster Shell-Derived Nacre Extract Improves Cognitive Performance and Attenuates Alzheimer's Disease-Like Pathology in APPNL-G-F/NL-G-F Knock-In Mice.},
journal = {Journal of dietary supplements},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/19390211.2026.2718077},
pmid = {42647155},
issn = {1939-022X},
abstract = {Alzheimer's disease is characterized by cognitive decline, amyloid-β deposition, tau-related pathology, neuroinflammation, and oxidative stress. Pearl oyster shell-derived nacre extract is used in dietary supplement-related applications, but evidence from animal models should be interpreted cautiously and its effects on Alzheimer's disease-like pathology remain incompletely defined. To evaluate whether long-term oral dietary supplementation with nacre extract is associated with changes in cognitive performance and Alzheimer's disease-like pathological features in APPNL-G-F/NL-G-F knock-in mice. A controlled preclinical animal study was performed using male C57BL/6 wild-type mice and male APP[NL-G-F/NL-G-F] knock-in mice over a 6-month dietary supplementation period. Six mice were assigned to each group. APP knock-in mice received a standard diet with or without 0.5% (w/w) nacre extract, corresponding to an estimated intake of approximately 20 mg/mouse/day or approximately 600 mg/kg/day. Cognitive performance was assessed using the Y-maze and novel object recognition tests. Brain pathology and molecular responses were evaluated by histology, immunohistochemistry, RNA sequencing, qPCR, Western blotting, and oxidative stress-related assays. Nacre supplementation was associated with improved performance in the Y-maze and novel object recognition tests, reduced amyloid-β deposition and Congo red-positive plaque burden, lower phosphorylated tau immunoreactivity, and fewer histologically degenerated hippocampal neurons. Exploratory RNA sequencing of non-microdissected brain tissue excluding the cerebellum (n = 3/group) identified 53 genes meeting the criteria of an absolute fold change ≥ 1.5 and a valid non-zero FDR-adjusted p value < 0.05. A2M showed a 1.51-fold increase (FDR-adjusted p = 0.00091), and increased A2M abundance was confirmed at the protein level. Iba1 and GFAP immunoreactivity was reduced, and oxidative stress-related parameters were altered in the nacre-supplemented group. Long-term nacre supplementation was associated with improvements in behavioral performance and attenuation of several Alzheimer's disease-like pathological features in male APP knock-in mice. These findings represent an exploratory preclinical signal and do not establish a causal mechanism, dose-response relationship, comprehensive safety profile, or efficacy as a dietary supplement in humans.},
}

@article {pmid42647218,
year = {2026},
author = {Malafaia, D and Melo, L and Silva, AMS and Albuquerque, HMT},
title = {Xanthones and Their Nitrogen and Sulfur Analogs in Alzheimer's Disease: Recent Progress Toward Multifunctional Therapeutics.},
journal = {ChemMedChem},
volume = {21},
number = {16},
pages = {e70453},
pmid = {42647218},
issn = {1860-7187},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Xanthones/chemistry/therapeutic use/pharmacology ; *Sulfur/chemistry ; *Nitrogen/chemistry ; Molecular Structure ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Animals ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia among the elderly worldwide. In medicinal chemistry and drug discovery, heterocycles are widely recognized as privileged scaffolds due to their structural versatility and biological relevance. In the context of AD, heterocyclic compounds have been extensively investigated for the development of potential therapeutic agents. Among fused heterocyclic systems, oxygen-, nitrogen-, and sulfur-containing heterocycles are particularly prominent in approved drugs. This review focuses on recent advances in the exploration of xanthone derivatives, alongside with their nitrogen- and sulfur-containing analogs, as promising template scaffolds for the development of prospective anti-AD therapeutics.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Xanthones/chemistry/therapeutic use/pharmacology
*Sulfur/chemistry
*Nitrogen/chemistry
Molecular Structure
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
Animals

@article {pmid42647276,
year = {2026},
author = {Papadopoulou, K and Tsokkou, S and Konstantinidis, I and Pavlidis, P and Sardeli, C and Kouvelas, D and Meditskou-Efthymiadou, S and Sioga, A and Papamitsou, T},
title = {Beyond the Central Nervous System: Uncovering Memantine's Modulatory Role in the Peripheral Nervous System.},
journal = {Medicines (Basel, Switzerland)},
volume = {13},
number = {3},
pages = {},
pmid = {42647276},
issn = {2305-6320},
abstract = {Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer's disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine's modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine's effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2-mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials.},
}

@article {pmid42647328,
year = {2026},
author = {Merino-País, M and López-Ortiz, S and Emanuele, E and Imbimbo, C and Imbimbo, BP and Lista, S and Santos-Lozano, A},
title = {Physical Exercise and Gut Microbiota: Implications for Alzheimer's Disease in Experimental Models: A Systematic Review and Meta-Analysis.},
journal = {Journal of functional morphology and kinesiology},
volume = {11},
number = {3},
pages = {},
pmid = {42647328},
issn = {2411-5142},
abstract = {Background and Objectives: The concept of the gut-muscle-brain axis encompasses the intricate, multidirectional interactions between the gut microbiota (GM), physical exercise (PE), and the central nervous system. Within this framework, gut dysbiosis has been implicated in the pathogenesis of Alzheimer's disease (AD). Given that cognitive functions in AD appear to benefit from PE, it is plausible to hypothesize that these improvements may be partially mediated by PE-induced alterations in GM taxonomy. Therefore, the objective of this study is to evaluate the potential effects of PE in the GM and their implications for AD. Methods: A systematic review was conducted in PubMed, Web of Science and Scopus following the PRISMA guidelines up to July 2025 for preclinical controlled trials that assessed the effects of PE on the GM of AD animal models. A random-effects model meta-analysis was performed to estimate the pooled effect of PE on GM frequency or composition. This study received no external funding. Results: Eight studies were included in the systematic review (sample size, n = 126), of which two could be meta-analyzed. We found that PE significantly reduced Actinobacteria abundance (MD = -0.005%; 95% CI, -0.008 to -0.002; p = 0.001) with no statistically significant evidence of heterogeneity (I[2] = 89.60%, Q = 0.102, p = 0.950) or publication bias observed (Begg's test, p = 0.296), but no significant effects were found for other phylums or genera. Conclusions: PE appears capable of modulating the GM of animal models with AD in a selective and heterogeneous manner. Further studies are needed to clarify the mechanisms by which this is possible and to determinate its impact on the pathogenesis of the disease.},
}

@article {pmid42647485,
year = {2026},
author = {, },
title = {Expression of Concern: Constipation in Tg2576 mice model for Alzheimer's disease associated with dysregulation of mechanism involving the mAChR signaling pathway and ER stress response.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0356955},
pmid = {42647485},
issn = {1932-6203},
}

@article {pmid42647766,
year = {2026},
author = {Paranhos, T and Katsumi, Y and Brickhouse, MJ and Eloyan, A and Eckbo, R and Zaitsev, A and Du, A and La Joie, R and Thangarajah, M and Taurone, A and Vemuri, P and Jack, CR and , and Hammers, DB and Aisen, PS and Beckett, LA and Koeppe, R and Kukull, WA and Toga, AW and Atri, A and Clark, DG and Day, GS and Duara, R and Graff-Radford, NR and Grant, IM and Honig, LS and Johnson, E and Jones, DT and Masdeu, JC and Mendez, MF and Musiek, ES and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, T and Wolk, DA and Womack, KB and Carrillo, MC and Rabinovici, GD and Apostolova, LG and Dickerson, BC and Eldaief, MC and Touroutoglou, A},
title = {EOAD-Signature Atrophy Predicts Dementia in Early-Onset MCI due to Alzheimer Disease: An MRI-Based Prognostic Biomarker.},
journal = {Neurology},
volume = {107},
number = {7},
pages = {e218519},
doi = {10.1212/WNL.0000000000218519},
pmid = {42647766},
issn = {1526-632X},
mesh = {Humans ; Female ; Atrophy/pathology ; *Alzheimer Disease/diagnostic imaging/pathology/complications ; Magnetic Resonance Imaging ; Disease Progression ; *Cognitive Dysfunction/diagnostic imaging/pathology/etiology ; Prognosis ; Male ; Middle Aged ; Biomarkers ; Adult ; Longitudinal Studies ; *Dementia/diagnostic imaging ; },
abstract = {BACKGROUND AND OBJECTIVES: Early-onset Alzheimer disease (EOAD) is associated with substantial variability in clinical progression, and reliable biomarkers to predict the transition from mild cognitive impairment (MCI) to dementia remain limited. Structural MRI measures have demonstrated prognostic value in late-onset Alzheimer disease, but their utility for predicting progression in EOAD is less well understood. The goal was to examine whether baseline cortical atrophy predicts progression to dementia in patients with MCI because of EOAD.

METHODS: This study included a well-characterized cohort of patients with EOAD enrolled in the large multisite natural history Longitudinal Early-Onset Alzheimer's Disease Study. Participants underwent standardized clinical assessments and structural MRI at baseline. Participants were aged between 40 and 64 years with biomarker-supported sporadic EOAD at the MCI stage. Cortical atrophy was measured within the EOAD-signature, a set of predominantly parieto-temporal regions showing greater atrophy in EOAD than in controls. Clinical severity was measured with the global Clinical Dementia Rating. Cox proportional hazards models estimated the association between baseline EOAD-signature atrophy burden and the hazard of progression to dementia over time. We evaluated whether EOAD-signature atrophy improved prognostic performance beyond baseline clinical severity using likelihood ratio tests, Akaike Information Criterion (AIC), and Harrell concordance index.

RESULTS: A total of 130 patients with MCI due to EOAD (mean age 59.6 ± 4.1 years; 49% female) and 97 cognitively normal controls (mean age 56.9 ± 6.0 years; 64% female) were included. Greater baseline atrophy within the EOAD-signature predicted faster progression to dementia (hazard ratio [HR] = 1.24 per 1-SD increase in atrophy; 95% CI 1.13-1.37; p < 0.002). Adding EOAD-signature atrophy burden to a model including baseline clinical severity significantly improved model fit (ΔAIC = -4.5; likelihood ratio test p = 0.011).

DISCUSSION: Baseline cortical atrophy within the EOAD-signature predicts progression from MCI to dementia in EOAD and provides prognostic information beyond baseline clinical severity. These findings support the potential value of EOAD-signature atrophy as an MRI-based biomarker for individualized prognostication and clinical trial stratification.},
}

Humans
Female
Atrophy/pathology
*Alzheimer Disease/diagnostic imaging/pathology/complications
Magnetic Resonance Imaging
Disease Progression
*Cognitive Dysfunction/diagnostic imaging/pathology/etiology
Prognosis
Male
Middle Aged
Biomarkers
Adult
Longitudinal Studies
*Dementia/diagnostic imaging

@article {pmid42648141,
year = {2026},
author = {Gao, X and Ma, D and Liu, R and Guo, T and Dong, Z and Yan, J and Huang, J},
title = {Domain-specific deficits in categorical perception unveil the neural architecture of auditory agnosia in dementia.},
journal = {Hearing research},
volume = {481},
number = {},
pages = {109783},
doi = {10.1016/j.heares.2026.109783},
pmid = {42648141},
issn = {1878-5891},
abstract = {Auditory processing deficits are a prominent early feature of Alzheimer's disease (AD), yet whether they reflect generalized cognitive slowing or domain-specific neural degradation remains unclear. This study combined a categorical perception paradigm with high-temporal-resolution electroencephalography (EEG) to evaluate neural responses to distinct combinations of acoustic cues, rapid temporal dynamics (consonants) versus stable spectral configurations (lexical tones), across a continuum of healthy aging, mild cognitive impairment (MCI), and AD. Rather than a monolithic functional loss, behavioral analysis revealed a differential vulnerability: while psychomotor slowing was global, categorical precision collapsed specifically for rapid consonant cues but remained remarkably resilient for tones. Neurophysiologically, this divergence was underpinned by a distinct trajectory transitioning from successful compensatory hyper-activation in normal aging to a state of inefficient hyper-activation in clinical cohorts, characterized by sustained P300 amplitudes but severe temporal processing delays. Crucially, we demonstrated the clinical utility of these domain-specific electrophysiological signatures using a fivefold cross-validated machine learning approach. Advanced classification algorithms, notably the gradient boosting machine (GBM), distinguished participants with MCI from cognitively normal older adults with an area under the receiver operating characteristic curve (AUC) of 0.836. These findings reframe auditory deficits in dementia as a nuanced erosion of specific neural codes and highlight the efficacy of interpretable, EEG-based neurocomputational tools for the early clinical screening of pre-dementia states.},
}

@article {pmid42648288,
year = {2026},
author = {Quenez, O and Schramm, C and Cassinari, K and Nicolas, A and Groeneveld, J and Huguet, G and Grenier-Boley, B and Hulsman, M and Walters, GB and de Rojas, I and Rovelet-Lecrux, A and Feuillette, S and Miguel, L and Richard, AC and Rousseau, S and Ahmad, S and Amin, N and Amouyel, P and Belbin, O and Bellenguez, C and Berr, C and Bossù, P and Bouwman, F and Bras, J and Clarimon, J and Daniele, A and Dartigues, JF and Debette, S and Deleuze, JF and Denning, N and Dols-Icardo, O and van Duijn, CM and Fortea, J and Fox, NC and Frikke-Schmidt, R and Galimberti, D and Ghidoni, R and Giedraitis, V and Gille, JJP and Grozeva, D and Guerreiro, R and Grünblatt, E and Hardy, J and Riedel-Heller, SG and Hiltunen, M and Holmes, C and Hort, J and Hummerich, H and Ikram, MA and Ikram, MK and Ingelsson, M and Jansen, IE and Kawalia, A and Kraaij, R and Kehoe, PG and Lathrop, M and Lacour, M and Lemstra, AW and Lleó, A and Luckcuck, L and Mannens, MMAM and Marshall, R and Masullo, C and Mead, S and Mecocci, P and de Mendonça, A and Meggy, A and Mehrabian, S and Mol, MO and Morgan, K and Morin, A and Nacmias, B and Norsworthy, PJ and Olaso, R and Pasquier, F and Pastor, P and Piras, F and Popp, J and Ramirez, A and Raybould, R and Redon, R and Reinders, MJT and Rivadeneira, F and van Rooij, JGJ and Ryan, NS and Saad, S and Sanchez-Juan, P and Scarmeas, N and Scheltens, P and Schott, JM and Seripa, D and Sie, D and Sims, R and Sistermans, EA and Sorbi, S and Sleegers, K and van Spaendonk, R and van Swieten, JC and Tesi, N and Tijms, BM and Tsolaki, M and Uitterlinden, AG and Vijverberg, J and Visser, PJ and Wagner, M and Williams, J and Zarea, A and , and Génin, E and Holstege, H and Gudbjartsson, DF and Wallon, D and Lecourtois, M and Fernandez, MV and Stefansson, H and Jacquemont, S and Lambert, JC and van der Lee, SJ and Charbonnier, C and Nicolas, G},
title = {Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2026.07.013},
pmid = {42648288},
issn = {1537-6605},
abstract = {Copy-number variants (CNVs) are major contributors to human disease. In Alzheimer disease (AD), APP duplications cause autosomal-dominant forms, but the role of CNVs in non-monogenic AD remains poorly characterized. We analyzed rare CNVs (frequency <1%) from 22,319 exomes (4,150 early-onset AD [EOAD, ≤65 years], 8,519 late-onset AD [LOAD], 9,650 unaffected control subjects) using harmonized calling and quality control. After identifying 17 individuals with a pathogenic CNV, we performed exome-wide and gene-set burden analyses. EOAD-affected individuals showed increased burdens of rare CNVs affecting coding genes, particularly deletions in AD-related genes. Integrated loss-of-function (LoF) analysis gathering short truncating variants with deletions showed that ABCA1 (odds ratio [OR] = 5.77 [95% confidence interval 2.25; 17.06], p = 0.0002) and ABCA7 deletions contribute to this deletion burden (OR = 2.29 [1.44; 3.65], p = 0.0006), while CTSB LoF alleles appear as candidates (OR = 5.03 [1.50; 20.71], p = 0.0089). We then performed exome-wide gene-level dosage analysis and highlighted 18 genes across five loci with a false discovery rate of <10%, including the 22q11.21 central region, where deletions were restricted to EOAD (including one de novo event) and duplications were enriched in control individuals, with intermediate frequencies in LOAD. We narrowed this locus to the SCARF2-KLHL22-MED15 region after integrating short truncating variants. Replication in 33,977 affected individuals and 362,322 control subjects confirmed association for 22q11.21 dosage with exome-wide significance (ORSCARF2 = 0.34 [0.21; 0.53]; mega-p value = 5.52 × 10[-7]). SCARF2 overexpression significantly increased amyloid-β uptake, congruent with duplication-associated decreased AD risk. We conclude that rare coding CNVs in a proportion of AD-associated genes and 22q11.21 deletions, including some found in DiGeorge syndrome, increase AD risk. Conversely, we identify 22q11.21 duplication as a strong AD-risk-decreasing factor.},
}

@article {pmid42648310,
year = {2026},
author = {Chen, J and Ji, H and Yuan, Y},
title = {40 Hz noninvasive transcranial ultrasound stimulation modulates multiscale nonlinear dynamics of hippocampal CA1 neural oscillations of Alzheimer's mouse model.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae9eed},
pmid = {42648310},
issn = {1741-2552},
abstract = {Aberrant nonlinear dynamics of hippocampal neural oscillations are a hallmark of early network dysfunction in Alzheimer's disease (AD), with critical roles in memory processing. Although transcranial ultrasound stimulation (TUS) has shown cognitive benefits in AD models and patients, its effects on the nonlinear dynamics of hippocampal CA1 oscillations and their multiscale organization remain unclear. Approach. Here, we applied 40 Hz non-invasive TUS to the hippocampal CA1 region of AD mouse model and recorded local field potentials before, during, and after stimulation. Analyses integrated nonlinear dynamical metrics, power spectral dependencies, cross-frequency coupling, and event-level oscillatory features. Main results. We found that (1) 40 Hz TUS decreases complexity and irregularity of CA1 activity, and enhances dynamical activity and long-range temporal correlations in broadband and high-frequency ranges, increases complexity in the theta and beta bands. (2) TUS also significantly reduced theta-gamma and intra-gamma phase-amplitude coupling, while producing frequency-specific changes in the rate, amplitude, duration, and temporal organization of theta, gamma, and ripple events. (3) Furthermore, the relationship between nonlinear dynamics and power spectral density was modulated across stimulation phases. Significance. 40 Hz TUS can modulate multiscale nonlinear dynamics of neural oscillations in hippocampal CA1 of Alzheimer's mouse model, which lays a theoretical foundation for the clinical intervention of Alzheimer's disease via ultrasound stimulation. .},
}

@article {pmid42648361,
year = {2026},
author = {Maria de Campos, R and Carraro, MF and Brandão Bitencourt, AL and Jerisha, JJ and Ayon, NJ and Juska, VB and Pinheiro, NR and Johnson, EA and Nowar, RN and McGee, JP and Alfaro, ME and Oberholzer, MV and Grippo, V and Cline, EN and Viola, KL and Kelleher, NL and Habif, M and Jerusalinsky, DA and Shekhawat, GS and Elmor, MB and Lah, JJ and Levey, AI and Klein, WL and Sebollela, A},
title = {Use of high-affinity scFv antibody NUsc1 for isolation and sensitive detection of Alzheimer's-associated amyloid beta oligomers.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113499},
doi = {10.1016/j.jbc.2026.113499},
pmid = {42648361},
issn = {1083-351X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which soluble amyloid-beta oligomers (AβOs) play a key role in disease onset and progression. This study further explores NUsc1, a single-chain variable fragment (scFv) antibody with high specificity for neurotoxic AβOs over monomers or fibrils, to selectively isolate and assist characterization of AβO species. NUsc1 binds AβOs with a kinetic dissociation constant under 10nM, comparable to the affinity of Leqembi for protofibrils. NUsc1 inhibits aggregation of AβOs into protofibrillar and fibrillar structures and blocks AβO binding to cultured hippocampal neurons in a dose-dependent manner, with an IC50 of ∼100nM in experiments using 2.25ng/μL AβOs. Selectivity and high affinity of NUsc1 enabled immunoprecipitation of AβOs under non-denaturing conditions. Atomic force microscopy revealed globular NUsc1-AβO complexes with a z-height of ∼3-4 nm, while free NUsc1 measured ∼1.5nm. Mass spectrometry revealed a heterogeneous population of NUsc1-isolated AβOs, consistent with a stepwise species assembly, while non-denaturing size-exclusion chromatography revealed species of approximately 70kDa. In ELISA, phage-bound NUsc1 (pbNUsc1) detected ∼12pM AβOs, a 33-fold increase in detection sensitivity compared to a commercial anti-Aβ antibody. NUsc1 also detected AβOs from 5xFAD mouse brain extracts, cerebrospinal fluid from AD rats, and, notably, from CSF of human donors, demonstrating direct detection of AD-relevant oligomers in a clinically relevant human biofluid. Collectively, these results highlight NUsc1's promise not only as a powerful research tool for structural and mechanistic studies of AβOs but also as a highly sensitive diagnostic tool for clinical use.},
}