@article {pmid42471199,
year = {2026},
author = {Yang, S and Astill-Vaccaro, J},
title = {Transdermal Methylphenidate for Apathy in Alzheimer's Dementia.},
journal = {Journal of the Academy of Consultation-Liaison Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaclp.2026.07.005},
pmid = {42471199},
issn = {2667-2960},
}

@article {pmid42471426,
year = {2026},
author = {Ahmad, A and Khan, MM},
title = {DNA Sensing and Neuroinflammation: Mechanistic Insights into cGAS-STING Biology and Therapeutic Translation in Age-Related Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42471426},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism/therapy/genetics/pathology ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; STING Protein ; *Membrane Proteins/metabolism ; *Aging/pathology/metabolism/genetics ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; *Neuroinflammatory Diseases/metabolism/genetics/therapy ; *DNA/metabolism ; Inflammation ; },
abstract = {Emerging evidence suggests that some of the earliest events contributing to neurodegeneration may occur upstream of classical proteinopathies, underscoring the urgency of identifying molecular pathways that link age-associated genomic instability to chronic neuroinflammation. Among these, DNA sensing through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis has emerged as an important mechanism by which nuclear and mitochondrial stress may promote innate immune activation. In aging and Alzheimer's disease (AD), oxidative stress, impaired DNA repair, and mitochondrial dysfunction can lead to the accumulation of cytosolic DNA and activation of cGAS-STING, contributing to sustained inflammatory signaling, cellular senescence, and synaptic dysfunction. In this review, we synthesize emerging mechanistic and translational insights linking cGAS-STING to genomic instability and neuroinflammation. We highlight the expanding roles of this pathway beyond classical immunity, including its influence on autophagy, cellular senescence, microglial activation, and neurovascular integrity as well as its interactions with key pathological features of age-related neurodegenerative disorders, particularly AD. Finally, we highlight recent advances in pharmacological and genetic modulation of cGAS-STING that support its potential as a therapeutic target for age-related neurodegenerative diseases. By reframing neurodegeneration through the lens of DNA sensing, this review provides an updated perspective on the potential role of cGAS-STING in age-related neurodegenerative diseases.},
}

Humans
Animals
*Neurodegenerative Diseases/metabolism/therapy/genetics/pathology
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
STING Protein
*Membrane Proteins/metabolism
*Aging/pathology/metabolism/genetics
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
*Neuroinflammatory Diseases/metabolism/genetics/therapy
*DNA/metabolism
Inflammation

@article {pmid42471447,
year = {2026},
author = {Zhu, Y and Brown, DC and Chen, C and Singh, RK and Bekena, S and Ances, BM and Lenze, EJ and Carr, DB and Trani, JF and Babulal, GM},
title = {Tau pathology and depression interact to accelerate driving decline in cognitively normal older adults.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42471447},
issn = {1476-5578},
support = {R01AG056466//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067428//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Driving is a complex task that can be compromised by mood disorders and neurodegenerative conditions. Major depressive disorder (MDD) and Alzheimer's disease (AD) increase in prevalence with older age. Preclinical AD, identified through protein biomarkers, is strongly associated with an increased risk of developing AD. This study tracked the daily driving behaviors of older adults over an average period of 54 months and found participants with MDD and Positron Emission Tomography (PET) biomarker tau had a faster increase in risky driving behaviors, such as hard braking, and a slower decline in randomness of driving patterns, compared to healthy controls. Notably, participants with MDD were more likely to exhibit PET tau positivity than PET amyloid positivity, suggesting a potential interaction between MDD and tau pathology. These findings highlight the importance of monitoring older drivers for emerging functional vulnerability associated with mood disorders and neurodegeneration at an early stage.},
}

@article {pmid42471578,
year = {2026},
author = {Li, Z and Zeng, C and Ge, S},
title = {Bayesian brain edge-based connectivity (BBeC): a Bayesian model for brain edge-based connectivity inference.},
journal = {BMC bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12859-026-06549-2},
pmid = {42471578},
issn = {1471-2105},
abstract = {BACKGROUND: Brain connectivity analysis based on magnetic resonance imaging is crucial for understanding neurological mechanisms. However, edge-based connectivity inference faces significant challenges, particularly the curse of dimensionality when estimating high-dimensional covariance matrices. Existing methods often struggle to account for the unknown latent topological structure among brain edges, leading to inaccurate parameter estimation and unstable inference.

METHODS: To address these issues, this study proposes a Bayesian hierarchical model based on a finite-dimensional Dirichlet distribution. Unlike non-parametric approaches, our method utilizes a finite-dimensional Dirichlet distribution to model the latent topological structure of brain networks, ensuring constant parameter dimensionality and improving algorithmic stability. We reformulate the covariance matrix structure to guarantee positive definiteness and employ a Metropolis-Hastings algorithm to simultaneously infer network topology and correlation parameters. Furthermore, to alleviate the computational burden of parameter inference in large-scale networks, we optimized the calculation process of the likelihood function to reduce the algorithm's time complexity. Our implementation is available at https://github.com/mimi6501/BBeC.

RESULTS: Simulations validated the recovery of both network topology and correlation parameters across various settings. Furthermore, we quantitatively compared the proposed framework with the Graphical Lasso and a Dirichlet process-based non-parametric Bayesian model. Experimental results show our model offers flexible parameter tuning while outperforming baselines in estimation accuracy and convergence stability. Sensitivity analysis reveals the diagonal adjustment parameter λ has minimal impact on model accuracy, and parameter sampling order has negligible impact on final inference. When applied to the Alzheimer's Disease Neuroimaging Initiative dataset, the model successfully identified structural subnetworks. The identified clusters were not only validated by composite anatomical metrics but also consistent with established findings in the literature, collectively demonstrating the model's reliability. The estimated covariance matrix also revealed that intragroup connection strength is stronger than intergroup connection strength.

CONCLUSIONS: This study introduces a Bayesian framework for inferring brain network topology and high-dimensional covariance structures. The model configuration effectively reduces parameter dimensionality while ensuring the positive definiteness of covariance matrices. As a result, it offers an efficient and reliable tool for investigating intrinsic brain connectivity in large-scale neuroimaging studies.},
}

@article {pmid42471701,
year = {2026},
author = {Marshall, CR and Moser, FA and Scott, CF and Ventura-Antunes, L and Romero-Fernandez, W and Migas, ŁG and Tideman, LEM and Colley, ME and Dufresne, M and Schrag, MS and Van de Plas, R and Spraggins, JM},
title = {Multimodal molecular mapping of the vasculature in human cortex reveals lipid markers of cerebral amyloid angiopathy.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02361-4},
pmid = {42471701},
issn = {2051-5960},
abstract = {Cerebral amyloid angiopathy (CAA) commonly co-occurs with Alzheimer's disease (AD), yet the molecular changes that accompany vascular [Formula: see text]-amyloid deposition in human tissue remain incompletely defined. Herein, we use a novel imaging approach that combines matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS) with immunofluorescence microscopy on the same sections of postmortem human frontal cortex to map the lipid microenvironment of leptomeningeal vasculature in cases with and without CAA. Autofluorescence-guided regions-of-interest were imaged by IMS in both negative and positive ion modes and registered to post-IMS-acquired microscopy images. Immunofluorescence microscopy using markers for collagen IV, [Formula: see text]-smooth muscle actin ([Formula: see text]SMA), and thiazine red enabled automated segmentation of total, amyloid-positive, and amyloid-negative vasculature regions. A CAA index, the ratio of amyloid-positive area to total vasculature area in a region imaged by IMS, was used to define vasculature and classify each case into having CAA, or CAA-present, and not having CAA, or CAA-absent. An interpretable machine learning approach (XGBoost models with Shapley additive explanations for interpretation) was trained on pixel-level spectra and identified lipid signatures of vascular identity shared across groups as well as class-specific marker candidates that distinguished CAA-present from CAA-absent vasculature. CAA-absent vessels were characterized by higher contributions from phosphatidylserines (e.g., long-chain polyunsaturated PS species). Univariate differences were inconsistent between the two groups, but multivariate models in negative mode yielded stable discriminatory features. These results define spatial lipid correlates of vascular amyloid pathology in the human brain and establish a multimodal framework for mechanistically linking lipid metabolism, vascular integrity, and CAA in AD.},
}

@article {pmid42471719,
year = {2026},
author = {Yamada, K and Ishida, K and Sakamoto, A and Shimada, H and Watanabe, M and Shimojo, M and Igarashi, H and Iwatsubo, T},
title = {AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00977-7},
pmid = {42471719},
issn = {1750-1326},
support = {JP23wm0625001//AMED/ ; 23H0279//Japan Society for the Promotion of Science/ ; 25K10766, 20K21568, 18H02762//Japan Society for the Promotion of Science/ ; 2023-23012//Niigata University/ ; },
abstract = {BACKGROUND: The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.

METHODS: Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.

RESULTS: PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.

CONCLUSIONS: Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.},
}

@article {pmid42471753,
year = {2026},
author = {Travison, TG and Davis-Plourde, K and Goldfeld, KS and Li, F and Lou, Y and Monin, JK and Taljaard, M and Turner, J and Vranceanu, AM and Allore, HG},
title = {The design of embedded pragmatic clinical trials: methodological developments and statistical lessons learned from the first cycle of the NIA IMPACT collaboratory.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71660},
pmid = {42471753},
issn = {1552-5279},
support = {U54AG063546/NH/NIH HHS/United States ; },
mesh = {Humans ; *Pragmatic Clinical Trials as Topic/methods ; *Research Design ; United States ; National Institute on Aging (U.S.) ; *Alzheimer Disease/therapy ; },
abstract = {INTRODUCTION: The National Institute on Aging-funded IMbedded Pragmatic Alzheimer's disease and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory was established to build capacity for conducting embedded pragmatic clinical trials (ePCTs) within healthcare systems for people living with dementia and their care partners. Here we present methodology and describe lessons learned from the first five years of IMPACT's Design and Statistics Core (DSC).

METHODS: The DSC assembled a multidisciplinary team focused on advancing the design, analysis, and implementation of ePCTs.

RESULTS: The DSC developed and disseminated methods for design and sample size of cluster randomized designs with complex correlation structures; guidance for pilot ePCTs; approaches to patient-care partner ePCTs; approaches to testing health-equity-relevant hypotheses; and guidance for training quantitative and clinical scientists developing ePCTs.

DISCUSSION: Key gaps remain in applying dyadic designs and when studying heterogeneity of treatment effects, which will be major priorities for the next funding cycle.},
}

Humans
*Pragmatic Clinical Trials as Topic/methods
*Research Design
United States
National Institute on Aging (U.S.)
*Alzheimer Disease/therapy

@article {pmid42471754,
year = {2026},
author = {Xia, CA and Salarian, M and Gartshore, CJ and Scaglione, A and Hayes, T and Liu, S and Tsai, HM and Echavarren, J and Cid, JM and Matzeu, A and Szardenings, AK},
title = {Development and characterization of a novel TDP-43 positron emission tomography tracer: [[18]F]JNJ-TDP43-1.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71675},
pmid = {42471754},
issn = {1552-5279},
support = {//Johnson & Johnson/ ; },
mesh = {Animals ; *Positron-Emission Tomography/methods ; *DNA-Binding Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Rats ; Mice ; Humans ; Male ; Disease Models, Animal ; TDP-43 Proteinopathies/diagnostic imaging ; *Radiopharmaceuticals/pharmacokinetics ; Fluorine Radioisotopes ; },
abstract = {INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.

METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.

RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.

DISCUSSION: [[18]F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.},
}

Animals
*Positron-Emission Tomography/methods
*DNA-Binding Proteins/metabolism
*Brain/diagnostic imaging/metabolism
Rats
Mice
Humans
Male
Disease Models, Animal
TDP-43 Proteinopathies/diagnostic imaging
*Radiopharmaceuticals/pharmacokinetics
Fluorine Radioisotopes

@article {pmid42472451,
year = {2026},
author = {Docteur, NG and Huston, HGP and Krupa, AA and Callahan, BL},
title = {A systematic review of neuroimaging studies of adults aged 35 and older with clinical, symptomatic and genetic risk for attention-deficit/hyperactivity disorder.},
journal = {Dialogues in clinical neuroscience},
volume = {28},
number = {1},
pages = {259-276},
doi = {10.1080/19585969.2026.2700984},
pmid = {42472451},
issn = {1958-5969},
mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity/genetics/diagnostic imaging ; *Neuroimaging/methods ; Adult ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Aged ; *Genetic Predisposition to Disease ; Aging ; },
abstract = {Attention-deficit/hyperactivity disorder (ADHD) affects 2.5% of adults and is associated with cognitive decline and dementia. The neurobiological mechanisms contributing to adverse outcomes in ADHD are poorly understood. ADHD-related brain alterations may persist into later life and interact with ageing-related processes, potentially increasing susceptibility to neuropathology. This preregistered systematic review synthesised neuroimaging findings in adults aged 35 years and older with clinical, symptomatic, or genetic risk for ADHD, and summarised cognitive and clinical correlates. A search of five databases produced 13 included studies. Risk of bias was assessed using the Newcastle-Ottawa Scale. Most studies (11/13) had low risk of bias. Compared to controls, ADHD groups exhibited alterations in fronto-striatal, fronto-parietal, and limbic systems implicated in executive control and attention. Middle-aged adults with clinical ADHD showed more widespread cortical structural differences, whereas older adults demonstrated abnormalities primarily in frontal regions, possibly reflecting attenuation of differences through ageing. Two functional studies in those with clinical ADHD reported frontal hypoactivation alongside parietal hyperactivation, consistent with compensatory recruitment. Among undiagnosed samples, there were interactions between genetic risk for ADHD and Alzheimer's disease-related pathology affecting brain and cognitive outcomes. Overall, ADHD-associated neurobiological alterations appear to persist into older age. Longitudinal investigations are needed to clarify these relationships.},
}

Humans
*Attention Deficit Disorder with Hyperactivity/genetics/diagnostic imaging
*Neuroimaging/methods
Adult
*Brain/diagnostic imaging/pathology
Middle Aged
Aged
*Genetic Predisposition to Disease
Aging

@article {pmid42472492,
year = {2026},
author = {Damirchi, EK and Barani, A and Hamidi, SM and Ebrahimzadeh, MA},
title = {Melatonin hybrids as multifunctional therapeutic agents: A comprehensive review.},
journal = {European journal of medicinal chemistry},
volume = {318},
number = {},
pages = {119156},
doi = {10.1016/j.ejmech.2026.119156},
pmid = {42472492},
issn = {1768-3254},
abstract = {Compound hybridization has received attention due to its potential to address several diseases, including neurological disorders, cancer, infectious diseases, and others. Melatonin is a hormone with antioxidant, anti-inflammatory, and neuroprotective effects. Some drug design research has focused on synthesizing hybrid molecules in which melatonin is hybridized with other pharmacologically active compounds to increase therapeutic efficacy and reduce toxicity. These hybrids demonstrate improved binding affinity, selectivity, and pharmacokinetic characteristics compared to their separate components. This review shows the pharmacological assessment and therapeutic potential of diverse melatonin-based hybrids. These hybrids have exhibited significant efficacy in the treatment of complex diseases such as Alzheimer's disease, cancer, and inflammatory disorders. Hybridization leads to the synthesis of a new generation of structures that represent a promising therapeutic approach for disease treatment.},
}

@article {pmid42472573,
year = {2026},
author = {Yanagisawa, D and Ohgita, T and Kawashima, H and Yoshikawa, H and Saito, H and Tooyama, I and Takata, K},
title = {Neurotheranostics in Alzheimer's Disease: Current concepts and experimental strategies.},
journal = {Pharmacology & therapeutics},
volume = {},
number = {},
pages = {109084},
doi = {10.1016/j.pharmthera.2026.109084},
pmid = {42472573},
issn = {1879-016X},
abstract = {In Alzheimer's disease (AD), pathological changes start decades before symptoms appear; by the time cognitive issues are noticeable, widespread neuronal and glial dysfunction and significant neuronal loss have already occurred. Recent regulatory approvals of monoclonal antibodies targeting aggregated amyloid-β (Aβ) species, including oligomers and fibrils, represent a major advance in disease-modifying therapy. However, therapeutic efficacy is strongly dependent on intervention at the earliest pathological stages, underscoring the importance of early diagnosis and treatment. Early diagnosis requires biomarkers that accurately reflect the initiation and progression of AD pathology as well as the development of methodologies capable of capturing these pathological states in vivo. Effective early treatment necessitates strategies that suppress the formation, activation, or toxicity of molecules that trigger downstream neurodegenerative cascades, thereby interrupting disease progression at its source. In parallel, advances in targeted brain delivery technologies are essential to enable sensitive detection and effective therapeutic modulation of central nervous system targets. Neurotheranostics is an integrated conceptual framework that aims to achieve early diagnosis and targeted therapy either simultaneously or in a coordinated manner using shared molecular targets and biological readouts. By unifying molecular imaging, biomarker analysis, and disease-modifying intervention, neurotheranostics aims to overcome the limitations of conventional diagnostic and therapeutic paradigms in neurodegenerative disorders, including AD. In this review, we summarize recent advances in neurotheranostic approaches for AD and highlight emerging molecular probes, low-molecular-weight compounds, and delivery technologies, including contributions from our studies.},
}

@article {pmid42472607,
year = {2026},
author = {Ren, K and Lu, D and Wang, L and Yang, J and Zhang, H},
title = {Phytochemicals modulating HSF-1-associated pathways: A systematic review of longevity-extending mechanisms in Caenorhabditis elegans.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103265},
doi = {10.1016/j.arr.2026.103265},
pmid = {42472607},
issn = {1872-9649},
abstract = {Aging is characterized by progressive loss of proteostasis, and heat shock transcription factor 1 (HSF1) is the master regulator of the cellular stress response, making it an attractive pharmacological target for interventions aimed at extending lifespan. However, a systematic synthesis of phytochemicals that modulate HSF1 has been lacking. Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science, Scopus, Embase, and the Cochrane Library from March 2016 to March 2026, identifying 42 original studies that provided clear evidence of HSF-1 activation (nuclear translocation, phosphorylation, or transcriptional activity), together with downstream stress-response markers such as upregulation of heat shock protein genes by phytochemicals with lifespan-extending or health span-improving outcomes. All 42 studies exclusively used Caenorhabditis elegans as the model organism, and the phytochemicals were classified into six categories: plant extracts/mixtures (11 studies), flavonoids (9 studies), carbohydrates/sugars (8 studies), terpenoids (7 studies), phenolic compounds (4 studies), and alkaloids (3 studies). Across all studies, these phytochemicals extended lifespan, enhanced resistance to thermal and oxidative stress, and delayed neurodegenerative pathology (Alzheimer's, Parkinson's, and Huntington's disease models) through activation of HSF-1 and its cooperating transcription factors DAF-16/FOXO and SKN-1/Nrf2. While sharing a common dependency on HSF-1, different classes engaged additional signaling pathways including autophagy, mitochondrial unfolded protein response, insulin/IGF-1 signaling, and lipid metabolism, reflecting class-specific mechanistic signatures. This systematic review provides the first comprehensive evidence base for developing HSF-1-associated longevity strategies using phytochemicals; however, all available evidence is limited to C. elegans models, and urgent validation in mammals and clinical translation are needed before these findings can be applied to human aging.},
}

@article {pmid42472674,
year = {2026},
author = {Jancev, M and Eliasson, B and Biessels, GJ and DeVries, JH and Serné, EH and Visseren, FLJ and Rawshani, A and Rawshani, A and Cukierman-Yaffe, T and Sattar, N and Gerstein, HC and van Sloten, TT},
title = {Age of Type 1 Diabetes Onset and Dementia Risk: A Swedish Nationwide, Register-Based Cohort Study.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.71123},
pmid = {42472674},
issn = {1463-1326},
support = {2021.81.004//Diabetes Fonds/ ; 2024.35.001//Diabetes Fonds/ ; //European Foundation for the Study of Diabetes/ ; },
abstract = {AIMS: Individuals with Type 1 diabetes are at a higher risk of dementia compared to individuals without diabetes. Younger age at Type 1 diabetes onset has been linked to an increased risk of cardiovascular disease and higher mortality. This study aimed to determine whether younger age at Type 1 diabetes onset was also associated with all-cause dementia.

MATERIALS AND METHODS: This nationwide prospective cohort study used data from individuals with Type 1 diabetes from the Swedish National Diabetes Register. All-cause dementia, including Alzheimer's disease, vascular dementia and non-Alzheimer's-non-vascular dementia, was prospectively ascertained as ICD-10 codes. Age at onset was stratified into < 10 years, 10-17 years and 18-30 years. The 18-30 years group was used as the reference group for all analyses. Cox regression modelling with age as the time-axis, from age at diabetes onset, was deployed to investigate dementia risk.

RESULTS: Of 43 440 included individuals (mean age 33.0 (SD 14.0) years; 44% female), Type 1 diabetes developed before age 10 in 11 776 individuals (27%), between age 10 and 17 in 15 846 (36%) and between 18 and 30 (reference group) in 15 818 (36%). During a median 29.3 [17.6-43.7] years follow-up, 530 (1.2%) developed all-cause dementia. Compared to the reference group, all-cause dementia risk was increased in individuals aged < 10 years at onset (HR 1.37 [95% CI 1.08-1.73]), but not in individuals aged 10-17 years at onset (HR 1.04 [95% CI 0.85-1.26]) (fully adjusted model).

CONCLUSIONS: Type 1 diabetes onset before age 10 is associated with an increased risk of all-cause dementia compared to onset between ages 18 and 30.},
}

@article {pmid42472714,
year = {2026},
author = {Khan, M and Khan, T and Tariq, A},
title = {From biomarker expansion to equitable implementation in mild cognitive impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42472714},
issn = {1590-3478},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; },
abstract = {The expanding role of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease diagnosis represents a major shift toward biologically driven dementia care. In response to the article by Poli et al., we discuss important considerations regarding the broader implementation of CSF biomarker testing in patients with mild cognitive impairment (MCI), particularly in the era of emerging anti-amyloid therapies. While biomarker-guided approaches may improve identification of atypical or non-amnestic Alzheimer's disease presentations, widespread adoption remains limited by disparities in diagnostic infrastructure, standardized testing availability, expertise in lumbar puncture procedures, and longitudinal monitoring capacity across healthcare systems. In addition, expanded eligibility for anti-amyloid therapies introduces challenges related to patient selection, treatment accessibility, and equitable allocation of healthcare resources. Ethical considerations surrounding biomarker disclosure and prognostic uncertainty also warrant continued discussion. We emphasize the need for future studies evaluating accessibility, cost-effectiveness, and standardized patient selection frameworks to support equitable integration of biomarker-guided dementia care into routine neurological practice.},
}

Humans
*Cognitive Dysfunction/diagnosis/cerebrospinal fluid
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/diagnosis/cerebrospinal fluid

@article {pmid42472726,
year = {2026},
author = {Chen, Y and Li, Z and Luo, S and Li, Z and Jiang, Y and Chen, K and Wang, J and Zhang, Z and , },
title = {Apolipoprotein E ε4 and type 2 diabetes cooperatively accelerate amyloid beta and tau neurodegeneration.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42472726},
issn = {1619-7089},
support = {2023YFC3605400//National Key Research and Development Program of China/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; Beijing Nova Program//Beijing Nova Program/ ; },
abstract = {PURPOSE: Both type 2 diabetes mellitus (T2DM) and Apolipoprotein E (APOE) ɛ4 allele are recognized risk factors for Alzheimer's disease (AD). However, the impact of the APOE ɛ4 allele on the accumulation of AD-related neuropathology in patients with T2DM remains unclear.

METHODS: We analyzed amyloid beta (Aβ) and tau deposition patterns via positron emission tomography (PET) imaging in 163 T2DM patients (64 ɛ4 carriers) and 1654 normal glucose metabolism subjects (687 ɛ4 carriers).

RESULTS: Findings reveal that Aβ deposition has a broader range of influence in diabetics carrying the ɛ4 allele, especially in the deep cortical areas. In terms of tau accumulation, diabetic carriers exhibit progression to the posterior and frontal cortices. Specifically, a greater Aβ PET burden is associated with higher levels of plasma Aβ42 and lower levels of cerebrospinal fluid (CSF) Aβ42, Aβ42/40, and Aβ42/38. A significant positive correlation was observed between tau PET burden and CSF tau and phosphorylated tau (pTau), and plasma pTau181. Importantly, higher Aβ and tau standardized uptake value ratio were associated with poorer memory performance and lower scores on the Montreal Cognitive Assessment.

CONCLUSIONS: These findings highlight the allele's region-specific synergism with T2DM in driving AD-related pathology, potentially informing the development of a neuroimaging-based grading system to evaluate diabetic neuropathology severity and progression dynamics.},
}

@article {pmid42472733,
year = {2026},
author = {Kwon, HS and Moon, SY and Hwang, M and Kim, HJ and Lee, SM and Jung, NY and Jang, H and Baek, JM and Kim, MJ and Han, MH and Zetterberg, H and Blennow, K and Apostolova, LG and Koh, SH and Kim, EJ and , },
title = {Blood-based multimodal biomarker models for differentiating early-onset Alzheimer's disease from frontotemporal dementia: a longitudinal study of early-onset dementia and family members (LEAF) study.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42472733},
issn = {1432-1459},
support = {2021-ER1004-01//Korea National Institute of Health research project/ ; 2024-ER1001-00//Korea National Institute of Health research project/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; Female ; *tau Proteins/blood ; Male ; *Frontotemporal Dementia/blood/diagnosis ; Biomarkers/blood ; *Glial Fibrillary Acidic Protein/blood ; Longitudinal Studies ; Middle Aged ; Diagnosis, Differential ; *Neurofilament Proteins/blood ; Age of Onset ; Aged ; Adult ; },
abstract = {BACKGROUND: Plasma phosphorylated tau (p-tau) biomarkers have improved the diagnosis of Alzheimer's disease (AD), but evidence in early-onset populations remains limited. We evaluated the diagnostic performance of plasma p-tau217 and p-tau181 levels in patients with early-onset AD (EOAD) and early-onset frontotemporal dementia (EOFTD).

METHODS: We analyzed 185 patients (EOAD = 150, EOFTD = 35) aged ≤ 65 years from the LEAF study (2021-2023). Plasma p-tau217, p-tau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) levels were measured by immunoassays.

RESULTS: Both plasma p-tau217 (AUC = 0.831) and p-tau181 (AUC = 0.862) levels demonstrated high discriminative performance, with no significant difference between the two p-tau isoforms. P-tau levels were higher in patients with EOAD, whereas NfL levels were higher in EOFTD and were elevated in those with EOAD participants with severe hippocampal atrophy. Adding NfL, GFAP, and APOE ε4 status further improved the discriminative accuracy for differentiating EOAD from EOFTD.

CONCLUSIONS: Plasma p-tau217 and p-tau181 are effective biomarkers for distinguishing biologically defined EOAD from EOFTD. Incorporating NfL, GFAP, and APOE ε4 status further enhances diagnostic accuracy.},
}

Humans
*Alzheimer Disease/blood/diagnosis
Female
*tau Proteins/blood
Male
*Frontotemporal Dementia/blood/diagnosis
Biomarkers/blood
*Glial Fibrillary Acidic Protein/blood
Longitudinal Studies
Middle Aged
Diagnosis, Differential
*Neurofilament Proteins/blood
Age of Onset
Aged
Adult

@article {pmid42473039,
year = {2026},
author = {Koppisetti, RK and Barthélemy, NR and Horie, K and Ly, CV and Roberts, KF and Koutarapu, S and Perrin, RJ and Franklin, EE and Pedicone, C and Orrick, J and Melendez, J and Miller, TM and Sato, C and Ghoshal, N and Goate, AM and Karch, CM and Bateman, RJ and Mukherjee, S},
title = {Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78300},
pmid = {42473039},
issn = {1531-8249},
support = {UL1TR004419/TR/NCATS NIH HHS/United States ; 1U54NS123746-01/NS/NINDS NIH HHS/United States ; R01NS095773/NS/NINDS NIH HHS/United States ; R01NS110890/NS/NINDS NIH HHS/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; P41GM103422/GM/NIGMS NIH HHS/United States ; P01AG026276/AG/NIA NIH HHS/United States ; P01AG03991/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance.

METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment.

RESULTS: Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology.

INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026.},
}

@article {pmid42473091,
year = {2026},
author = {Jessup, RE and Ehrlich, RS and Teppang, KL and Dasgupta, S and Sigurdson, CJ and Yang, J},
title = {Development of Aryl Cyano Amides for Fluorescence Discrimination of Tau and Amyloid Beta Deposits in Tissue.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00316},
pmid = {42473091},
issn = {1948-7193},
abstract = {The accumulation of amyloid aggregates such as amyloid beta (Aβ) and tau deposits in the brain is a hallmark of many neurodegenerative diseases including Alzheimer's disease. Recent advances in optical imaging have shown that fluorescent probes can detect amyloids in living patients, potentially aiding in diagnosis. Here, we investigate structural modifications of amyloid-targeting Aryl Cyano Amide-based fluorophores aimed at enhancing their ability to discriminate between different amyloid aggregates, such as Aβ and tau. We identify two structural parameters that synergistically enable increased sensitivity to environmental polarity, which makes it possible to discriminate these amyloids through inspection of the color of fluorescence emission. This colorimetric discrimination can provide detailed information on amyloid composition and could expand the use of fluorescence imaging for diagnosis and monitoring of neurodegenerative diseases.},
}

@article {pmid42473207,
year = {2026},
author = {Dutta, S and Singh, MK and Dehury, B},
title = {Unlocking the Dynamics of Human SPPL2a: First Atomistic Characterization of an Alzheimer's-Linked Intramembrane Protease.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.6c01556},
pmid = {42473207},
issn = {1549-960X},
abstract = {The failure of γ-secretase inhibitors in clinical trials of Alzheimer's disease (AD) has shifted the focus toward more selective targets, specifically SPPL2a (signal peptide-peptidase-like 2a), which is emerging as a critical therapeutic target in AD because of its role in processing TMEM106B. While recent cryo-EM structures have provided essential static snapshots, the dynamic mechanisms governing substrate entry and inhibitor recognition remain unresolved. Here, we present the first microsecond-time scale, all-atom molecular dynamics characterization of human SPPL2a in its apo and inhibitor-bound states, alongside a comparative analysis of the γ-secretase catalytic subunit, PS1. Our simulations reveal that SPPL2a is highly dynamic and undergoes an inhibitor-induced disorder-to-order transition in the TM6a region, where the helicity increases from 10% to 77%. We characterized the lateral gate dynamics of TM2, revealing that inhibitor binding fundamentally remodels the interhelical contact network and quenches conformational sampling. Moreover, we identified a unique inhibitor-stabilized lipid hotspot at Trp189 and demonstrated that SPPL2a utilizes a distributed polar network for binding energy, in contrast to the concentrated aspartate-driven affinity of PS1. These findings provide a quantitative atomistic blueprint of SPPL2a dynamics, offering a structural basis that can be exploited for the design of selectivity-guided therapeutics to bypass the clinical failures associated with nonspecific intramembrane protease inhibition.},
}

@article {pmid42473218,
year = {2026},
author = {Keskin, A and Mogulkoc, R and Baltaci, AK},
title = {Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575484348260702044851},
pmid = {42473218},
issn = {1875-5607},
abstract = {The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).},
}

@article {pmid42473227,
year = {2026},
author = {Rodrigues, JFR and Rodrigues, LP and Rodrigues, FCP and Cavalcante, LL and Payão, SLM and Tavares, AR and Forlenza, OV and de Godoy, MF and Filho, GMA},
title = {Cardiovascular Comorbidities with Alzheimer's Disease: A Systematic Review and Meta-analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050468989260629094050},
pmid = {42473227},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease stands as the most prevalent form of dementia, characterized by a progressive decline in cognitive function and memory. Numerous risk factors have been linked to its development, creating a complex interplay of influences. In this study, we aim to delve into the relationship between cardiovascular disease and Alzheimer's disease, exploring how conditions affecting heart health may impact the onset and progression of this debilitating neurological disorder. Through this research, we could find potential connections that inform prevention strategies and therapeutic approaches.

MATERIALS AND METHODS: We adopted the PRISMA guidelines and defined the PECOS framework as follows: Population (P) = individuals; exposure (E) = cardiovascular disease; comparison (C) = without cardiovascular disease; outcome (O) = Alzheimer's disease; and study design(S) = all kinds of studies with an association between cardiovascular disease and Alzheimer's disease without time limits. A meta-analysis was conducted using case-control, cohort, and genetic studies to estimate Odds Ratios (ORs) or Hazard Ratios (HRs).

RESULTS: The pooling of data in meta-analysis demonstrated that a person with any Cardiovascular Disease (CVD), Heart Failure (HF), Coronary Artery Disease (CAD), Atrial Fibrillation (AF), Hypertension (HTN), and Myocardial Infarction (MI) had more risk of developing Alzheimer's disease [CVD: HR = 1.30 (CI: 1.27-1.33) / HF: HR = 1.63 (CI: 1.37-1.94) / CAD: HR = 1.43 (CI: 1.40-1.46) / AF: HR = 1.38 (CI: 1.34-1.42) / HTN: HR = 1.22 (CI: 1,10-1.35) / MI: HR = 1.07 (CI: 1,01-1.13)]. Cross-sectional studies demonstrated an association between cardiovascular diseases and Alzheimer's disease [OR = 1.29 (CI: 1.23-1.35)]. Mendelian randomization meta-analysis did not demonstrate a causal relation between cardiovascular disease and Alzheimer's disease [AF: OR = 1.03 (CI: 1.00-1.01) / HF: OR = 1.00 (CI: 0,79-1.36)]. A Mendelian randomization meta-analysis demonstrated that a person with AD had a higher risk of developing myocardial infarction [OR = 1.07 (CI: 1.03-1.10)].

DISCUSSION: This review examines the connection between AD and CVD, noting that HF increases the risk of developing AD with a hazard ratio of 1.63. It suggests that altered brain perfusion and hypoxia appear to be one important neurodegenerative factor. Some genetic changes in individuals with CVD made them more vulnerable to AD. Effective prevention and treatment of CVD can help reduce the risk of AD.

CONCLUSION: HF, AF, and CAD were the CVDs with the highest risk of developing AD. The results suggest that changes in cerebral blood perfusion are a principal neuropathological event that leads to genetic alterations that end in AD.},
}

@article {pmid42473272,
year = {2026},
author = {Kouchache, T and Chan, T and Sun, S and Liu, L and Delva, A and Gan-Or, Z and Rosa-Neto, P and Gagnon, JF and Dagher, A and Postuma, RB and Sharp, M},
title = {Association Between Plasma Phosphorylated Tau-217 and Cognition in Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70400},
pmid = {42473272},
issn = {1531-8257},
support = {N/A//Fonds de Recherche du Québec - Santé/ ; N/A//Healthy Brains for Healthy Lives/ Canada First Research Excellence Fund/ ; N/A//Parkinson Canada/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) co-pathology contributes to dementia in PD, but its role in earlier cognitive impairment remains uncertain.

OBJECTIVE: To determine if p-tau217, a biomarker of early AD, is associated with cognitive impairment in PD.

METHODS: Plasma p-tau217 levels in 167 PD patients without dementia and 63 controls were related to performance on standard neuropsychological testing, and to cognitive impairment as defined by a MoCA score <26 and by self-report. Plasma GFAP, NfL and APOE ε4 carrier status were also examined.

RESULTS: No significant differences in p-tau217, GFAP and NfL level were observed between groups (pFDR > 0.08). Higher p-tau217 was associated with worse visuospatial function and greater self-reported cognitive impairment, but these associations did not survive correction (pFDR > 0.08). There was no association with cognitive impairment (pFDR > 0.08).

CONCLUSION: These results suggest that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid42473545,
year = {2026},
author = {Gabriel, V and Chabran, E and Sourty, M and Cretin, B and Philippi, N and Muller, C and Anthony, P and Demuynck, C and de Sousa, PL and Botzung, A and Sanna, L and Bousiges, O and Blanc, F},
title = {Cerebrospinal fluid α-synuclein and Aβ42 link with default mode and salience networks connectivity in dementia with Lewy bodies.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70266},
pmid = {42473545},
issn = {2352-8737},
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are neurocognitive disorders characterized by distinct but often overlapping pathological processes. These include α-synuclein, amyloid-beta 42 (Aβ42), and tau protein aggregation. While cerebrospinal fluid (CSF) biomarkers provide in vivo insight into these pathologies, their relationship with large-scale brain network dysfunction remains poorly understood. This study aimed to investigate the associations between CSF biomarker concentrations and resting-state functional connectivity in patients with DLB, AD, and mixed AD/DLB.

METHODS: Sixty-nine DLB patients, 17 AD patients, and 24 patients with mixed AD/DLB underwent clinical and neuropsychological evaluations, lumbar puncture for CSF biomarker analysis (total α-synuclein, Aβ42, pTau181, and tTau), and resting-state functional MRI. Patients were stratified by disease stage for subgroup analyses. Besides CSF total α-synuclein levels, α-synuclein seeding activity was assessed using real-time quaking-induced conversion (RT-QuIC) assays. ROI-to-ROI analyses were conducted using the CONN toolbox to explore associations between CSF biomarker levels and functional connectivity within and between major brain networks.

RESULTS: In DLB patients, lower CSF α-synuclein levels correlated with increased connectivity within the default mode network (DMN) (p FDR < 0.05). In dementia-stage DLB (d-DLB), lower Aβ42 levels correlated with reduced connectivity within the salience network (SN) (p FDR < 0.05). In AD, higher tTau levels correlated with decreased connectivity between the DMN and the SN (p FDR < 0.05). No significant associations were observed for CSF pTau181 or any RT-QuIC metric in any group, and the mixed AD/DLB group showed no biomarker-connectivity correlations at all.

DISCUSSION: We identified distinct patterns of DMN and SN connectivity changes associated with CSF α-synuclein and Aβ42 levels, respectively. These findings reflect key functional disruptions that may contribute to core clinical symptoms. They underscore the value of combining CSF biomarkers with functional MRI to elucidate DLB pathophysiology.},
}

@article {pmid42473637,
year = {2026},
author = {Kashiwagi-Hakozaki, M and Uchigami, H and Naka, Y and Kokawa, A and Mano, T and Cho, J and Yamada, K and Miyashita, A and Hara, N and Ikeuchi, T and Serrano-Pozo, A and Frosch, MP and Hyman, BT and Toda, T and Fukayama, M and Ushiku, T and Wakabayashi, T and Iwatsubo, T and Hashimoto, T},
title = {Soluble high-molecular-weight amyloid-β species derived from amyloid-β-laden brains induce cerebral β-amyloidosis.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag188},
pmid = {42473637},
issn = {2632-1297},
abstract = {Spatiotemporal spreading of amyloid-β peptide deposition as senile plaques is a key pathogenic process in the brains of patients with Alzheimer's disease; however, the molecular properties of amyloid-β strains that initiate the spreading of amyloid-β peptide as aggregation seeds in vivo remain poorly understood. In this study, we discovered that the intrahippocampal injection of soluble amyloid-β species with a molecular weight of >150 kDa isolated from the brains of plaque-laden amyloid-β precursor protein transgenic mice or patients with Alzheimer's disease using size-exclusion chromatography, dramatically accelerated β-amyloidosis in the transgenic mice brains. In contrast, intrahippocampal injection of soluble amyloid-β species with 50-70 kDa or 10-20 kDa never induced β-amyloidosis. Moreover, injection of the soluble amyloid-β species with >150 kDa into cerebrospinal fluid of young transgenic mice via the cisterna magna predominantly induced amyloid-β deposition within the wall of leptomeningeal arteries surrounding the brain, reminiscent of cerebral amyloid angiopathy. The seeding activity of the soluble high-molecular-weight amyloid-β was prevented by the immunodepletion of amyloid-β and abolished by formic acid denaturation, suggesting that these amyloid-β oligomers are crucial in inducing β-amyloidosis. Furthermore, we have shown that the soluble high-molecular-weight amyloid-β is present in the brains of patients with Alzheimer's disease and induced β-amyloidosis. These results indicate that the soluble high-molecular-weight amyloid-β oligomers may play an important role in the spatiotemporal spreading of amyloid-β deposition in Alzheimer's disease brains.},
}

@article {pmid42473871,
year = {2026},
author = {Guarnieri, B and Hoxhaj, D and Buracchi Torresi, F and Arnaldi, D and Bonanni, E and Carpi, M and Cremascoli, R and Liguori, C and Lombardi, G and Mainieri, G and Provini, F and Silvestri, R and Puligheddu, M and Tassoni, MM},
title = {A gradual and sustainable approach to diagnosing sleep and circadian disturbances in dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71654},
doi = {10.1002/alz.71654},
pmid = {42473871},
issn = {1552-5279},
mesh = {Humans ; *Sleep Wake Disorders/diagnosis/etiology ; *Dementia/complications ; *Chronobiology Disorders/diagnosis/etiology ; Circadian Rhythm/physiology ; Polysomnography ; Surveys and Questionnaires ; },
abstract = {Evidence linking sleep and circadian disruptions to the course of dementias, particularly Alzheimer's disease, has expanded. Such alterations are detectable from preclinical stages and parallel the disease progression. Assessing and managing sleep and circadian disturbances in patients with dementia remains challenging. New technologies are emerging, but their validation is still pending. We prepared a clinical review outlining a stepped-care, gradual, and sustainable approach aimed at achieving the most accurate possible diagnosis of different sleep disturbances. This review encompasses diagnostic methods ranging from questionnaires to instrumental assessments, progressing from simpler to more complex techniques including biological evaluations of circadian rhythm alterations. This work reflects a scientific consensus within the "Sleep" study group of the Italian Association for Dementia (SINdem), supported by certified sleep specialists. The document aims to support clinicians in adopting a tailored approach to the evaluation of sleep disturbances in dementia offering a dynamic framework balancing complexity and feasibility.},
}

Humans
*Sleep Wake Disorders/diagnosis/etiology
*Dementia/complications
*Chronobiology Disorders/diagnosis/etiology
Circadian Rhythm/physiology
Polysomnography
Surveys and Questionnaires

@article {pmid42473913,
year = {2026},
author = {Ay, U and Alaylioglu, M and Sahin, E and Oner, SSY and Iskan, G and Cakan, GCY and Kizilates-Evin, G and Hari, E and Kurt, E and Dursun, E and Bilgic, B and Hanagasi, H and Gurvit, H and Demiralp, T and Gezen-Ak, D and Samanci, B},
title = {Stage-Dependent β-Synuclein Links MRI and Cognitive Decline in Alzheimer's Disease.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70494},
pmid = {42473913},
issn = {2328-9503},
abstract = {OBJECTIVE: Synaptic degeneration drives cognitive decline in Alzheimer's disease (AD), but synaptic biomarkers are scarce. Brain-enriched β-synuclein emerged as a synaptic damage marker. We investigated its diagnostic, prognostic, and structural correlates across the AD continuum.

METHODS: In a tertiary-center cohort (n = 306), CSF β-synuclein was measured. Cognitively unimpaired (CU), AD-MCI, AD dementia (ADD), and non-AD (FTD, PD, DLB, others) groups were included. ANCOVA compared groups (age/sex adjusted); ROC assessed diagnostic performance. Multivariable regression examined 2-year MMSE decline associations. Voxel-wise interaction models evaluated β-synuclein-gray matter volume (GMV) relationships.

RESULTS: CSF β-synuclein differed across groups (p < 0.001), with highest levels observed in AD-MCI and lower levels in ADD. AD-MCI levels exceeded CU/ADD. AD-MCI versus CU AUC was 0.874. Baseline β-synuclein predicted greater MMSE decline in AD-MCI (β = 0.72, p < 0.001) and ADD (β = 0.47, p = 0.017). Voxel-wise analyses revealed stage-dependent β-synuclein-GMV reversals in precentral and temporoparietal regions.

CONCLUSION: CSF β-synuclein shows a stage-dependent pattern across the AD continuum, predicts cognitive decline, and dynamic structural coupling. It supports β-synuclein as a relevant synaptic biomarker in AD.},
}

@article {pmid42474014,
year = {2026},
author = {Yu, Y and Zhao, H and He, Y and Zhao, J and Yang, X and Liu, X and Cheng, X},
title = {Therapeutic Effects of the Traditional Chinese Formula Qifuyin on Cognition, Lipid Metabolism, and Gut Microbiota in ApoE4 Mice.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073453341260621182306},
pmid = {42474014},
issn = {1875-5402},
abstract = {INTRODUCTION: Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Qifuyin is a promising herbal formula used clinically for cognitive decline, but its effects on ApoE4-associated cognitive and systemic phenotypes remain unclear. This study aimed to evaluate the effects of Qifuyin on cognitive performance in ApoE4 transgenic mice and to preliminarily explore its associations with lipid metabolism and gut microbiota alterations.

METHODS: Ten-month-old ApoE4 transgenic mice were treated with Qifuyin by gavage for 321 days, once daily for the first 123 days and once every two days thereafter. Cognitive function was assessed using the step-down test, novel object recognition test (NORT), and Morris water maze test (MWM). Aging- and frailty-related phenotypes were evaluated using senescence grading scores. Serum triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels were measured to assess lipid metabolism. Gut microbiota composition and functional profiles were analyzed by 16S rRNA and metagenomic sequencing.

RESULTS: Qifuyin treatment significantly reduced error counts and prolonged latency in the stepdown test, increased the 24h preference index in the NORT, shortened escape latency, and increased platform crossings in the MWM in ApoE4 transgenic mice. High-dose Qifuyin reduced aging scores in males and in all doses in females and in the pooled dataset. Qifuyin decreased serum TG and ApoB levels, and increased serum HDL-C levels. 16S rRNA sequencing indicated that Qifuyin increased alpha diversity and shifted beta diversity toward the control profile. At the phylum level, Qifuyin altered the relative abundances of Firmicutes, Bacteroidota, Cyanobacteria, and Synergistota. At the family and genus levels, Qifuyin treatment was associated with increased abundances of Helicobacteraceae, Bacteroidaceae, Helicobacter, and Bacteroides, and a reduced abundance of Ruminococcaceae. Metagenomic annotation analysis showed altered abundances of K02003, K06147, COG1961, CBM37, and GH35-related features.

DISCUSSION: These findings suggest that Qifuyin may benefit ApoE4-associated cognitive and systemic dysfunction through its integrated effects on lipid metabolism and gut microbiota alterations. The microbiota-related changes observed in this study may provide a potential link between peripheral metabolic regulation and cognitive improvement, although their mechanistic significance requires further validation.

CONCLUSIONS: Qifuyin improved cognitive performance and lipid metabolism, and was associated with alterations in gut microbiota composition in ApoE4 transgenic mice. These findings suggest that Qifuyin may exert beneficial effects on cognitive and systemic phenotypes in this model, while the biological significance of specific microbial changes warrants further investigation.},
}

@article {pmid42474022,
year = {2026},
author = {Li, OY and Herrera Guerra, D and Anthony, M and Oh, K and Vankee-Lin, F and Turnbull, A},
title = {Combining MRI-Derived Imaging Measures and Peripheral Proteomics to Improve the Mechanistic Understanding of Alzheimer's Disease Beyond Core Pathology: A Scoping Review.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050472412260629113636},
pmid = {42474022},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Alzheimer's Disease (AD) core pathology involves amyloidβ and ptau, leading to neurodegeneration (ATN model), yet individuals with comparable core pathology show considerable biological and clinical heterogeneity, motivating new models that consider non-specific processes and co-pathology. MRI and peripheral proteomics offer complementary, non-invasive approaches for capturing biological variation beyond core pathology, and many researchers have begun integrating them. However, no systematic overview of this literature exists. This scoping review evaluated studies combining MRI and peripheral plasma proteomics in AD within revised diagnostic frameworks, summarizing strengths and gaps.

MATERIALS AND METHODS: Following PRISMA 2020 guidelines, PubMed, Embase, and Scopus were searched through June 14, 2023, yielding 3,185 records; 63 studies met the inclusion criteria. For each study, study design, participant characteristics, proteomic platforms, imaging modalities, statistical approaches, and significant associations between non-core-pathological proteins and MRIderived measures were extracted.

RESULTS: Across studies, methodological variability was high. Grey matter volume was the most commonly examined imaging metric, followed by cerebrovascular dysfunction, cortical thickness, white-matter and whole-brain volume, and connectivity measures. Overall, 127 non-core-pathology proteins, mostly related to inflammation/immune function, were associated with MRI metrics, though only three appeared in five or more studies. Roughly half of the studies incorporated core AD biomarkers.

DISCUSSION: This scoping review of 63 studies demonstrates that integrating peripheral proteomics with MRI is an increasingly common approach in AD research, with GFAP, CRP, and IL-6 as the most frequently reported proteins, and grey matter volume and vascular dysfunction as the most commonly examined imaging phenotypes. However, effect sizes are generally modest, findings are heterogeneous, and many studies lack core AD biomarkers, highlighting the need for greater methodological consensus and more mechanistic, multimodal, and longitudinal research.

CONCLUSION: Integrating MRI and peripheral proteomics is increasingly common in AD research, but consensus on analytic and imaging approaches is limited. Heterogeneity in proteomic platforms and statistical methods constrains comparability; most associations are modest, and observational designs limit causal inference. Future work should emphasize methodological harmonization, reproducibility, multivariate and machine-learning approaches, and randomized trials to test mechanistic pathways.},
}

@article {pmid42474120,
year = {2026},
author = {Zhang, J and Wang, Y and Huang, X and Wu, H and Lin, Q and Gu, H and Jiang, L and Zhu, L and Xu, H},
title = {Radical-Mediated In Situ Fluorescence Dye Deposition: A Simple Interfacial Signal Amplification Reaction for Ultrasensitive Immunoassay on Barcode Beads.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76670},
doi = {10.1002/advs.76670},
pmid = {42474120},
issn = {2198-3844},
support = {2023YFB3210301//National Key Research and Development Program of China/ ; 2024YFA0917700//National Key Research and Development Program of China/ ; 2024YFA1803501//National Key Research and Development Program of China/ ; 2023YFA1802000//National Key Research and Development Program of China/ ; 82272122//National Natural Science Foundation of China/ ; 82172062//National Natural Science Foundation of China/ ; 22507071//National Natural Science Foundation of China/ ; 20250202//SJTU Trans-Med Awards Research/ ; YG2024ZD12//Fundamental Research Funds for the Central Universities/ ; YG2024QNA09//Fundamental Research Funds for the Central Universities/ ; 24ZR1432500//Natural Science Foundation of Shanghai/ ; },
abstract = {Ultrasensitive detection of low-abundance protein biomarkers is crucial for early disease diagnosis but remains challenging for the conventional barcode beads-based suspension chip platform due to the limited detection sensitivity. Here, we report a conceptually novel reaction termed "radical-mediated in situ fluorescence dye deposition" (RIFD) as a simple interfacial signal amplification strategy to overcome the limitation. This first discovered RIFD follows a universal "three-element principle", where the coexistence of beads, free radicals, and dyes suffices for fluorescence labeling, eliminating the pre-conjugation of dyes to detection probes required in traditional methods. Mechanistic studies reveal that this radical-triggered RIFD possibly follows three distinct pathways, including amide condensation on lysine residues, covalent biphenyl formation on tyrosine residues, or radical-dye co-deposition. It facilitates local and ultrafast (within 5 min) dye-trapping specifically on target-positive barcode beads. Consequently, the established RIFD-based immunoassay achieves a limit of detection of 12 fg/mL for IL-10, a 100-fold improvement over the conventional suspension chip method, and also successfully differentiates Alzheimer's disease patients from healthy controls by quantifying low-abundance plasma p-Tau217. Multiplexed detection is further validated with a three-plex cytokines panel. Our reported RIFD represents a powerful in situ fluorescence labeling tool, advancing protein biomarker detection toward the sub-pg/mL level with broad implications for clinical diagnostics.},
}

@article {pmid42474289,
year = {2026},
author = {Fang, S and Sha, Y and Zhou, Y and Sun, G and Li, E and Yao, M and Zhou, L and Zhu, Y and Peng, B and Ni, J},
title = {Brain iron, cortical atrophy and cognition impairment in cerebral amyloid angiopathy: A quantitative susceptibility mapping study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469524},
doi = {10.1177/13872877261469524},
pmid = {42474289},
issn = {1875-8908},
abstract = {BackgroundBrain iron deposition is associated with cognitive impairment in cerebral amyloid angiopathy (CAA) and Alzheimer's disease, but the exact mechanisms remain unclear.ObjectiveTo investigate whether cortical atrophy mediates iron-related cognitive impairment in CAA.MethodsWe prospectively enrolled CAA patients to collect clinical characteristics, conduct global cognitive assessment and magnetic resonance imaging. Iron levels of each brain region were quantified by susceptibility values from quantitative susceptibility mapping. Three-dimensional T1-weighted imaging was collected to calculate cortex volume. For statistical analyses, first, we conducted univariable linear regressions to identify regions with potential associations to cognitive impairment, with p < 0.1 as threshold. Second, we used elastic net analysis to identify regions where iron depositions strongly correlated with cognitive deficits. Finally, we conducted mediation analysis, using these selected regions to test whether iron-related cognitive dysfunction occurs through cortical atrophy.ResultsForty-four patients were included. The median age was 71.5 years old (IQR 62.3, 75.0), and twenty-two were male. Two-thirds of patients presented with mild cognitive impairment or dementia. Elastic net analysis revealed that iron accumulations in the right Rolandic area, left inferior occipital gyrus, left posterior cingulate gyrus and cerebellum were associated with worse cognitive performance. Mediation analysis showed significant total effect of iron in left posterior cingulate gyrus on Mini-Mental State Examination (β = -0.156, p = 0.002), but the average causal mediation effect was insignificant (p = 0.77).ConclusionsWhile regional iron deposition was associated with cognitive impairment in CAA, cortical atrophy did not significantly mediate this relationship in this exploratory study.},
}

@article {pmid42474291,
year = {2026},
author = {Nong, Y and Wellman, S and Zhang, H and Liu, YA and Argyrousi, EK and Arancio, O and Wang, Q},
title = {Long-term locus coeruleus stimulation exacerbates tau pathology in PS19 mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468577},
doi = {10.1177/13872877261468577},
pmid = {42474291},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common form of dementia, characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. The locus coeruleus (LC) is among the first brain regions to show degeneration and tau pathology during the early stages of AD. Previous studies have demonstrated that short-term chemogenetic LC stimulation can improve memory performance in the TgF344-AD rat model, while long-term norepinephrine reuptake inhibition can worsen memory deficits in the ADLP[Tau] mouse model. However, the effects of long-term LC stimulation in tau mouse models on memory, synaptic plasticity, and tauopathy remain unclear.ObjectiveTo evaluate the impact of long-term LC stimulation on memory, synaptic plasticity, and tauopathy in PS19 mice using behavioral paradigms, electrophysiological recordings, and immunofluorescence analysis.MethodsThe radial arm water maze and fear conditioning test were conducted to assess memory performance in PS19 mice with and without long-term LC stimulation. Hippocampal long-term potentiation (LTP) was recorded to evaluate the effect of long-term LC stimulation on synaptic plasticity. Immunofluorescence was employed to examine tau phosphorylation, neurodegeneration, and neuroinflammation.ResultsLong-term LC stimulation in PS19 mice exacerbated spatial memory deficits in the water maze, impaired contextual fear memory, reduced hippocampal LTP, and increased asparagine endopeptidase (AEP) expression, tau hyperphosphorylation, and neuroinflammation.ConclusionsLong-term LC stimulation may exacerbate memory deficits in PS19 mice by impairing synaptic plasticity and increasing neural degeneration in the hippocampus. Increased AEP expression and tau hyperphosphorylation in the LC further suggest a possible association between LC overactivation and AEP-associated tau pathology.},
}

@article {pmid42474295,
year = {2026},
author = {Pereira De Souza, NA and Belfort Almeida Dos Santos, TT and Lima Nogueira, MM and Nascimento Dourado, MC},
title = {From mild cognitive impairment to moderate Alzheimer's disease: Associations between decision-making capacity and awareness.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468737},
doi = {10.1177/13872877261468737},
pmid = {42474295},
issn = {1875-8908},
abstract = {BackgroundEvidence on how distinct stages of mild cognitive impairment (MCI) and Alzheimer's disease (AD) affect decisional capacity and disease awareness remains limited.ObjectiveWe aim to examine the impairment of decision-making capacity, hypothesizing that people with MCI would demonstrate greater capacity and awareness than those with AD. We also aim to explore associations with cognitive and clinical variables.MethodsWe conducted a cross-sectional study including 137 participants: MCI (n = 37), mild AD (n = 50), and moderate AD (n = 50). Standardized assessments were used to evaluate domains of decision-making capacity and awareness of the illness.ResultsPeople with MCI performed significantly better in understanding, appreciation, and reasoning domains, while expression of choice was preserved across all groups. Disease awareness was higher in MCI, whereas AD participants showed marked deficits, particularly in cognitive and functional domains. Differences in socioemotional awareness were less consistent.ConclusionsOur findings indicate a decline, from MCI to moderate AD, in decisional capacity and awareness, with expression of choice remaining relatively intact. These results have important ethical and clinical implications for shared decision-making and dementia care.},
}

@article {pmid42474304,
year = {2026},
author = {Tong, Y and Lv, X and Liu, J and Cheng, Z and Wang, J and Hua, W and Li, R and Zheng, J and Guo, G and Tang, S},
title = {Disease burden of Alzheimer's disease and other dementias in older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469808},
doi = {10.1177/13872877261469808},
pmid = {42474304},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease and other dementias are major contributors to mortality and disability in older adults worldwide, posing an escalating threat to individuals, families, and communities.ObjectiveThis study analyzed the global burden, sex disparities, and socioeconomic inequalities of Alzheimer's disease and other dementias among adults aged 65 and older from 1990 to 2021.MethodsData from the Global Burden of Disease Study 2021 were used to calculate age-standardized rates for prevalence, mortality, disability-adjusted life-years (DALYs). Joinpoint regression analyzed temporal trends. Sex differences were quantified and correlated with the Socio-demographic Index (SDI), while cross-country inequality was assessed using the slope index of inequality (SII) and concentration index.ResultsIn 2021, an estimated 49.1 million older adults lived with Alzheimer's disease and other dementias. Although age-standardized incidence rates were generally stable, a small increase occurred during the 2019-2021 COVID-19 pandemic. However, these observations cannot be inferred causality from the present data. Females bore a consistently higher burden than males, with disparities widening with age and lower SDI. Although sex differences in DALYs showed a slight global decline, the most significant disparities were found in Africa, Asia, and Australasia. Cross-country inequality (SII) decreased between 1990 and 2021.ConclusionsThe absolute burden of Alzheimer's disease and other dementias has grown substantially and disproportionately affects females. Persistent disparities necessitate targeted policies and investments to ensure equitable access to prevention, diagnosis, and care, particularly for women and populations in lower-SDI regions.},
}

@article {pmid42474305,
year = {2026},
author = {Han, X and Li, Y and Wang, J and Liu, X and Cao, E and Song, Y and Song, L and Cong, L and Zhang, Q and Tang, S and Wang, Y and Du, Y and Qiu, C},
title = {Early- and late-life brain reserve proxies and their interactions with education on cognitive outcomes in older adults: A population-based MRI study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469556},
doi = {10.1177/13872877261469556},
pmid = {42474305},
issn = {1875-8908},
abstract = {BackgroundThe interplay between early- and late-life brain reserve (BR) and early-life education in shaping late-life cognitive function requires further elucidation.ObjectiveWe sought to examine the associations of early- and late-life BR and cognitive function among rural older adults in China, and to assess whether education influenced their relationships.MethodsIn this cross-sectional study (n = 1304), early-life and late-life BR were proxied by total intracranial volume (TIV) and the ratio of total normal brain tissue volume-to-TIV, respectively. Both measures were dichotomized into high and low BR according to their median. Education was classified as high (any formal schooling) and low (no formal schooling). We administered a neuropsychological test battery to assess memory, verbal fluency, executive function, and attention. Mild cognitive impairment (MCI) was diagnosed following Petersen's criteria. Regression analyses were performed.ResultsHigher late-life BR was associated with better performance across all cognitive domains (p < 0.01) and reduced likelihoods of MCI and amnestic MCI (p < 0.001). Joint-exposure analyses suggested that compared to participants with low BR and low education, individuals with both high late-life BR and high education showed best cognitive performance and lowest likelihoods of MCI, followed by those with low BR and high education. Moreover, higher late-life BR was linked to better executive function, attention, and global cognition only in participants with high education (p for interaction<0.05).ConclusionsLate-life BR has a stronger association with cognitive health than early-life BR, even among older adults without formal schooling. Furthermore, formal education may enhance the association between late-life BR and cognitive function.},
}

@article {pmid42474486,
year = {2026},
author = {Santos de Carvalho, RL and Dos Santos, LAP and Ferrison, J and Bomilcar, I and Bertrand, E and Dourado, MCN and Morris, RG and Mograbi, DC},
title = {"Has your Memory Been Letting you Down?" Use of Figurative Language Modulates Expression of Awareness of Impairments in Alzheimer's Disease.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261469563},
doi = {10.1177/08919887261469563},
pmid = {42474486},
issn = {1552-5708},
abstract = {IntroductionWe compared responses of people with Alzheimer's disease (PwAD) on the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia and an adapted figurative language version. We hypothesize that figurative language improves acknowledgment of difficulties, varying by awareness object.Methods27 mild to moderate PwAD completed measures of cognition, depression and self-reported impairments. Caregivers informed about functionality, apathy and neuropsychiatric symptoms.ResultsAcknowledgment of difficulties in activities of daily living was higher in the figurative version, while acknowledgment in the emotional domain was higher in the regular version, in both cases with medium effect sizes. No significant differences emerged for total scores, acknowledgement of cognitive deficits, or changes in social relationships, all with small effect sizes.DiscussionLanguage modulation altered acknowledgment by awareness object. Findings support clear, not complex language in assessments. Future studies should define strategies to improve awareness and its predictors across clinical groups.},
}

@article {pmid42474503,
year = {2026},
author = {Vourkas, O and Zhang, L and Jimenez-Pérez, A and Sánchez-Martín, C and Fernández-Álvarez, M and Rabano, A and Sánchez-Juan, P and Silva-Rodríguez, J and Grothe, MJ and , },
title = {[[18]F]FDG PET outperforms MRI for detecting early tau-related neurodegeneration.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42474503},
issn = {1619-7089},
support = {RYC2023-043746-I//Ministerio de Ciencia e Innovación/ ; CNS2024-154295//Ministerio de Ciencia e Innovación/ ; PMP22/00022, PI20/01011, PI24/00089, TED2021-131676B-100//Instituto de Salud Carlos III/ ; E.6.4 FRS-CUERPOS DE LEWY//Reina Sofia Foundation/ ; },
abstract = {PURPOSE: Neurodegeneration is a hallmark of Alzheimer's disease (AD), measurable in-vivo with [[18]F]FDG PET or MRI. However, the relative sensitivities of these modalities at different stages of AD remain poorly understood. Here, we directly compared associations of hypometabolism and gray matter (GM) atrophy with tau pathology staging at autopsy.

METHODS: Eighty-eight individuals from the ADNI autopsy cohort with Braak tau staging and ante-mortem [[18]F]FDG PET and T1-weighted MRI scans were analyzed. Spearman correlations assessed associations between Braak stage and hypometabolism or GM atrophy across 52 regions of interest. Regions showing significant correlations were further assessed for differences between early/intermediate (II-IV; n=24) and advanced (V/VI, n=56) Braak stages compared to controls (0/I, n=8). To address the limited size of the pathological control group, analyses were replicated using a larger sample of age-matched cognitively unimpaired individuals with no evidence of amyloid or tau pathology on PET imaging (n=45).

RESULTS: Higher Braak stages were associated with [[18]F]FDG PET hypometabolism in temporo-parietal regions, with large effects detectable even at early/intermediate stages and further reductions in advanced stages. Concomitant MRI-derived GM atrophy showed similar but smaller effects, significant only for advanced stages. Direct cross-modality comparisons confirmed more pronounced hypometabolism than GM atrophy across most affected regions. Replication analyses using the larger cognitively unimpaired control sample yielded highly similar findings.

CONCLUSION: [[18]F]FDG PET hypometabolism is a sensitive and early marker of AD-related neurodegeneration, preceding MRI-detectable GM atrophy and more closely reflecting underlying tau pathology across disease stages.},
}

@article {pmid42474555,
year = {2026},
author = {Singh, P and Rath, SL},
title = {Neural network-enhanced investigation of ferroptosis and druggability in early-onset alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42474555},
issn = {1573-7365},
mesh = {*Ferroptosis/physiology/genetics/drug effects ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Humans ; Biomarkers/metabolism ; MicroRNAs/genetics/metabolism ; Oxidative Stress/physiology ; *Neural Networks, Computer ; Machine Learning ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder which is multifactorial in nature. Some of its characteristics are slow cognitive decline, memory problems and behavioral changes. AD patient brains show a progressive synaptic toxicity, autophagy, neuroinflammation, excess generation of reactive oxygen species (ROS), neuronal death and oxidative stress, which occurs due to disrupted metal homeostasis along with tau and amyloid-β protein deposition. Notably, lipid peroxidation, iron buildup and elevated oxidative stress in AD brains suggest a possible molecular connection between ferroptosis and AD neurodegeneration. This study explores the genetic and bioinformatics perspective on the relationship between ferroptosis and AD aiming to identify potential therapeutic potential biomarkers using Neural network (NN) and Machine learning models. Six ferroptosis related genes were found to be differentially expressed in AD. Further machine learning analysis shortlisted four key biomarker genes. An NN-based diagnostic prediction model was developed and validated using AUC-ROC anaysis, which gave high diagnostic values (AUC- 0.92) in the analysis. The findings highlight a strong correlation between ferroptosis and altered metabolic functions in AD. miRNA-gene interaction analysis revealed that two biomarker genes, CYBB and ACSL4 can be regulated by several regulatory miRNAs i.e., hsa-miR-146-5p, hsa-miR-106b-5p, hsa-miR-223-3p, hsa-miR-155-5p, hsa-miR-34a-5p, hsa-miR-125b-5p and hsa-miR-27a-3p suggesting their potential as early diagnostic potential biomarkers. Immune microenvironment analysis revealed strong neuroinflammatory responses in AD with increased infiltration of macrophages (M0, M1 and M2), monocytes and multiple T cell subsets. This heightened immune activity may be driven by ferroptosis-induced oxidative stress contributing to neuronal death. Furthermore, druggability of these targets was evaluated and several drugs were identified that may be potentially repurposed for therapeutic intervention in AD pathogenesis. This study presents a diagnostic predictive model integrating gene expression, miRNA regulation and immune infiltration analysis, offering a novel perspective on early AD detection. The identified ferroptosis-related potential biomarkers and regulatory miRNAs could serve as valuable tools for clinical diagnosis and targeted therapeutic intervention, advancing personalized treatment strategies for Alzheimer's disease.},
}

*Ferroptosis/physiology/genetics/drug effects
*Alzheimer Disease/metabolism/drug therapy/genetics
Humans
Biomarkers/metabolism
MicroRNAs/genetics/metabolism
Oxidative Stress/physiology
*Neural Networks, Computer
Machine Learning

@article {pmid42474734,
year = {2026},
author = {Zheng, Y and Bhalala, OG and Chin, KS and Watson, R and Yassi, N},
title = {Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42474734},
issn = {1432-1459},
mesh = {Humans ; *Neurofilament Proteins/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Biomarkers/blood ; *Clinical Trials as Topic ; },
abstract = {INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions.

METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised.

RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions.

CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.},
}

Humans
*Neurofilament Proteins/blood
*Neurodegenerative Diseases/blood/diagnosis
Biomarkers/blood
*Clinical Trials as Topic

@article {pmid42474786,
year = {2026},
author = {Kale, D and Dcunha, BV and Lakshmi, S and Raghu, SV and Elumalai, P},
title = {Neuroprotective potential of marine-derived polysaccharide against Aβ42-induced toxicity in a Drosophila Alzheimer's disease model.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42474786},
issn = {1573-4978},
support = {ICMR (2021 - 11092 No. 52/08/2022 BIO/BMS//ICMR/ ; },
mesh = {Animals ; *Polysaccharides/pharmacology/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism/genetics/toxicity ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology ; Drosophila melanogaster/metabolism ; Disease Models, Animal ; Humans ; Reactive Oxygen Species/metabolism ; Animals, Genetically Modified ; *Peptide Fragments/metabolism ; Antioxidants/pharmacology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition caused by amyloid β (Aβ42) accumulation, neuroinflammation, oxidative stress and cholinergic dysfunction, resulting in neuronal death and cognitive decline. Excessive Aβ42 accumulation disrupts redox equilibrium, increases reactive oxygen species (ROS), and activates inflammatory and apoptotic pathways. Natural bioactive compounds with immunomodulatory and antioxidant properties are increasingly being explored as possible multi-target therapies. Alkylglycerol (AKG), a lipid-derived immunomodulator, and fucoidan, a sulfated polysaccharide found in brown algae, have both shown neuroprotective properties. This study examines the effectiveness of Fucoidan and AKG in preventing Aβ42-induced diseases in a Drosophila melanogaster model, both individually and in combination.

METHODOLOGY: Transgenic Drosophila expressing human Aβ42 in the brain were divided into control, Aβ42, Fucoidan-treated, AKG-treated, and combination-treated groups. Oxidative stress indicators such as nitric oxide (NO), hydrogen peroxide (H2O₂), malondialdehyde (MDA), and total ROS were measured using biochemical tests. To evaluate redox reactions, the activity of the antioxidant enzymes glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were evaluated. Cholinergic function was assessed by measuring acetylcholinesterase (AChE) activity. The analysis of gene expression focused on genes linked with oxidative stress (SOD, CAT, PHPGx, TRx1), inflammatory markers (TNFα, TNFαR), apoptotic regulator p53, and neurogenesis-related genes (Wnt pathway, SOX2, Nanog).

RESULTS AND DISCUSSION: Aβ42 expression disrupted neurogenic signaling and cholinergic balance while markedly increasing oxidative markers and inflammatory mediators. Although AKG and fucoidan separately decreased inflammation and oxidative stress, the combination treatment yielded the biggest results. Dual therapy increased the activity of antioxidant enzymes, decreased the activity of AChE, downregulated TNFα and p53, and restored the expression of Wnt, SOX2, and Nanog. These results demonstrate the translational potential of Fucoidan and AKG act for AD care by showing that their combined treatment helps to restore redox stability, suppress inflammation, boost neurogenesis, and mitigate Aβ42-induced neurotoxicity.},
}

Animals
*Polysaccharides/pharmacology/metabolism
*Alzheimer Disease/metabolism/drug therapy
*Amyloid beta-Peptides/metabolism/genetics/toxicity
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology
Drosophila melanogaster/metabolism
Disease Models, Animal
Humans
Reactive Oxygen Species/metabolism
Animals, Genetically Modified
*Peptide Fragments/metabolism
Antioxidants/pharmacology

@article {pmid42475091,
year = {2026},
author = {Wang, SH and Lin, MC and Fan, CC and Huang, WL and Hsu, CC and Wu, CS},
title = {Spousal Dementia Exposure and Risk of Dementia.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2624175},
doi = {10.1001/jamanetworkopen.2026.24175},
pmid = {42475091},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; Taiwan/epidemiology ; Aged ; *Dementia/epidemiology ; *Spouses/statistics & numerical data/psychology ; Risk Factors ; Cohort Studies ; Middle Aged ; Socioeconomic Factors ; Aged, 80 and over ; Incidence ; },
abstract = {IMPORTANCE: Previous studies suggest that spouses of individuals with dementia may be at increased risk of developing dementia, but evidence regarding subgroup variation and absolute risk remains limited.

OBJECTIVE: To examine whether spouses of individuals with dementia have an increased risk of developing dementia and to assess whether this association is modified by demographic, socioeconomic, and family context factors.

This nationwide population-based cohort study used Taiwan's National Health Insurance Research Database from 1998 to 2022, with follow-up through 2022. To address prior limitations of small sample size and limited subgroup evaluation, spouses of individuals with incident dementia were identified and matched 1 to 4 to unexposed controls by birth year, sex, income, and urbanicity. The analysis was conducted between July 15, 2025, and May 15, 2026.

EXPOSURE: Spousal exposure to incident dementia.

MAIN OUTCOMES AND MEASURES: Incident all-cause dementia, Alzheimer disease, and vascular dementia. Hazard ratios (HRs) and 5-year absolute risk differences were estimated using Cox regression and g-computation.

RESULTS: The matched cohort included 955 105 individuals, with 118 904 exposed women and 72 117 exposed men as well as 475 616 unexposed women and 288 468 unexposed men. The largest proportion were aged 65 to 74 years at cohort entry, for women (47 084 [39.6%]) and men (28 477 [39.5%]). Spouses of individuals with dementia had a higher risk of all-cause dementia than unexposed spouses. For women, the HR was 1.74 (95% CI, 1.70-1.78), with a 5-year adjusted risk difference of 2.75 percentage points (pp) (95% CI, 2.63-2.87 pp). For men, the HR was 1.69 (95% CI, 1.64-1.73), with a 5-year adjusted risk difference of 3.49 pp (95% CI, 3.30-3.69 pp). Similar patterns were observed in analyses of Alzheimer disease and vascular dementia. Relative risks were more prevalent at younger ages, whereas absolute risk differences increased with age. For all-cause dementia, the association was attenuated among individuals with higher income or more children. Associations were otherwise broadly similar across sex and urbanicity.

CONCLUSIONS AND RELEVANCE: In this cohort study of married individuals in Taiwan, spouses of individuals with dementia had a higher risk of dementia than unexposed spouses. The association varied across family and socioeconomic contexts, highlighting the relevance of household context in dementia risk assessment.},
}

Humans
Female
Male
Taiwan/epidemiology
Aged
*Dementia/epidemiology
*Spouses/statistics & numerical data/psychology
Risk Factors
Cohort Studies
Middle Aged
Socioeconomic Factors
Aged, 80 and over
Incidence

@article {pmid42475211,
year = {2026},
author = {Dong, Z and Liu, H and Ge, X and Zhang, H and Li, Z and Chen, Y and Li, W},
title = {Brain Region-Centered MultiModal Hypergraph Fusion for MCI Conversion Prediction.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3715131},
pmid = {42475211},
issn = {2168-2208},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with mild cognitive impairment (MCI) as its prodromal stage. Accurate MCI conversion prediction is critical for early intervention and resource allocation. Recently, deep learning-based multimodal neuroimaging fusion has become a hot research topic in AI-assisted AD diagnosis. Existing multimodal fusion approaches are limited by modality heterogeneity, insufficient ability to model inter-regional interactions, and insufficient interpretability. To address these challenges, BRC-MMHF, a Brain Region-Centered MultiModal Hypergraph Fusion framework, is proposed. In this framework, parameter-free channel exchange and ROI-level feature extraction mechanisms are employed to reduce modality heterogeneity and extract structurally consistent features from MRI and PET. A multimodal hypergraph models high-order inter regional cross-modal relationships, while a lesion-aware module highlights disease-relevant regions to enhance interpretability. Structured clinical data are incorporated through a lightweight tabular encoder to improve adaptability and diagnostic robustness. Experiments on the ADNI dataset show that BRC-MMHF achieves 80.79% accuracy and 89.78% AUC in MCI conversion prediction, outperforming a range of state-of-the-art methods based on MRI and PET imaging, while providing auxiliary interpretability.},
}

@article {pmid42475384,
year = {2026},
author = {Ma, L and Wang, D and Li, Z and Ye, G and Chen, M},
title = {Exosomal gene-based predictive model and therapeutic target identification for Alzheimer's disease: A bioinformatics analysis.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0354014},
doi = {10.1371/journal.pone.0354014},
pmid = {42475384},
issn = {1932-6203},
mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism ; Humans ; *Computational Biology/methods ; Molecular Docking Simulation ; *Exosomes/genetics/metabolism ; Gene Regulatory Networks ; Gene Expression Profiling ; Databases, Genetic ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative central nervous system disorder characterized by progressive cognitive and behavioral impairment. As nanoscale intercellular communication vesicles that carry AD-related pathological molecules, exosomes are promising biomarkers and therapeutic carriers for AD. In this study, we downloaded AD-related gene expression profiles and clinical data from the Gene Expression Omnibus (GEO) database (datasets GSE138260, GSE29378, GSE36980, and GSE5281). Through a series of bioinformatics analyses, clinical predictive model construction, pharmacological network analysis, and molecular docking simulations, we developed an exosomal gene-based predictive model for AD pathogenesis and identified potential pharmacological networks and molecular docking targets for AD treatment.

MATERIALS AND METHODS: AD-related gene expression and clinical data were retrieved from the GEO database. Bioinformatics analyses, clinical model construction, drug-gene network analysis, and molecular docking were subsequently performed to explore exosomal gene models for predicting AD pathogenesis, as well as potential pharmacological networks and molecular docking targets for AD therapy.

RESULTS: A five-exosomal-gene predictive model was established, comprising CD44, CXCR4, TUBB, PSMA5, and PSMB3. Pharmacological network analysis of these five genes revealed their significant associations with chelidonine, 2-chloro-1,4-dinitrobenzene, oxazolone, phencyclidine, thioridazine, and etodolac. Further molecular docking simulations identified key binding targets, including R41, Y42, R78, Y79, C77, I88, C97, A98, I96, I72, L70, E67, G103, I91, and T102.

CONCLUSIONS: Our comprehensive analyses successfully established a reliable exosomal gene-based model for predicting AD pathogenesis, and identified relevant pharmacological networks and core molecular docking targets, providing novel insights for AD diagnosis and targeted therapy.},
}

*Alzheimer Disease/genetics/drug therapy/metabolism
Humans
*Computational Biology/methods
Molecular Docking Simulation
*Exosomes/genetics/metabolism
Gene Regulatory Networks
Gene Expression Profiling
Databases, Genetic

@article {pmid42475397,
year = {2026},
author = {Aponte, EA and Perumal, TM and Cormack, F and Chatham, CH},
title = {Beyond memory capacity: A probabilistic, dual store model of visuospatial working memory.},
journal = {PLoS computational biology},
volume = {22},
number = {7},
pages = {e1014535},
doi = {10.1371/journal.pcbi.1014535},
pmid = {42475397},
issn = {1553-7358},
abstract = {The last decades have seen a great improvement in our understanding of visuospatial working memory (VSWM). Despite this progress, less is known about how information is stored, retained, and removed from VSWM when novel information is presented sequentially. Here, we present a novel computational model of the dynamics of VSWM that extends and improves classical ideas. Our analysis relies on data from three clinical trials involving neurotypicals and people with autism performing a smartphone based sequential VSWM task. In addition, we applied the model to data from a large clinical trial in prodromal Alzheimer's disease. We demonstrate that visual information in our sequential task is stored in independent pools of contrasting resources, with perfect and imperfect retrieval rates. Our findings illustrate how computational models combined with remote cognitive testing are mature enough for applications in large-scale clinical research.},
}

@article {pmid42475419,
year = {2026},
author = {Elshekh, A and Abdelmaguid, AM and Eltanany, RMA and El-Kordy, YH and Khedr, AA and Mekkawy, SA and El-Khadragy, MF and Albrakati, A and Abdelfattah, MS and Abdel Moneim, AE},
title = {Computational Evaluation of Oleuropein Interactions with Alzheimer's Disease-Related Proteins Using Molecular Docking and Molecular Dynamics.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {232},
pages = {},
doi = {10.3791/71430},
pmid = {42475419},
issn = {1940-087X},
mesh = {*Molecular Dynamics Simulation ; Iridoid Glucosides ; *Alzheimer Disease/metabolism/drug therapy ; *Molecular Docking Simulation/methods ; *Iridoids/chemistry/metabolism ; Humans ; tau Proteins/metabolism/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder associated with amyloid aggregation, tau pathology, and neuroinflammation. In this study, an integrated computational workflow combining ADMET prediction, PASS-based activity screening, molecular docking, and molecular dynamics (MD) simulations was employed to evaluate the interactions of oleuropein with five AD-related protein targets, including β-amyloid, tau, apolipoprotein E4 (ApoE4), triggering receptor expressed on myeloid cells 2 (TREM2), and complement protein C1q. ADMET and PASS analyses predicted pharmacokinetic properties and potential biological activities associated with neurodegenerative disease-related pathways. Docking analysis predicted favorable binding affinities across the investigated targets, with the strongest predicted interaction observed for the C1q protein (-7.5 kcal/mol). Molecular dynamics (MD) trajectory analyses, including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), dynamic cross-correlation matrix (DCCM), principal component analysis (PCA), and distance-based metrics, were used to evaluate the dynamic behavior of the protein-ligand complexes during the simulations. The computational analyses suggested relatively stable interactions for tau, C1q, and TREM2 complexes, whereas β-amyloid and ApoE4 exhibited comparatively higher conformational variability during portions of the simulations. These findings provide a preliminary computational assessment of oleuropein interactions with AD-related proteins and may support future experimental studies investigating its potential biological relevance in neurodegenerative disease models.},
}

*Molecular Dynamics Simulation
Iridoid Glucosides
*Alzheimer Disease/metabolism/drug therapy
*Molecular Docking Simulation/methods
*Iridoids/chemistry/metabolism
Humans
tau Proteins/metabolism/chemistry
Amyloid beta-Peptides/metabolism/chemistry

@article {pmid42475614,
year = {2026},
author = {Jarrell, L and Vanhoy, S},
title = {Doll therapy: Innovative treatment for patients with Alzheimer disease to improve patient and staff safety in a hospital setting.},
journal = {Nursing},
volume = {56},
number = {8},
pages = {56-61},
doi = {10.1097/NSG.0000000000000419},
pmid = {42475614},
issn = {1538-8689},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; *Patient Safety/standards ; Aged ; *Play Therapy/methods ; Accidental Falls/prevention & control ; Aged, 80 and over ; },
abstract = {BACKGROUND: Patients with Alzheimer disease may display negative neuropsychiatric symptoms that can pose patient safety risks.. Doll therapy is described in the literature as a successful diversional activity for these patients.

PURPOSE: This project aimed to provide doll therapy to patients with Alzheimer disease at their facility to reduce neuropsychiatric symptoms, improve patient safety, patient outcomes, and the patient and family experience, and to positively impact the health care team's experience when caring for this patient population.

METHODS: A total of 55 patients with a diagnosis of Alzheimer disease participated in the doll therapy program. Quantitative and qualitative data were collected and analyzed. These included patient's behavior prior to doll therapy and the patient's response to doll therapy.

RESULTS: Patients experienced a sense of purpose and comfort, as well as decreased risk for falls, physical workplace violence events, and being placed in restraints as a result of doll therapy.},
}

Humans
*Alzheimer Disease/therapy/psychology
Female
Male
*Patient Safety/standards
Aged
*Play Therapy/methods
Accidental Falls/prevention & control
Aged, 80 and over

@article {pmid42475650,
year = {2026},
author = {Tang, C and Yang, J and Luo, W and Lei, X and Peng, X and Chen, Y and Guan, S and He, D},
title = {Rapidly Progressive Alzheimer Disease and Related Dementias as a Phase Transition: Symptom Cascades and Survival Inflection.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218350},
doi = {10.1212/WNL.0000000000218350},
pmid = {42475650},
issn = {1526-632X},
mesh = {Humans ; Disease Progression ; Female ; *Alzheimer Disease/mortality/physiopathology/diagnosis ; Male ; Aged ; Retrospective Studies ; Longitudinal Studies ; Aged, 80 and over ; *Dementia/mortality ; },
abstract = {BACKGROUND AND OBJECTIVES: Rapidly progressive Alzheimer disease and related dementias (rpADRD) is a clinically urgent syndrome characterized by accelerated deterioration. Because it is often confounded by acute etiologies, its definition remains poorly characterized. We aimed to evaluate rpADRD as a distinct clinical state, testing the hypothesis that it represents a clinical "phase transition" rather than a simple linear acceleration of typical neurodegenerative decline. Our objective was to define this transition threshold and quantify its impact on survival and disease trajectory.

METHODS: We conducted a retrospective cohort study using longitudinal data from participants recruited across US Alzheimer's Disease Research Centers. We defined incident rpADRD as dementia development (global Clinical Dementia Rating [CDR] ≥1) within 1 year of symptom onset, or progression to moderate-to-severe impairment (global CDR ≥2) within 2 years. To isolate primary neurodegeneration, we excluded prion, infectious, metabolic, toxic, and autoimmune etiologies. We used time-dependent Cox regression, multistate modeling, and restricted cubic spline analyses to model nonlinear survival dynamics.

RESULTS: The final analysis cohort included 2,307 participants (mean baseline age 78.9 years; 57.1% female). Over a mean follow-up of 7.3 years, 270 patients (11.7%) developed incident rpADRD. Patients transitioning to rpADRD were older than non-rpADRD patients (mean 80.0 vs 78.8 years). Crucially, the transition to rpADRD was strongly associated with increased subsequent mortality (hazard ratio = 4.03; 95% CI 3.53-4.61, p < 0.001). Multistate and spline modeling confirmed that this shift represents a distinct, nonlinear clinical phase transition rather than a linear exacerbation of functional decline. Furthermore, this critical tipping point was reliably preceded by an early cascade of neuropsychiatric symptoms.

DISCUSSION: These findings validate a clinical "phase transition" model for rpADRD, demonstrating that survival decline is not merely a linear function of disease severity. Rather, rpADRD constitutes a distinct state of clinical homeostatic failure fundamentally shifting subsequent mortality risk, often predicted by early neuropsychiatric symptoms. Recognizing this nonlinear shift is vital for accurate prognostication and segregation of rapidly progressing phenotypes in trials. Major limitations include reliance on observational data, potential recall bias regarding symptom onset, and the exclusion of neuroimaging and fluid biomarkers because of high missingness.},
}

Humans
Disease Progression
Female
*Alzheimer Disease/mortality/physiopathology/diagnosis
Male
Aged
Retrospective Studies
Longitudinal Studies
Aged, 80 and over
*Dementia/mortality

@article {pmid42475746,
year = {2026},
author = {Yang, A and Manaswi, A and Fischer, MW and Fischer, IC and Na, PJ and Pietrzak, RH},
title = {Comorbid Cardiovascular Disease and Posttraumatic Stress Disorder in Older US Veterans: Prevalence, Health Burden, and Functional Impairment.},
journal = {The primary care companion for CNS disorders},
volume = {28},
number = {4},
pages = {},
doi = {10.4088/PCC.26m04187},
pmid = {42475746},
issn = {2155-7780},
mesh = {Humans ; *Veterans/statistics & numerical data ; *Stress Disorders, Post-Traumatic/epidemiology ; Male ; United States/epidemiology ; *Cardiovascular Diseases/epidemiology ; Prevalence ; Aged ; Comorbidity ; Female ; Middle Aged ; Aged, 80 and over ; },
abstract = {Objective: Cardiovascular disease (CVD) and posttraumatic stress disorder (PTSD) are prevalent and disabling conditions among older US veterans. Both are independently associated with poor physical, mental, and functional outcomes, but little is known about the combined burden. This study aims to examine the prevalence, risk correlates, health comorbidities, and functional outcomes of comorbid CVD+PTSD in older US veterans. Methods: Data were analyzed from 3,001 US veterans aged 60 years and older who participated in the 2019-2020 National Health and Resilience in Veterans Study. Self-reported CVD, PTSD, health comorbidities, and functional outcomes were examined using weighted bivariate and multivariable analyses. Results: A total of 23.1% of veterans had CVD only, 5.5% PTSD only, and 2.2% comorbid CVD+PTSD. Veterans with CVD+PTSD were more likely to report combat exposure, childhood adversity, and greater lifetime trauma compared to other groups. Relative to controls, they had particularly elevated odds of major depressive disorder (MDD), generalized anxiety disorder (GAD), cognitive disorder (ie, mild cognitive impairment, dementia, or Alzheimer disease), sleep disorder, and concussion/traumatic brain injury (TBI; odds ratios [ORs] = 4.78-13.27). Compared to CVD-only veterans, those with CVD+PTSD had higher odds of GAD, MDD, cognitive disorder, sleep disorder, suicidal ideation, and chronic pain (ORs = 1.89-9.64). Relative to PTSD-only veterans, they had greater odds of kidney disease, concussion/TBI, MDD, and sleep disorder (ORs = 2.67-4.85). Veterans with CVD+PTSD also showed moderately greater impairments in psychosocial and cognitive functioning compared to single-diagnosis groups (d's = 0.50-0.66). Conclusions: Older veterans with comorbid CVD+PTSD have a markedly elevated burden of health and functional difficulties, underscoring the importance of integrated, trauma-informed care to improve outcomes in this high-risk population. Prim Care Companion CNS Disord 2026;28(4):26m04187. Author affiliations are listed at the end of this article.},
}

Humans
*Veterans/statistics & numerical data
*Stress Disorders, Post-Traumatic/epidemiology
Male
United States/epidemiology
*Cardiovascular Diseases/epidemiology
Prevalence
Aged
Comorbidity
Female
Middle Aged
Aged, 80 and over

@article {pmid42475908,
year = {2026},
author = {Shin, H and Lim, S and Yeom, J and Jeong, HC and Yoon, T},
title = {Irreversible mechanical weakening of amyloid-β K16 mutants via electrostatic torque.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {173},
number = {},
pages = {109394},
doi = {10.1016/j.bioelechem.2026.109394},
pmid = {42475908},
issn = {1878-562X},
abstract = {BACKGROUND: Amyloid-beta (Aβ) fibrils act as the structural core of Alzheimer's disease pathology and maintain exceptional mechanical stability through dense β-sheet networks. However, the molecular mechanisms through which external physical stimuli disrupt these robust scaffolds remain poorly understood, particularly the residue-specific responses.

METHODS: Here, we systematically evaluated the structural collapse and mechanical attenuation of Aβ fibrils and their K16 mutants, including the charge-reversal K16D and bulky K16W, under a 1.0 V/nm electric field (EF) using molecular dynamics (MD) simulations.

RESULTS: We demonstrated that this external stimulus persistently disrupts the β-sheet hydrogen-bond network within the simulated recovery window and leads to a drastic reduction in Young's modulus driven by dipole-field misalignment. Notably, this response was highly mutation dependent since the K16D mutant exhibited severe orientation-dependent collapse due to an amplified electrostatic torque, whereas K16W maintained its structural resistance via enhanced steric packing. Furthermore, EF induced a sustained increase in the solvent-accessible surface area (SASA).

CONCLUSION: These findings suggest that external EF can serve as a potent physical modulator to destabilize pathogenic amyloid aggregates, potentially overcoming the physical barrier of dense plaques, enhancing the penetration and efficacy of therapeutic agents.},
}

@article {pmid42476126,
year = {2026},
author = {Lee, J and Gilligan, M and Skoblow, HF and Huo, M and Ogle, DM and Killoren, SE},
title = {Hair Cortisol Concentration among Siblings Caring for a Parent with Dementia: A Dyadic Approach to Sibling Relationship Quality and Perceived Caregiving Stress.},
journal = {Biopsychosocial science and medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001511},
pmid = {42476126},
issn = {2998-8756},
abstract = {OBJECTIVE: Sibling relationship quality and perceived caregiving stress contribute to dementia caregivers' well-being. However, few studies have examined the biopsychosocial mechanisms underlying sibling interdependence in the caregiving context, particularly using cortisol. The aim of this study was to examine the dyadic associations between sibling relationship quality (i.e., closeness, tension, ambivalence: simultaneous positive and negative feelings), perceived caregiving stress (i.e., emotional and physical stress experienced by caregivers) and hair cortisol concentration (HCC) among siblings caring for a parent with Alzheimer's disease and related dementias (ADRD).

METHODS: Data came from 66 sibling dyads (M age=56.5; 91% women) caring for a parent with ADRD. Participants reported their sibling relationship quality and perceived caregiving stress through a self-report survey. Cortisol was extracted from hair samples using optimized liquid chromatography-tandem mass spectrometry.

RESULTS: The actor-partner interdependence model revealed that individuals exhibited higher HCC when they felt emotionally closer to their sibling (i.e., actor effect), as well as when their sibling reported greater ambivalence toward them and more severe emotional caregiving stress (i.e., partner effects). Neither the actor nor partner effects of sibling tension or physical caregiving stress on HCC were significant.

CONCLUSIONS: This study contributes to the understanding of the biopsychosocial processes shaping siblings' experiences in parental dementia caregiving by highlighting the dyadic associations between sibling relationship quality, perceived caregiving stress, and HCC.},
}

@article {pmid42476266,
year = {2026},
author = {Zaman, W and Ayaz, A and Ullah, A},
title = {Decoding lactate signals in Alzheimer's disease: redox control, receptor pharmacology, lactylation chemistry, and neuroglial vulnerability.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118275},
doi = {10.1016/j.bcp.2026.118275},
pmid = {42476266},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) develops within a metabolically heterogeneous brain in which lactate functions as an oxidative substrate, a redox-coupled metabolite, a proton-linked transport signal, a receptor ligand, and a precursor of lysine lactylation. These roles are often considered independently, obscuring why lactate supports neuronal function in some settings yet accompanies persistent inflammation and neurodegeneration in others. This review introduces a lactate signal-decoding framework that emphasizes cellular interpretation rather than concentration alone. The framework integrates the lactate/pyruvate ratio, the cytosolic reduced-to-oxidized nicotinamide adenine dinucleotide (NADH/NAD +) state, lactate dehydrogenase (LDH) isoenzyme context, proton-coupled monocarboxylate transport, extracellular pH, hydroxycarboxylic acid receptor 1 (HCAR1) signaling, and enzymatic or non-enzymatic lactylation. We compare neuronal, astrocytic, microglial, and neurovascular responses and examine how aging, apolipoprotein E ε4 (APOE4), amyloid pathology, hypoperfusion, sleep disruption, and systemic metabolic disease reshape them. Particular attention is given to the chemistry and analytical validation of histone and non-histone lactylation; the proposed interaction of tau lactylation with other post-translational modifications; and links to proteostasis, iron homeostasis, and mitochondrial quality control. As a hypothesis-generating model, AD progression may involve loss of coordination among lactate transport, oxidation, receptor signaling, pH control, and covalent modification. This framework prioritizes restoration of metabolic coordination over indiscriminate lactate suppression and identifies biomarker and experimental requirements for clinical translation.},
}

@article {pmid42476282,
year = {2026},
author = {Abbaszadeh, F and Amini, NB and Davoody, S and Rezaei, M and Ghasemi, R and Javadpour, P},
title = {Unlocking new uses: The promise of antidepressants in treating Alzheimer's and Parkinson's through Neuroinflammation modulation.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111848},
doi = {10.1016/j.pnpbp.2026.111848},
pmid = {42476282},
issn = {1878-4216},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive cognitive and motor decline, largely driven by chronic neuroinflammation and oxidative stress. Conventional therapies primarily provide symptomatic relief without targeting underlying disease mechanisms. Emerging evidence suggests that antidepressants, beyond their canonical role in mood regulation, exhibit anti-inflammatory, antioxidant, and neurotrophic effects that may modulate disease progression. Preclinical studies demonstrate that selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) can reduce pro-inflammatory cytokines, attenuate glial activation, enhance neurotrophic signaling, and improve cognitive and motor function in experimental models of AD and PD. Clinical findings are mixed, with some antidepressants showing modest cognitive or symptomatic benefits, particularly in patients with comorbid depression, while others may pose risks due to anticholinergic effects or interference with neuronal autophagy. This narrative review synthesizes mechanistic and translational evidence on the off-label use of antidepressants for neurodegenerative diseases, highlighting the potential of drug repurposing to target neuroinflammation and support neuroprotection, while emphasizing the need for careful patient-specific therapy selection.},
}

@article {pmid42470017,
year = {2026},
author = {Wang, X and Deng, L and Wang, T and Luo, S},
title = {Exploring the cognitive effects of arthritis: A Mendelian randomization study and cross-sectional analysis of NHANES data.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49805},
doi = {10.1097/MD.0000000000049805},
pmid = {42470017},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Arthritis, Rheumatoid/genetics/psychology/blood ; Female ; *Osteoarthritis/genetics/psychology/blood ; Cross-Sectional Studies ; Polymorphism, Single Nucleotide ; Male ; Nutrition Surveys ; Aged ; Middle Aged ; *Cognition/physiology ; Growth Differentiation Factor 5/genetics ; Linkage Disequilibrium ; },
abstract = {This study aimed to investigate the relationship between cognitive performance and the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA), emphasizing the role of plasma metabolites and proteins. Using National Health and Nutrition Examination Survey 2011 to 2014 data, cognitive functions of participants aged >60 years were evaluated, examining their correlation with OA and RA. Covariates, including demographics and health-related factors, were included. Genetic causality was determined using Mendelian randomization with single-nucleotide polymorphisms from the UK Biobank and other datasets. Linkage disequilibrium score regression and colocalization analyses were performed to validate genetic correlations and identify shared genetic variants. Cognitive performance was assessed in 387 and 237 OA and RA patients, respectively, compared with 1569 controls. OA patients had significantly lower Consortium to Establish a Registry for Alzheimer's Disease-4 cognitive scores (odds ratio [OR]: 0.962, P = .001), while RA patients had lower digit symbol substitution test scores (OR: 0.980, P = .001). Mendelian randomization revealed a negative causal association between cognitive performance and OA (OR: 0.767, P = .001) and RA (OR: 0.712, P = .006). Plasma components, including bone sialoprotein 2, NKP44, and the metabolite X-11478, were causally linked to cognitive performance. Mediation analysis identified mediators, including FGR and 6CKine. Linkage disequilibrium score regression revealed a genetic correlation between cognitive performance and OA and RA, with colocalization analysis identifying shared genetic factors. GDF5 and TRAIP were associated with OA, and EHMT2 with RA. Cognitive factors, influenced by plasma components, may influence OA and RA onset. This relationship highlights the need for integrated interventions targeting cognitive function and joint health.},
}

Humans
Mendelian Randomization Analysis
*Arthritis, Rheumatoid/genetics/psychology/blood
Female
*Osteoarthritis/genetics/psychology/blood
Cross-Sectional Studies
Polymorphism, Single Nucleotide
Male
Nutrition Surveys
Aged
Middle Aged
*Cognition/physiology
Growth Differentiation Factor 5/genetics
Linkage Disequilibrium

@article {pmid42470073,
year = {2026},
author = {Chen, K and Deng, Y and Yan, D and Wang, J and Ding, Y},
title = {Clinical characteristics of patients with Alzheimer's disease and caregiver burden, mental health, and sleep quality: A cross-sectional comparative study in psychiatric hospitals and nursing homes.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49761},
doi = {10.1097/MD.0000000000049761},
pmid = {42470073},
issn = {1536-5964},
mesh = {Humans ; *Alzheimer Disease/psychology ; Cross-Sectional Studies ; Female ; *Hospitals, Psychiatric/statistics & numerical data ; *Nursing Homes ; Male ; *Caregivers/psychology ; Aged ; *Sleep Quality ; *Mental Health ; Aged, 80 and over ; Cost of Illness ; China ; Middle Aged ; Depression/epidemiology ; Anxiety/epidemiology ; Sleep Wake Disorders ; },
abstract = {As Alzheimer's disease (AD) care shifts to institutions, differences between psychiatric hospitals and nursing homes remain unclear. We compared AD patients and professional caregivers across these settings and explored institution-specific links between caregiver burden, mental health, and sleep quality. A cross-sectional study (January to November 2024) enrolled 121 AD patients and 123 caregivers from 2 psychiatric hospitals and 2 nursing homes in Shanghai. Assessments used standardized scales. Analyses included nonparametric tests, χ2 tests, Spearman correlations, and stepwise regression. Post hoc power was adequate for moderate-to-large effects. AD patients in psychiatric hospitals are more severe, and caregivers face greater burden and psychological risk. Tailored, institution-specific mental health interventions are needed. Psychiatric hospital patients had poorer cognition and greater functional dependence (P < .001). Hospital caregivers reported higher burden, depression, anxiety, and worse sleep in specific domains (P < .05; effect sizes r = 0.18-0.47). Burden correlated positively with depression, anxiety, and poor sleep (r = 0.397-0.458). In the total sample, anxiety and poor sleep predicted burden (adjusted R2 = 0.285). In psychiatric hospitals, sleep quality was the dominant predictor (β = 0.483). In nursing homes, anxiety and workload predicted burden (adjusted R2 = 0.418); sleep quality was a negative predictor (β = -0.222), likely from floor effects and adaptive coping.},
}

Humans
*Alzheimer Disease/psychology
Cross-Sectional Studies
Female
*Hospitals, Psychiatric/statistics & numerical data
*Nursing Homes
Male
*Caregivers/psychology
Aged
*Sleep Quality
*Mental Health
Aged, 80 and over
Cost of Illness
China
Middle Aged
Depression/epidemiology
Anxiety/epidemiology
Sleep Wake Disorders

@article {pmid42470526,
year = {2026},
author = {Fu, Y and Gao, PY and Xu, W and Tan, L},
title = {Associations of Insulin Sensitivity with Risk of All-Cause and Cause-Specific Dementia: A Prospective Cohort Study.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42470526},
issn = {1559-1182},
support = {2022ZD0211600//Brain Science and Brain-like Intelligence Technology - National Science and Technology Major Project/ ; 82271475//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Insulin Resistance/physiology ; *Dementia/epidemiology/metabolism ; Female ; Male ; Prospective Studies ; Risk Factors ; Aged ; Genetic Predisposition to Disease ; },
abstract = {Impaired insulin sensitivity has been implicated in neurodegeneration, but whether clinically accessible indices of insulin sensitivity predict dementia risk in the general population remains unclear. We examined associations of the estimated glucose disposal rate (eGDR), a validated marker of insulin sensitivity, with incident all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD), and assessed whether eGDR modifies genetic susceptibility to AD. We included 290,898 dementia-free participants from the UK Biobank. eGDR was calculated using waist circumference, hypertension, and glycated hemoglobin. AD polygenic risk score (AD-PRS) was categorized into tertiles. Longitudinal associations were assessed using Kaplan-Meier (KM) survival analysis and Cox proportional hazards models, with restricted cubic splines employed to examine potential non-linear relationships. Joint effects and interactions between eGDR and AD-PRS were evaluated. The robustness of findings was tested through extensive subgroup and sensitivity analyses. Over a mean follow-up of 13.23 years, 4794 participants developed ACD, 2138 developed AD, and 1070 developed VaD. KM curve revealed that dementia incidence differed significantly across eGDR quartiles (all log-rank P < 0.001). RCS showed significant non-linear inverse associations between eGDR and dementia risk (all P for non-linearity < 0.001). In fully adjusted Cox models, each 1-unit higher eGDR was associated with lower risk of ACD (HR 0.92, 95% CI 0.90-0.94), AD (0.94, 0.92-0.97), and VaD (0.82, 0.78-0.85). Compared with eGDR-Q1, Q4 had lower risks of ACD (HR 0.67), AD (HR 0.70), and VaD (HR 0.42) (all P < 0.001). eGDR modified AD genetic risk (P for interaction < 0.001); participants with low AD-PRS and high eGDR had the lowest AD risk (HR 0.17, 95% CI 0.12-0.23 vs. high AD-PRS and low eGDR group). Findings were consistent across subgroup and sensitivity analyses. Higher eGDR, indicative of greater insulin sensitivity, was associated with reduced risk of incident all-cause and cause-specific dementia, with a significant non-linear inverse dose-response relationship observed. Individuals with both high eGDR low high AD-PRS exhibited the lowest risk of developing AD. These findings suggest that insulin sensitivity may represent a modifiable target for dementia prevention, particularly among individuals with elevated genetic susceptibility.},
}

Humans
*Insulin Resistance/physiology
*Dementia/epidemiology/metabolism
Female
Male
Prospective Studies
Risk Factors
Aged
Genetic Predisposition to Disease

@article {pmid42470846,
year = {2026},
author = {Rollo, E and Tafuri, B and Tamburrino, L and Urso, D and Giugno, A and Vilella, D and Zecca, C and De Blasi, R and Gnoni, V and Logroscino, G},
title = {Association of hypoxic burden with brain atrophy in Alzheimer's disease.},
journal = {Journal of the neurological sciences},
volume = {489},
number = {},
pages = {126088},
doi = {10.1016/j.jns.2026.126088},
pmid = {42470846},
issn = {1878-5883},
abstract = {BACKGROUND: Obstructive Sleep Apnea (OSA) is a common comorbidity in Alzheimer's Disease (AD) and may exacerbate neurodegeneration. This study investigates the association between a novel metric of OSA severity-hypoxic burden (HB)-and measures of AD-related neurodegeneration.

METHODS: In this retrospective exploratory study, patients with AD at stage 3 and stage 4 (NIA-AA 2018 criteria), enrolled at a Center for Neurodegenerative Diseases, underwent a complete sleep assessment including polysomnography and 3 T brain Magnetic Resonance Imaging. Correlation analyses were conducted between HB and brain volumes.

RESULTS: Twenty-two patients (36.4% males, mean age 69.8 ± 7.5) were enrolled. OSA was diagnosed in 40.9% of patients. HB inversely correlated with left hippocampus (ρ = -0.553, p = 0.02) and left amygdala (ρ = -0.496, p = 0.04) volumes. AD patients with OSA showed significantly reduced left hippocampal volume than those without OSA (p = 0.038).

CONCLUSIONS: This study highlights that greater OSA severity, measured by HB, correlates with left hippocampus and amygdala atrophy, suggesting a possible association between chronic hypoxia and neurodegeneration in AD.},
}

@article {pmid42470860,
year = {2026},
author = {Fornaro, M and Di Lorenzo, C and Esposito, A and Perona, D},
title = {Cardiovascular risks in psychiatric disorders and psychiatric risks in cardiovascular disorders: implications for prevention and clinical management - a large-scale umbrella review encompassing 76 meta-analyses.},
journal = {Journal of psychosomatic research},
volume = {210},
number = {},
pages = {112930},
doi = {10.1016/j.jpsychores.2026.112930},
pmid = {42470860},
issn = {1879-1360},
abstract = {OBJECTIVE: Psychiatric and cardiovascular disorders often co-occur, complicating their assessment and management. No umbrella review(UR) has summarized the meta-analytic evidence on the co-occurrence of psychiatric and cardiovascular disorders and assessed its credibility.

METHODS: Meta-analytic systematic reviews of observational studies documenting the prevalence, risk factors, and outcomes associated with the co-occurrence of cardiovascular and psychiatric disorders, indexed from inception through March.16.2026, and meeting established diagnostic criteria, were included. Meta-analytic association and prevalence estimates were recalculated and graded based on established or adapted criteria. The AMSTAR-2 assessed the quality of the meta-analyses, while several subgroup analyses and meta-regressions aimed to explain the heterogeneity.

RESULTS: We included 76 meta-analyses yielding 131 meta-analytic estimates. Based on pre-existing meta-analytic evidence, 22/24 prevalence estimates (91.7%) met moderate/strong credibility criteria. Strong credibility emerged for: orthostatic hypotension in Lewy body(58%;95%C.I. = 50-66%) and Alzheimer's dementias(28.0% = 95%C.I. = 17.0-40.0%); pericardial effusion in anorexia nervosa(25.0%;95%C.I. = 17.0-34.0%); in heart failure(HF): major depressive disorder(MDD)(41.9%;95%C.I. = 36.7-47.1%), mild cognitive impairment(MCI)(41.4%;95%C.I. = 38.3-45.6%), anxiety(32.0%;95%C.I. = 26.5-37.6%), MDD + anxiety(24.7%;95%C.I. = 17.9-34.3%), and dementia(19.8%;95%C.I. = 12.9-27.8%); in atrial fibrillation(AF): MCI(26.0%;95%C.I. = 21.0-30.0%), anxiety in patients undergoing pulmonary vein isolation(PVI)(25.0%;95%C.I. = 12.0-46.0%), MDD in PVI patients (20.0%;95%C.I. = 13.0-29.0%); in coronary artery disease: MDD + anxiety(19.8%;95%C.I. = 16.0-24.6%): in schizophrenia spectrum disorders: clozapine-associated-cardiomyopathy(0.6%;95%C.I. = 0.2-2.3%); clozapine-associated-cardiomyopathy absolute death rates (0.0003;95%C.I. = 0.0001-0.0012); clozapine-associated-cardiomyopathy case fatality rate (0.078;95%C.I. = 0.018-0.285). Several additional disorders were multimorbid in>5% of people, yet with a lower credibility rating. No re-pooled risk factors/outcomes reached strong credibility criteria.

CONCLUSIONS: The present study provides an atlas of cardiovascular and psychiatric multimorbidity across varying levels of credibility, reinforcing the need for an integrated, multidisciplinary approach to patient care and for more research on actionable risk/protective factors and outcomes.},
}

@article {pmid42470923,
year = {2026},
author = {Aydoğdu, GS and Ağagündüz, D and Roviezzo, F and Romano, B and Capasso, R},
title = {Therapeutic potential of curcumin in Alzheimer's disease: Multi-target mechanisms of action, experimental and clinical evidence, safety aspects.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {202},
number = {},
pages = {119776},
doi = {10.1016/j.biopha.2026.119776},
pmid = {42470923},
issn = {1950-6007},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impaired cognitive functions; its prevalence is increasing with the growth of the global elderly population. Unfortunately, early diagnostic and treatment methods developed by modern medicine have limited effectiveness for this disease. This situation has increased interest in natural ingredients, such as curcumin, which have beneficial effects on health. Some preclinical studies evaluating the efficacy of curcumin in Alzheimer's disease suggest that it may have preventive, protective, and therapeutic effects through various mechanisms, including anti-amyloidogenic effects, improvement of tau pathology, cholinesterase inhibition, anti-inflammatory and antioxidant effects, metal chelation, microbiota modulation, and epigenetic regulation. Similarly, some preclinical studies indicate that curcumin-based probes may offer a promising approach to the diagnosis of Alzheimer's disease. However, inconsistencies exist between preclinical and clinical studies. Curcumin's low bioavailability and high systemic elimination may be among the most significant causes of these inconsistencies. It is also thought that this situation may be related to differences and limitations in preclinical and clinical study designs. There is a need for preclinical studies that follow comprehensive, standardized protocols and for larger-scale, long-term, well-designed clinical trials to evaluate the effectiveness of curcumin in the early diagnosis, prevention, and treatment of Alzheimer's disease. In addition, potential risks, such as the toxicological effects of curcumin with increased bioavailability and curcumin-drug interactions in Alzheimer's patients, should be evaluated.},
}

@article {pmid42471032,
year = {2026},
author = {Barrera-Chamorro, L and Gonzalez-de la Rosa, T and Arzalluz-Luque, J and Torrecillas-Lopez, M and Marquez-Paradas, E and Claro-Cala, CM and Navarro-Hortal, MD and Eichau, S and Garcia-Sanchez, MI and Montserrat-de la Paz, S},
title = {Sustainable next-generation prebiotics for brain health: microbiota-gut-brain axis in neurodegenerative and demyelinating diseases.},
journal = {Critical reviews in food science and nutrition},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/10408398.2026.2703335},
pmid = {42471032},
issn = {1549-7852},
abstract = {Neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are increasingly associated with disruption of the microbiota-gut-brain axis. Common alterations include reduced beneficial microbial taxa, impaired short-chain fatty acid production, intestinal and blood-brain barrier dysfunction, and sustained inflammatory responses. These findings support the development of microbiota-targeted dietary interventions. This review summarizes current evidence on polyphenols, bioactive peptides, and pectin-derived oligosaccharides (POS) as prebiotic or prebiotic-like compounds with potential activity through the microbiota-gut-brain axis. Particular attention is given to structure-function relationships, host-microbe interactions, and the sustainable recovery of these compounds from food by-products. Preclinical studies suggest that these bioactives may reduce microglial activation, improve mitochondrial function, strengthen intestinal and blood-brain barrier integrity, and enhance cognitive or motor performance. Early clinical studies also indicate possible benefits on mood, selected cognitive outcomes, metabolic regulation, and inflammatory biomarkers, although evidence remains limited. Microbiota-derived metabolites from polyphenols, such as urolithins, together with glycomacropeptide and POS, appear to be key mediators. However, clinical validation in major neurodegenerative diseases remains fragmented. Standardized formulations, mechanistic trials, harmonized endpoints, and precision-nutrition strategies are required to confirm their therapeutic potential.},
}

@article {pmid42471071,
year = {2026},
author = {Hu, K and Gao, W and Pan, J and Xu, X and You, P and Li, K and Yang, G and Wang, D and Jiang, M and Wang, X and Zhao, Y and Xu, Y},
title = {Ginkgo biloba Extract 50 alleviates memory and synaptic plasticity deficits by inhibiting neuroinflammation via the blockage of ATP-P2X7R axis in presenilin 1/2 conditional double knockout mice.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122199},
doi = {10.1016/j.jep.2026.122199},
pmid = {42471071},
issn = {1872-7573},
abstract = {Ginkgo biloba L. has been widely utilized in traditional Chinese medicine for its potential to enhance memory-related functions. In traditional medical practices, it is also commonly prescribed for conditions associated with cognitive decline and age-related disorders. These ethnopharmacological uses are closely linked to neurodegenerative disorders, in which neuroinflammation plays a central role. Ginkgo biloba has shown anti-inflammatory and neuroprotective properties, yet its underlying mechanisms in modulating neuroinflammation are still not fully understood.

AIM OF THE STUDY: Neuroinflammation is critically involved in cognitive impairment and neurodegenerative diseases, while therapeutic options remain limited. Ginkgo biloba extract 50 (GBE50) is a standardized formulation with potential neuroprotective properties. This study aimed to assess its effects on neuroinflammation-associated cognitive dysfunction and to clarify the mechanisms involved.

METHODS: Presenilin 1/2 conditional double knockout mice served as a cognitive impairment model, with behavioral tests used to evaluate cognitive function. The constituents of GBE50 were identified by UPLC-Q-TOF-MS, and ATP content was quantified using biochemical assays. The expression of P2X7 receptor, NLRP3 inflammasome-related proteins, inflammatory cytokines, and synaptic markers was determined at both mRNA and protein levels using qRT-PCR and Western blotting. Microglial activation and P2X7R distribution were assessed via immunofluorescence, and hippocampal synaptic plasticity was examined using LTP recordings.

RESULTS: Using UPLC-Q-TOF-MS, 51 compounds were characterized in GBE50, mainly flavonoids and terpene lactones, which are likely responsible for its biological activities. Treatment with GBE50 markedly alleviated cognitive impairment in PS cDKO mice. It downregulated P2X7R and key components of the NLRP3 inflammasome (NLRP3, NEK7, Caspase-1, and ASC), while also reducing the transcription of pro-inflammatory cytokines including Il-1β, Il-18, and Tnf-α. In parallel, GBE50 restored synaptic protein levels and improved long-term potentiation deficits.

CONCLUSION: Collectively, our findings suggest that modulation of the ATP-P2X7R-NLRP3 axis contributes to the neuroprotective effects of GBE50 in AD, highlighting this pathway as a promising therapeutic target for preventing AD-related neurodegeneration.},
}

@article {pmid42471077,
year = {2026},
author = {Liu, Y and Li, Y and Zhou, Y and Hei, Y and Wang, S and Bajpai, AK and Chang, X and Wang, X and Xu, F and Yao, C},
title = {STAT3 mediated the isoleucine-induced Alzheimer's disease progression.},
journal = {Brain research},
volume = {},
number = {},
pages = {150472},
doi = {10.1016/j.brainres.2026.150472},
pmid = {42471077},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts millions globally, with rising prevalence among the aging population, emphasizing the need for effective interventions. Isoleucine, a branched-chain amino acid, crosses the blood-brain barrier and plays a role in various neurological disorders. In this study, we investigated the association of isoleucine with AD traits using the BXD mouse reference population, revealing significant correlations with Y-maze performance, anxiety assays, contextual fear conditioning, and the age of onset for working memory deficits. In vitro, exogenous isoleucine supplementation in HT22 and PC12 cells increased amyloid precursor protein (APP) and phosphorylated tau (p-tau) levels. Subsequent analysis identified 2,000 probes correlated with isoleucine and revealed STAT3 as a candidate downstream regulator. Overexpression of STAT3 increased APP and p-tau levels, and STAT3 inhibition abolished this effect, suggesting that isoleucine modulates AD progression via STAT3 activation. Mendelian randomization analysis further supported a causal relationship between elevated isoleucine levels and AD risk. This work provides insights into isoleucine as a potential risk factor for AD and identifies STAT3 as a mediator of isoleucine-related AD susceptibility.},
}

@article {pmid42471087,
year = {2026},
author = {Yao, M and Liu, A and Xing, L and Song, J and Yang, Y and Yue, X and Li, H},
title = {Neurovascular unit senescence as a driver of blood-brain barrier dysfunction in Alzheimer's disease：mechanisms, consequences, and therapeutic implications.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103260},
doi = {10.1016/j.arr.2026.103260},
pmid = {42471087},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder (NDD), with ageing as its primary risk factor. Cellular senescence, characterized by permanent cell-cycle arrest, apoptosis resistance and acquisition of the senescence-associated secretory phenotype (SASP), is the cellular hallmark of ageing. Recent evidence indicates that blood-brain barrier (BBB) dysfunction precedes cognitive decline and pathological protein deposition, representing an early event in AD, with the neurovascular unit (NVU) providing the structural and functional basis of the BBB. Mounting evidence shows that the core NVU cells-brain microvascular endothelial cells (BMECs), pericytes and astrocytes-enter senescence under AD-related conditions. SASP factors released by these cells disrupt BBB junction proteins and trans-BBB transport systems, and propagate senescence within the NVU via paracrine signaling. Peripheral inflammatory mediators and immune cells then traverse the compromised BBB, aggravating AD pathology, while accumulating Aβ, tau and reactive oxygen species (ROS) reciprocally accelerate NVU senescence, constituting a proposed vicious cycle. At the molecular level, the cGAS-STING pathway concurrently drives senescence maintenance, SASP induction and type I interferon (IFN-I)-mediated downregulation of BBB junction proteins, serving as a key convergence point linking NVU senescence to BBB injury. From the NVU perspective, this review systematically examines how cellular senescence drives BBB dysfunction and AD progression, clarifies the role of cGAS-STING as a molecular node, and discusses therapeutic strategies targeting NVU senescence to preserve BBB integrity, aiming to offer new insights into AD mechanisms and treatment.},
}

@article {pmid42471130,
year = {2026},
author = {Manouvriez, D and Kuchcinski, G and Lecerf, S and Lahousse, H and Rogeau, A and Villain, N and Kas, A and Pyatigorskaya, N and Nguyen, M and Petrovic, S and Cole, JH and Zabihi, M and Hache, B and Bertoux, M and Lebouvier, T and Roca, V and Lopes, R and , and , and , and , },
title = {PatientSpace: A multimodal graph-based latent representation framework for modeling neurodegenerative disease heterogeneity.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122136},
doi = {10.1016/j.neuroimage.2026.122136},
pmid = {42471130},
issn = {1095-9572},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD) exhibit substantial biological and clinical heterogeneity, complicating diagnosis, subtype characterization, and prediction of disease progression. We introduce PatientSpace, a multimodal graph-based latent representation framework designed to model neurodegenerative disease heterogeneity using T1-weighted MRI and FDG-PET. PatientSpace is built upon a structured variational autoencoder that integrates multimodal neuroimaging features while organizing patients within a latent space constrained by age, diagnosis, and a consistency regularization term encouraging similarity between neuroimaging phenotypes. This design enables the construction of an interpretable patient graph in which neighborhood relationships reflect biological similarity. Applied to cohorts of cognitively normal individuals, AD, and FTD patients, PatientSpace revealed multiple disease clusters associated with distinct neuroimaging patterns and clinical severity. Diagnostic classification achieved performance comparable to state-of-the-art deep learning models, while graph-based neighborhood inference enabled prediction of structural volumes, metabolic activity, and cognitive severity. Projection of mild cognitive impairment (MCI) subjects from an independent cohort further showed that cluster membership was associated with differential risks of dementia conversion and distinct longitudinal trajectories. Together, these results demonstrate that PatientSpace provides an interpretable framework linking multimodal neuroimaging representations to disease subtypes, patient-level characterization, and progression modeling in neurodegenerative disorders.},
}

@article {pmid42468248,
year = {2026},
author = {Zhao, B and Shang, S and Zhang, M and Guo, X and Zhou, R and Qu, Q and Cao, H},
title = {Comparison of sleep characteristics between Alzheimer's disease dementia and Parkinson's disease dementia.},
journal = {Sleep medicine},
volume = {147},
number = {},
pages = {109140},
doi = {10.1016/j.sleep.2026.109140},
pmid = {42468248},
issn = {1878-5506},
abstract = {BACKGROUND: Alzheimer's disease (AD) dementia and Parkinson's disease dementia (PDD) both frequently involve sleep disturbances, but the characteristics of sleep disruption differ between the two patient groups, and the extent of these differences remains unclear.

METHODS: We consecutively enrolled 105 patients with AD and 104 with PDD from a memory clinic. All participants underwent assessments of global cognition (MMSE, MoCA), daily living (ADL), anxiety and depression (HAMA, HAMD), and sleep characteristics (PSQI, RBD, daytime nap questionnaire, Epworth Sleepiness Scale). Multivariable regression analyses were conducted to examine whether sleep characteristics differed independently between the two groups. ROC curves evaluated discriminative performance.

RESULTS: Global PSQI scores did not differ between the two groups. In univariate analyses, PDD patients reported worse subjective sleep quality (the first PSQI component), more sleep disturbances, greater use of hypnotics, higher daytime nap frequency and duration, and a much higher prevalence of RBD. After full adjustment, PDD remained independently associated with poorer sleep quality (B = 0.355, 95% CI: 0.092-0.619, p = 0.008), higher daytime nap frequency (B = 2.124, 95% CI: 1.327-2.920, p < 0.001), and RBD (OR = 18.482, 95% CI: 3.297-103.603, p = 0.001). A combination of sleep items (sleep quality, nap frequency, RBD) distinguished PDD from AD with an AUC of 0.763.

CONCLUSIONS: Despite a comparable total PSQI score, PDD patients showed significantly poorer sleep quality (the first PSQI component), more frequent daytime napping, and a much higher prevalence of RBD compared with AD patients. Subjective sleep profiling may help to understand the differential sleep burden in these common dementias.},
}

@article {pmid42468306,
year = {2026},
author = {Khalafi, M and Hojjati, SH and Wang, XH and Tanzi, EB and Liao, V and Kumar, S and Parikh, NS and Chiang, GC},
title = {Liver steatosis and cognitive performance in aging: A pilot cross-sectional study.},
journal = {Clinical imaging},
volume = {138},
number = {},
pages = {110903},
doi = {10.1016/j.clinimag.2026.110903},
pmid = {42468306},
issn = {1873-4499},
abstract = {PURPOSE: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to dementia. We investigated whether liver steatosis or fibrosis is associated with early cognitive changes, while exploring related mechanisms like body mass index (BMI) and cerebral β-amyloid deposition.

METHODS: In this cross-sectional study, we enrolled 26 cognitively unimpaired individuals, who underwent amyloid PET and comprehensive clinical, neurological, and neuropsychological evaluations, including the Telephone Interview for Cognitive Status (TICS). Liver steatosis and fibrosis were quantified noninvasively using vibration-controlled transient elastography (FibroScan®; Echosens, Paris, France) with an M-probe, with the controlled attenuation parameter (CAP) used to quantify liver steatosis. Multivariate regression models were used to assess relationships between liver and cognitive measures, adjusting for age.

RESULTS: In our cohort (mean age 72.2 ± 8.4 years), greater liver steatosis was associated with lower TICS scores, using both the CAP score (β = -0.03, p = 0.021) and steatosis grade (β = -1.39, p = 0.023). Higher liver stiffness was also negatively associated with TICS scores (β = -1.39, p = 0.042). BMI was significantly associated with greater cerebral amyloid burden (β = 9.03, p = 0.01), higher steatosis grade (β = 0.30, p = 0.03), and higher CAP scores (β = 9.47, p = 0.003).

CONCLUSION: Liver steatosis associates with lower cognitive scores in older adults. BMI associates with both steatosis and amyloid burden, which may reflect co-occurring metabolic pathways. These findings provide evidence for targeting metabolic health to preserve cognition and mitigate Alzheimer's pathology.},
}

@article {pmid42468396,
year = {2026},
author = {Du, H and Zhao, P and Yang, Z and Li, B and Bao, Y and Shi, X},
title = {Development and validation of a parsimonious and noninvasive clinical decision machine learning model for predicting the risk of long-term mild cognitive impairment in older adults: A multinational cohort study.},
journal = {International journal of medical informatics},
volume = {220},
number = {},
pages = {106612},
doi = {10.1016/j.ijmedinf.2026.106612},
pmid = {42468396},
issn = {1872-8243},
abstract = {BACKGROUND: Early identification of mild cognitive impairment (MCI) is crucial for delaying the progression of dementia. However, existing prediction models often require expensive testing or invasive biomarkers, limiting their scalability in primary care settings.

METHODS: Data were drawn from three prospective cohorts: the Chinese Longitudinal Healthy Longevity Survey (CLHLS), the English Longitudinal Study of Ageing (ELSA), and the Health and Retirement Study (HRS). We included 11,069 participants aged ≥60 years who were free of cognitive impairment at baseline. Incident MCI was defined via cohort-specific assessments. The CLHLS was used for internal training and testing, and the ELSA and HRS were used for independent external validation. After feature selection via Shapley additive explanations (SHAP) and recursive feature elimination, 9 machine learning models were developed. Model performance was evaluated on the basis of discrimination, calibration, and clinical utility. SHAP was used for model interpretation.

RESULTS: Over the 6-year follow-up period, 2486 participants developed MCI (CLHLS: n = 1008; ELSA: n = 488; HRS: n = 990). Five easily accessible baseline predictors were selected: age, sex, education, instrumental activities of daily living, and baseline cognitive score. The gradient boosting classifier demonstrated favorable overall performance, achieving an internal area under the curve (AUC) of 0.869 (95% CI 0.84-0.90). It maintained robust generalizability during external validation in the ELSA (AUC 0.786, 95% CI 0.76-0.81) and HRS (AUC 0.745, 95% CI 0.73-0.76) cohorts. Furthermore, an interactive web tool incorporating Shapley additive explanations was deployed to conduct a transparent risk assessment.

CONCLUSIONS: This study developed and externally validated a parsimonious, cross-national machine learning model utilizing five noninvasive features to predict long-term MCI risk. Integrated with a transparent SHAP framework and deployed as an interactive web application, it provides a cost-effective clinical decision support tool for early MCI screening in primary care (https://mcipredictor.streamlit.app/).},
}

@article {pmid42468562,
year = {2026},
author = {Lim, L and Little, D and Redman, S and Cookson, AN},
title = {Machine learning for predicting full-count FDG PET brain images from low-count acquisitions in suspected dementia: a clinical and quantitative evaluation.},
journal = {Physics in medicine and biology},
volume = {},
number = {},
pages = {},
doi = {10.1088/1361-6560/ae8c9f},
pmid = {42468562},
issn = {1361-6560},
abstract = {Objective.Artificial intelligence methods for denoising low-count FDG PET brain images are usually evaluated using image quality metrics alone, with limited direct clinical assessment, particularly in suspected dementia. This study evaluated a machine-learning image quality transfer (IQT) method for predicting full-count FDG PET brain images from low-count acquisitions using both quantitative metrics and blinded clinical assessment. Approach.Forty-one FDG PET/CT patients with suspected dementia were retrospectively included, with low-count images simulated using 5% of list-mode data. An IQT random forest model employing patch-wise regression was evaluated using image quality metrics, regional Z-scores, and blinded radiologist assessment against standard-count references. Main results.AI-predicted images showed an average peak signal to noise ratio (PSNR) improvement of approximately 4 dB and reduced root mean square error (RMSE) compared with low-count images. Clinically, uninterpretable scans were reduced to 0% for each reader, down from 20% and 50% respectively, with a shift from tentative to confident agreement with the reference standard reports. By contrast, the structural similarity index measure (SSIM) and regional Z-score agreement showed no improvement. Significance.In patients with suspected dementia, where motion and limited tolerance of long acquisitions are common, this study demonstrates for the first time the potential of an image quality transfer (IQT) method to improve the clinical usability of low-count FDG PET scans. The findings also indicate the importance of task-based clinical evaluation, since quantitative metrics alone were insufficient to capture the clinically relevant improvements observed in image interpretability and reader confidence.},
}

@article {pmid42468638,
year = {2026},
author = {Fu, T and Wei, C and Shen, D and Zhong, J and Liu, B and Xu, F},
title = {Ceanothane-type triterpenoids: Phytochemistry, biosynthesis, pharmacological activities, and therapeutic potential.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107390},
doi = {10.1016/j.fitote.2026.107390},
pmid = {42468638},
issn = {1873-6971},
abstract = {Ceanothane-type triterpenoids (CTTs) are a class of natural triterpenoids characterized by a distinctive 5/6/6/6/5 pentacyclic skeleton featuring a five-membered A-ring. They are mainly distributed in plants of the Rhamnaceae family, such as Ziziphus, Hovenia, Paliurus. To date, 64 natural CTTs and 28 synthetic derivatives have been reported. This review systematically summarizes their structural classification, pharmacological activities, putative biosynthetic pathways, and pharmacokinetic profiles. CTTs exhibit a broad spectrum of bioactivities, including antitumor, antimicrobial, antiinflammatory, hepatoprotective, anti-Alzheimer's disease (AD), antimalarial, and immunomodulatory effects, with mechanisms involving multi-target regulation. Furthermore, we discuss current challenges and future perspectives in structural modification, structure-activity relationship (SAR) studies, and mechanistic exploration, aiming to provide a comprehensive reference for the further development of CTTs as therapeutic agents.},
}

@article {pmid42468644,
year = {2026},
author = {Li, M and Zhao, Y and Xu, B and Wang, L and Luo, W and Tan, R and Zhang, X and Jiang, H},
title = {Polygonatum sibiricum polysaccharides and Alzheimer's disease: A review of preparation, structure, mechanisms, and application.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107393},
doi = {10.1016/j.fitote.2026.107393},
pmid = {42468644},
issn = {1873-6971},
abstract = {Polygonatum sibiricum is a well-established botanical resource with dual medicinal and edible applications. Polygonatum sibiricum polysaccharides (PSP), the principal bioactive constituent of P. sibiricum, have long attracted research interest due to their structural diversity and broad spectrum of biological activities. Beyond its well-documented antioxidant, antibacterial, anti-inflammatory, antitumor, and anti-aging properties, PSP has recently demonstrated promising therapeutic potential in alleviating Alzheimer's disease (AD). However, current research findings on PSP remain fragmented, and a comprehensive framework elucidating the specific mechanisms by which it ameliorates AD is lacking. Based on this, this review begins with the extraction, isolation, purification, and structural characterization of PSP, systematically summarizes the multiple mechanisms by which PSP ameliorates AD, and provides an overview of its structural modification, toxicological studies, and multi-domain applications, aiming to offer theoretical support for the further development and translational application of PSP in the prevention and treatment of AD.},
}

@article {pmid42468665,
year = {2026},
author = {Girish Oswal, D and Rane, M},
title = {Is Urolithin A(UA) a Pharmacologically Credible Neuro-Nutraceutical? A Critical Review of Mechanisms, Brain Exposure, and Evidence Gaps in Alzheimer's and Parkinson's Disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106224},
doi = {10.1016/j.neuint.2026.106224},
pmid = {42468665},
issn = {1872-9754},
abstract = {Urolithin A(UA) is a gut microbiota-derived metabolite of dietary ellagitannins and ellagic acid, generated by specific gut bacterial species and absent from food in free form. Preclinical evidence indicates that UA restores PINK1/Parkin-mediated mitophagy, attenuates NF-κB, NLRP3 inflammasome and cGAS-STING-driven neuroinflammation, and preserves synaptic and cognitive function across rodent and cell-culture models of Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. However, circulating UA in humans exists predominantly as phase II glucuronide and sulfate conjugates rather than free aglycone, and human clinical evidence to date establishes UA's safety, favorable pharmacokinetics, mitochondrial target engagement, and benefits to muscle strength and physical function in middle-aged and older adults, with no completed trial yet evaluating cognitive or neurodegenerative disease-modifying outcomes. This review critically examines whether UA's neuroprotective mechanisms are pathway-specific and supported by convergent preclinical and human data, while explicitly separating mechanistic plausibility from demonstrated clinical efficacy.UA therefore represents a promising but still investigational neuro-nutraceutical candidate, with a mechanistic foundation strong enough to justify dedicated, CNS-endpoint-focused clinical trials as the next logical step toward establishing its neuroprotective potential in humans.},
}

@article {pmid42468794,
year = {2026},
author = {Li, J and Wang, Y and Ma, X and Bi, X and Wu, T and Zhang, N and Wang, F and Liu, T and Geng, F},
title = {Microneedle-mediated drug delivery systems for brain diseases.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {},
number = {},
pages = {102996},
doi = {10.1016/j.nano.2026.102996},
pmid = {42468794},
issn = {1549-9642},
abstract = {Brain diseases pose a major global health challenge, with the blood-brain barrier (BBB) as the core obstacle for intracranial drug delivery. Microneedles, a minimally invasive technology, can bypass the BBB via intracranial implantation, nose-to-brain, trigeminal nerve, and transdermal systemic routes. This review covers the structural classification, biomaterials, and bypass BBB delivery mechanisms of brain-targeted microneedles. Using glioblastoma, Alzheimer's disease, and Parkinson's disease as models, we overview preclinical microneedle formulations and key signaling pathways, and establish a matching framework linking therapeutic targets, drugs, and microneedle types. We further analyze clinical translation bottlenecks including limited drug loading, unclear long-term biosafety, manufacturing challenges, and regulatory gaps, and propose future directions in technical innovation, standardized evaluation, and regulatory improvement. This work may guide the rational design and clinical translation of microneedle-mediated brain-targeted drug delivery systems.},
}

@article {pmid42468803,
year = {2026},
author = {Zhang, X and Huang, Q and Huang, J and Zhang, P and Feng, X and Li, Z and Raper, DMS and Mao, C},
title = {Frailty-related plasma proteomic signatures and key biomarkers for new-onset dementia and its subtypes: A prospective cohort study.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.07.040},
pmid = {42468803},
issn = {2090-1224},
abstract = {BACKGROUND: Frailty is a well-established clinical risk factor for dementia, but its underlying mechanisms remain poorly defined. We aimed to investigate whether proteomic signatures and individual proteins linked to frailty could predict and characterize the association between frailty and dementia.

METHODS: We analyzed over 52,000 UK Biobank participants free of dementia at baseline, with plasma profiles of 2,915 proteins. Physical frailty (PF) and a 49-item frailty index (FI) were assessed. Proteomic signatures were derived using multivariable linear regression and 100 repeated LASSO selections. Incident dementia was ascertained via linkage to hospital and mortality records. Associations with incident dementia were assessed using multivariable Cox proportional hazards models, dose-response, and mediation analyses.

RESULTS: During 13.6 years of follow-up, 1,437 participants developed dementia. Proteomic signatures for PF and FI were independently associated with dementia risk (hazard ratios [HRs] up to 2.80). Stratification by signature quintiles showed clear gradients in both absolute and relative dementia risk. For all-cause dementia, cumulative incidence ranged from 1.19% to 5.27% (HR up to 3.29), and for vascular dementia, from 0.16% to 1.19% (HR up to 4.53). Similar trends were observed for Alzheimer's dementia. Mediation analysis indicated that proteomic signatures statistically accounted for 46%-53% of the association between frailty and dementia risk. Key proteins, including GDF15, HPGDS, ITGAV, SPP1, CHGA, and LGALS4, were identified as top contributors and mapped to immune-inflammatory, neuroimmune, and extracellular matrix pathways.

CONCLUSION: Frailty-related proteomic signatures and key proteins predict dementia risk and capture biological features beyond clinical frailty. These molecular markers may facilitate early risk stratification and support future research into prevention strategies.},
}

@article {pmid42468901,
year = {2026},
author = {Halabian, N and Park, C and Omoto, L and Bocca, LF and Palacios, G and Wu, K and Hamani, C and Rabin, J and Abrahao, A and Davidson, B and Lipsman, N and Meng, Y},
title = {Focused ultrasound blood brain barrier opening for targeted therapeutics in neurodegenerative diseases.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.07.008},
pmid = {42468901},
issn = {1873-2402},
abstract = {Therapeutic focused ultrasound (FUS) leverages the non-invasive ultrasonic waves to modify the biological tissue. When administered alongside intravenous microbubbles, low-intensity FUS enables transient, targeted disruption of the blood-brain barrier (BBB), permitting passage of systemically administered therapeutics into the central nervous system (CNS) with high spatial precision. The ability to selectively modulate BBB permeability at the disease site has the potential to substantially expand the number of therapeutics that can be utilized in treating illnesses afflicting the CNS. Herein, we review the current applications of FUS for treating neurodegenerative disorders and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). We discuss the research developments to date and future directions.},
}

@article {pmid42468989,
year = {2026},
author = {Baraniuk, C},
title = {Alzheimer's drug lecanemab: FDA approves easier initial use, with "huge implications" for UK.},
journal = {BMJ (Clinical research ed.)},
volume = {394},
number = {},
pages = {e100318},
doi = {10.1136/bmj-2026-100318},
pmid = {42468989},
issn = {1756-1833},
}

@article {pmid42469165,
year = {2026},
author = {Ichimata, S and Hata, Y and Yoshida, K and Tanaka, R and Murayama, S},
title = {Clinicopathological and molecular heterogeneity of amyloid-β in unnatural deaths under 70 years: A forensic autopsy-based study.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70124},
doi = {10.1111/bpa.70124},
pmid = {42469165},
issn = {1750-3639},
support = {//Uehara Memorial Foundation/ ; },
abstract = {This study investigated the clinicopathological characteristics and molecular spectrum of amyloid-beta (Aβ) in unnatural deaths among relatively young individuals with moderate-to-severe Aβ deposition, including cases of early-onset Alzheimer's disease. A total of 856 forensic autopsy cases aged 40-69 years were analyzed. Detailed semiquantitative and quantitative immunohistochemical analyses were performed in the neocortex, striatum (caudate nucleus, putamen, and nucleus accumbens [NAc]), and amygdala using antibodies targeting multiple Aβ species (Aβ38, Aβ39, Aβ40, Aβ42, Aβ43, pyroglutamate-modified Aβ at the third glutamate residue [AβNp3E], and serine 8-phosphorylated Aβ), as well as phosphorylated tau. Ward's hierarchical cluster analysis was also performed. Thirty-three cases (eight females; 3.9%), including six early-onset Alzheimer's disease cases, were identified. Three cases exhibited genetic abnormalities (one with Down syndrome and two with presenilin 1 [PSEN1] mutations). Marked regional heterogeneity in Aβ molecular profiles was observed, particularly within the striatum. Notably, the NAc displayed a distinct pattern of Aβ deposition and occasional NAc-predominant cerebral amyloid angiopathy. Cases with cognitive impairment (CI) demonstrated more advanced Aβ and tau pathology than CI-negative cases; notably, interstitial Aβ42 and Aβ43 burdens were significantly elevated across all regions. Strikingly, siblings carrying the same PSEN1 mutation-one with CI and the other without-exhibited divergent pathological patterns. Although suicide accounted for approximately one-third of cases, a higher neocortical Aβ burden was associated with a lower frequency of suicide, and no significant difference in suicide rates was observed compared with cases lacking substantial Aβ deposition. Cluster analysis identified a subgroup characterized by relatively elevated striatal Aβ deposition, particularly AβNp3E. Collectively, these findings indicate that the severity of Aβ deposition is not directly associated with suicide. However, early involvement of the NAc may contribute to depressive states, and region-specific Aβ species-particularly Aβ42, Aβ43, and AβNp3E-may be associated with increased cognitive vulnerability in this age group.},
}

@article {pmid42469217,
year = {2026},
author = {Dodd, RB and Enomoto, M and Zhou, Y and Satoh, K and Zhang, Y and Chen, F and Acheson, B and Ghaffari, D and Sayn-Wittgenstein, E and Manning, JJ and Dukas, GV and Patel, R and Burguete, AS and Kralovec, MJ and Rashid, M and Hall, JL and Tamucci, KA and Chatila, Z and Liu, M and Lee, AJ and Vardarajan, BN and Taga, MF and Pollari, S and Rabinovitch, A and Rillahan, CD and Bobkov, AA and Sergienko, E and Meadows, W and Qamar, S and Randle, SJ and Johnson, CM and Sevalle, J and Griffin, J and Bohm, C and Ikura, M and Xian, X and Herz, J and Kelly, MA and West, J and Satapathy, S and Wilson, MR and Javitch, JA and Fraser, PE and Bennett, DA and De Jager, PL and Fishelson, Z and Frenkel, D and Asher, WB and Bradshaw, EM and George-Hyslop, PS},
title = {CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-75140-3},
pmid = {42469217},
issn = {2041-1723},
support = {203249/Z/16/Z//Wellcome Trust (Wellcome)/ ; 406915//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33[M] splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33[M] ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33[M], but not CD33[m]. We show that in human monocytes CD33[M]:CLU binding induces CD33[M] ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33[M] ectodomain fragment (sCD33[M]) - absent from CD33[m]-expressing cells - which could contribute to the role of CD33[M] in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33[M] axis, highlighting CD33[M] dimerization and ligand-binding sites as potential therapeutic targets.},
}

@article {pmid42469559,
year = {2026},
author = {Walker, L and Attems, J and Donaghy, P},
title = {Neuropathological correlates of imaging in dementia with Lewy bodies.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42469559},
issn = {1435-1463},
abstract = {Dementia with Lewy bodies (DLB) is a common yet underdiagnosed neurodegenerative dementia, characterised neuropathologically by nigrostriatal dopaminergic degeneration and widespread α-synuclein aggregation. Clinical diagnosis remains challenging due to marked heterogeneity in presentation and substantial overlap with Alzheimer's disease (AD), resulting in diagnostic delays and frequent misdiagnosis. The ability to identify underlying pathological processes ante-mortem is essential to improve diagnostic accuracy, refine prognosis, stratify patients for clinical trials, and ultimately enable personalised therapeutic approaches. Over recent decades, major advances have been made in the development of neuroimaging biomarkers that reflect key features in Lewy body disease pathology, many of which have informed diagnostic criteria. In addition to dopaminergic dysfunction and α-synuclein pathology, co-existing neuropathologies including amyloid-β, tau, neuroinflammation, and vascular changes are increasingly recognised as important modifiers of clinical phenotype and disease trajectory in DLB. This review summarises the current landscape of neuroimaging modalities in DLB and critically examines their relationships with confirmed neuropathological correlates. We discuss indicative biomarkers such as striatal dopamine imaging and [123]I-metaiodobenzylguanidine myocardial scintigraphy, alongside supportive imaging markers derived from structural magnetic resonance imaging and Fluorodeoxyglucose Positron Emission Tomography (FDG-PET). Emerging PET approaches targeting α-synuclein, as well as established amyloid and tau-PET techniques for assessing co-pathologies, are reviewed in the context of post-mortem validation studies. Finally, we consider Translocator protein PET imaging as a marker of neuroinflammation and highlight key methodological limitations and knowledge gaps. Together, these neuroimaging-pathological correlations provide critical insights into disease mechanisms and outline future directions toward earlier, biologically informed diagnosis and precision medicine in DLB.},
}

@article {pmid42469568,
year = {2026},
author = {Kaushik, S and Fatima, JE and Raheem, A and Barbhuiya, MA and Thirupathi, AT and Singh, LP and Khan, PA and Aparna, TN and Pramanik, S and Shahid, MAA},
title = {Nanomedicine targeting neuroinflammatory pathways in Alzheimer's disease: a new frontier in inflammopharmacology.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42469568},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative illness characterized by progressive cognitive impairment, synaptic compromise, and relentless neuroinflammation. Increasing evidence suggests that neuroinflammatory cascades orchestrated by microglial activation, astrocytic malfunction, cytokine hyperproduction, and inflammasome signalling are at the core of AD pathogenesis. Conventional anti-amyloid and cholinergic treatments are only symptomatic and neglect the inherent neuroimmune dysregulation. Nanomedicine is a revolutionary frontier in inflammopharmacology, which enables the accurate modulation of neuroinflammatory circuits and enhanced brain delivery of medicines. Nanocarriers designed by engineering, including liposomes, polymeric nanoparticles, dendrimers, and exosomes, allow for targeted delivery across the BBB, increase drug bioavailability, and provide controlled release. The nano-systems are capable of inhibiting pro-inflammatory signalling, such as NF-κB and MAPK pathways, reducing oxidative stress, and enhancing microglial M2 polarization and thus restoring neuronal homeostasis. Recent developments in surface-functionalized and stimuli-responsive nanoplatforms further enable active targeting through receptor-mediated pathways and theranostic imaging in real-time. Comparative studies show that interventions based on nanocarrier-based therapies enhance therapeutic efficacy and safety profiles in preclinical AD models. Future directions include integrating AI-driven nano-design, gene and siRNA delivery, and precision neuropharmacology to enable personalized anti-inflammatory therapies. Substantial progress, translational challenges remain regarding long-term biocompatibility, large-scale production, and clinical validation. Nanomedicine against neuroinflammatory pathways represents a new paradigm for Alzheimer's treatment, linking molecular pharmacology and sophisticated nanotechnology to next-generation neuroinflammatory medicine.},
}

@article {pmid42469606,
year = {2026},
author = {Low, A and Gunter, JL and Hu, M and Raghavan, S and Przybelski, SA and Schwarz, CG and Kantarci, K and Lowe, VJ and Petersen, RC and Graff-Radford, J and Jack, CR and Vemuri, P},
title = {Perivascular Spaces as Determinants of Amyloid, Tau, and Vascular Biomarker Progression.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78299},
pmid = {42469606},
issn = {1531-8249},
support = {R01 AG056366/NH/NIH HHS/United States ; R37 AG011378/NH/NIH HHS/United States ; U01 AG006786/NH/NIH HHS/United States ; R01 AG034676/NH/NIH HHS/United States ; U01 NS100620/NH/NIH HHS/United States ; P30 AG062677/NH/NIH HHS/United States ; },
abstract = {OBJECTIVE: Magnetic resonance imaging (MRI)-visible enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (SVD) and aging, processes implicated in both neurodegenerative and cerebrovascular pathologies. However, longitudinal positron emission tomography (PET) studies examining PVS as a mechanism underlying Alzheimer's disease (AD) pathophysiological progression are lacking. Our overall objective was to investigate the associations of baseline PVS burden with white matter hyperintensity (WMH) volume, amyloid-PET, and tau-PET, both cross-sectionally and longitudinally.

METHODS: We examined 2,229 participants across the aging-AD spectrum from the Mayo Clinic Study of Aging (MCSA) and the Mayo Alzheimer's Disease Research Center (ADRC) (mean age = 68.59 ± 12.70 and 48.94% women). PVS and WMH were quantified using a novel in-house algorithm. Amyloid on [[11]C]Pittsburgh Compound B (PiB)-PET and tau on AV1451-PET were measured. Cross-sectional regional and global associations were examined using canonical correlation analysis (CCA). Longitudinal associations were examined using age- and sex-adjusted linear mixed effect (LME) models with natural splines and subject-wise 10-fold cross-validation.

RESULT: Three distinct associations were observed: (1) PVS in the basal ganglia (PVS-BG) was associated with greater WMH volume both cross-sectionally and longitudinally; (2) PVS-BG covaried with higher PiB standardized uptake value ratio (SUVR) cross-sectionally, with longitudinal trajectory associations limited to amyloid-negative individuals; (3) PVS in the centrum semiovale (PVS-CSO) was not associated with amyloid or tau, but was associated with occipital WMH, a pattern characteristic of CAA.

INTERPRETATION: Findings lend support for PVS-BG as an early indicator of small vessel dysfunction and WMH pathogenesis. Individuals with higher PVS-BG burden exhibited higher WMH burden and faster WMH progression, suggesting that PVS-BG may identify individuals at increased risk of progressive SVD. Evidence linking PVS to downstream AD biomarker progression was weaker. Findings support the relevance of PVS-CSO to CAA, suggesting that they may reflect changes occurring early in the disease process. ANN NEUROL 2026.},
}

@article {pmid42469846,
year = {2026},
author = {Tang, X and Chen, R and Xing, J and Huang, Q and Luo, L and Ouyang, C and Ma, F and Wen, J and Zhang, J and Kong, L and Cai, Y and Wang, Y and Cui, L},
title = {Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03956-3},
pmid = {42469846},
issn = {1742-2094},
support = {20252BAC200485//Natural Science Foundation of Jiangxi Province/ ; 2025R201//Zhanjiang Science and Technology Plan Talent Enclave Special Project/ ; 82101269//National Natural Science Foundation of China/ ; 82071190//National Natural Science Foundation of China/ ; 2024A1515011464//Natural Science Foundation of Guangdong Province, China/ ; 2024B1515230001//Natural Science Foundation of Guangdong Province, China/ ; GCC2021010//high-level talents scientific research start-up funds of the Affiliated Hospital of Guangdong Medical University/ ; GCC2022001//the high-level talents scientific research start-up funds of the Affiliated Hospital of Guangdong Medical University/ ; GJPY004//National-Level Talent Cultivation Funding Program of The Affiliated Hospital of Guangdong Medical University/ ; },
abstract = {BACKGROUND: Current therapies for Alzheimer's disease (AD) offer only symptomatic relief, highlighting the urgent need for disease-modifying approaches capable of halting or reversing neurodegeneration. Extracellular vesicles (EVs) have attracted growing interest as therapeutic vehicles owing to their inherent capacity to bypass the blood-brain barrier and deliver complex biological cargo to the central nervous system.

METHODS: Here, we examined whether large EVs (LEVs) derived from microglia with stable Sirtuin-2 knockdown (SIRT2-KD) confer the neuroprotective effects associated with SIRT2 inhibition. LEVs harvested from SIRT2-KD microglia were administered intranasally to APP/PS1 mice. We assessed microglial uptake of LEVs, along with subsequent changes in cellular metabolism, migration toward amyloid-beta (Aβ) plaques, phagocytic activity, and downstream pathological and behavioral outcomes. Proteomic and acetylomic profiling were employed to characterize the molecular cargo of LEVs-SIRT2-KD.

RESULTS: LEVs-SIRT2-KD were readily internalized by microglia in vivo following intranasal delivery. Uptake of these vesicles markedly enhanced microglial bioenergetics, driving coordinated upregulation of both oxidative phosphorylation and glycolysis. This metabolic shift was accompanied by improved microglial recruitment to Aβ plaques and increased phagocytic clearance. Consequently, treated mice showed reduced Aβ plaque deposition, restored synaptic integrity, and reversal of cognitive deficits. Proteomic and acetylomic analyses revealed that LEVs-SIRT2-KD are selectively enriched in proteins and acetylation modifications linked to energy metabolism and phagocytic function, offering a mechanistic basis for the observed metabolic reprogramming.

CONCLUSION: Together, these results identify LEVs as a critical vesicle subtype mediating the effects of SIRT2 knockdown and support a cell-free therapeutic strategy for AD centered on EVs-driven metabolic reprogramming of microglia.},
}

@article {pmid42469894,
year = {2026},
author = {Jiang, Z and Ding, Y},
title = {Coffee as a polypharmacological modulator of mitochondrial health: from molecular mechanisms to translational implications.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08662-5},
pmid = {42469894},
issn = {1479-5876},
support = {LQ24H160009//Zhejiang Provincial National Natural Science Foundation of China/ ; LHZY24H020002//Hangzhou Joint Fund of the Zhejiang Provincial Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Coffee is one of the most widely consumed beverages worldwide, yet its biological effects have often been attributed primarily to caffeine. Emerging evidence suggests that coffee contains a complex array of bioactive compounds, including chlorogenic acids, trigonelline, diterpenes, and melanoidins that collectively exert pleiotropic effects on cellular metabolism. However, a comprehensive framework linking the full spectrum of coffee-derived bioactives to mitochondrial health and chronic disease prevention is still lacking.

MAIN BODY: This review proposes an integrated perspective on coffee as a systemic "mitochondrial network optimizer." We present this model as an integrative framework and hypothesis rather than an established causal model. We synthesize molecular, pre-clinical, and clinical evidence suggesting that coffee bioactives converge on key regulatory nodes, namely the AMPK/SIRT1/PGC-1α axis, Nrf2/ARE antioxidant pathway, PINK1/Parkin-mediated mitophagy, and mitochondrial calcium signaling to coordinately enhance mitochondrial biogenesis, quality control, redox defense, and metabolic efficiency. These multi-targeted mechanisms provide a plausible biological basis for the consistent epidemiological associations between moderate coffee consumption and reduced risk of metabolic diseases (type 2 diabetes, non-alcoholic fatty liver disease), neurodegenerative disorders (Parkinson's, Alzheimer's), and cardiovascular conditions. Furthermore, we critically examine key determinants of response heterogeneity, including non-linear hormetic dose-response relationships, inter-individual variability (CYP1A2 genotype, gut microbiota, sex), and the impact of coffee processing and brewing methods on bioactive composition.

CONCLUSIONS: Collectively, these findings support the hypothesis that coffee may serve as a paradigm of polypharmacological dietary intervention that targets fundamental pathways of mitochondrial resilience. Moving beyond reductionist views centered on single compounds, we propose that the holistic effects of coffee are best understood through systems-level modulation of mitochondrial homeostasis. Future research should prioritize precision nutrition approaches stratified by genotype, microbiome, and metabolic phenotype, to translate these mechanistic insights into personalized dietary recommendations and the development of mitochondria-targeted nutraceuticals. We caution that this integrative framework requires direct validation in human causal studies.},
}

@article {pmid42469913,
year = {2026},
author = {Janahi, M and Lorenzini, L and Oxtoby, NP and Barkhof, F and Mokrab, Y and Schott, JM and Altmann, A and Initiative, FTADN},
title = {Multi-threshold polygenic risk improves hippocampal-based cognitive decline prediction.},
journal = {Genome medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13073-026-01722-x},
pmid = {42469913},
issn = {1756-994X},
support = {MR/T046422/1/MRC_/Medical Research Council/United Kingdom ; 733051106/ZONMW_/ZonMw/Netherlands ; ANR-19-JPW2-000//Agence Nationale de la Recherche/ ; 1191535//National Health & Medical Research Council, Australia/ ; 2019-2.1.7-ERA-NET-2020-00008//National Research, Development and Innovation Office, Hungary/ ; },
abstract = {BACKGROUND: Predicting cognitive decline from brain MRI is a central question in neuroscience. Hippocampal volume (HV) is a key cognitive biomarker, and normative models can be augmented with multimodal information. Here we augment normative models with genetic information and show improvements in cognitive decline prediction across multiple experimental setups.

METHODS: We improve normative models for HV by integrating multi-threshold polygenic scores (PGS) with demographic and imaging data using Gaussian Process Regression (GPR). Models were trained on 23,997 participants from UK Biobank (UKBB) and validated on 3,000 out-of-sample participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the European Prevention of Alzheimer's Disease (EPAD) cohorts.

RESULTS: Our genetically-informed models significantly strengthened associations across six experimental designs and 13 key neurocognitive measures, including Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Alzheimer's Disease Assessment Scale (ADAS), while enhancing prediction of future cognitive decline.

CONCLUSIONS: Together, these findings underscore the promise of integrating multi-threshold PGS with neuroimaging-based predictive models to improve prognostication and early intervention strategies for neurodegenerative diseases.},
}

@article {pmid42469972,
year = {2026},
author = {Li, X and Li, L and Ren, Y and Shi, L and Sun, M and Liu, Z},
title = {A bibliometric analysis of research trends and mechanisms of olfactory dysfunction in Alzheimer's diseases from 2008 to 2024.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49799},
pmid = {42469972},
issn = {1536-5964},
support = {2025JC-YBQN-1144//Project of Shaanxi Provincial Department of Science and Technology/ ; },
mesh = {*Alzheimer Disease/complications/physiopathology ; *Bibliometrics ; Humans ; *Olfaction Disorders/physiopathology/etiology ; *Biomedical Research/trends ; },
abstract = {BACKGROUND: Olfactory dysfunction (OD) and Alzheimer disease (AD) represent significant global public health challenges. Growing evidence underscores the need to clarify the neuropathological mechanisms underlying their association. Our study intends to analyze global research trends and overlapping molecular mechanisms underlying OD and AD.

METHODS: Reviews and articles on OD and AD published between 2008 and 2024 were extracted from the Web of Science Core Collection. CiteSpace and VOSviewer were applied to for the analysis and visualization of the publication outputs, as well as the distribution of countries/regions, institutions and authors, the journals output, keywords co-occurrence, and reference citations. Molecular targets and associated pathways were investigated by GeneCards, STRING, and Metascape databases.

RESULTS: One thousand nine hundred sixteen publications were identified, demonstrating steady growth in research output across 7006 institutions from 398 countries. The USA emerged as the top contributor, excelling in both publication output and citation impact. The University of Pennsylvania, University of California San Francisco, and Chinese Academy of Sciences stood out as the top influential institutions. Among 10,476 authors, Thomas Hummel from Technische Universität Dresden, Germany, emerged as the most prominent scholar. In terms of journals, Journal of Alzheimer's Disease leaded in publications in this field. Keywords including "Alzheimer's disease," "olfactory bulb," and "cognitive impairment" represent the current research focuses. A total of 1779 overlapping genes were identified between OD and AD. ACTB, AKT1, TP53, CTNNB1, and INS were identified as the most central regulatory genes. Enrichment analyses revealed involvement in PI3K-Akt, mitogen-activated protein kinases, and cyclic adenosine monophosphate signaling pathways, as well as biological functions related to signaling receptor activator activity, growth factor activity, and cytokine activity.

CONCLUSION: Our study uncovers the dynamic research trends on OD and AD, while we further identified shared molecular mechanisms underlying these 2 disorders. Early olfactory risk assessment, diagnosis, and intervention may serve as critical components in the prevention and management in AD.},
}

*Alzheimer Disease/complications/physiopathology
*Bibliometrics
Humans
*Olfaction Disorders/physiopathology/etiology
*Biomedical Research/trends

@article {pmid42469999,
year = {2026},
author = {Xu, D and Zhou, W and Qiu, H},
title = {Association between dietary antioxidant quality score and cognitive function in older adults: A cross-sectional study based on NHANES 2011-2014.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49758},
doi = {10.1097/MD.0000000000049758},
pmid = {42469999},
issn = {1536-5964},
mesh = {Humans ; *Antioxidants/administration & dosage ; Cross-Sectional Studies ; Female ; Aged ; *Cognition/physiology/drug effects ; Nutrition Surveys ; Male ; *Diet ; Middle Aged ; *Cognitive Dysfunction/epidemiology ; Aged, 80 and over ; },
abstract = {The aim of this study was to examine the connection between the dietary antioxidant quality score (DAQS) and cognitive impairment in older adults. This cross-sectional study of 2713 older adults aged ≥ 60 years from the 2011 to 2014 National Health and Nutrition Examination Survey cohort evaluated cognitive performance at quartile thresholds using the digit symbol substitution test, the animal fluency test, and the consortium to establish a registry for Alzheimer disease word learning test. Vitamins A, C, E, zinc, selenium, and magnesium consumption were used to calculate the DAQS score. Multiple linear regression and logistic regression analyses were used to evaluate the association between DAQS and the cognitive capacities of senior citizens. In the fully adjusted model, higher DAQS was linked to less cognitive impairment (odds ratio = 0.34, 95% confidence interval: 0.22-0.53). According to our research, older adults' cognitive decline is adversely correlated with higher DAQS, and improving their antioxidant intake may help them improve cognitive function.},
}

Humans
*Antioxidants/administration & dosage
Cross-Sectional Studies
Female
Aged
*Cognition/physiology/drug effects
Nutrition Surveys
Male
*Diet
Middle Aged
*Cognitive Dysfunction/epidemiology
Aged, 80 and over

@article {pmid42461890,
year = {2026},
author = {Calandri, IL and Bocancea, DI and Allegri, RF and Suemoto, CK},
title = {Registry-Based Dementia Incidence in Argentina: A Nationwide, Decade-Long Analysis by Age, Sex, and Etiology.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-24},
doi = {10.1159/000553538},
pmid = {42461890},
issn = {1423-0208},
abstract = {BACKGROUND: National data on dementia incidence is scarce in low- and middle-income countries, limiting public health surveillance and planning. In Argentina, no nationwide estimates of dementia incidence exist despite rapid population aging. Administrative disability registries do not capture clinical disease onset; rather, they record certification events and therefore provide a registry-based proxy for population-level dementia surveillance in settings without prospective incidence cohorts.

METHODS: We conducted a population-based registry study using data from Argentina's National Registry of Persons with Disabilities between 2016 and 2022, excluding pandemic-disrupted years (2020-2021). Incident registry entries with dementia recorded as the primary cause of disability were identified using ICD-10 codes for Alzheimer's disease and related disorders (ADRD), vascular dementia, and other etiologies. Crude and age-standardized incidence (ASI) of dementia certification per 100,000 inhabitants were estimated by sex, age group, dementia subtype, and early- (<65 years) versus late-onset (≥65 years) dementia. Pre-specified sensitivity analyses quantified capture fraction against regional cohorts and adjusted temporal trends for an exogenous proxy of registry maturation.

RESULTS: In 2022, the registry-based crude dementia incidence was 47.7 per 100,000 inhabitants (95% CI: 46.6-48.7). Crude incidence was higher in women than men, whereas age-standardized incidence was comparable between sexes (48.1 vs. 45.5 per 100,000). Incidence increased steeply with age, from 0.9 per 100,000 at ages 40-45 to nearly 480 per 100,000 among individuals aged ≥95 years. ADRD predominated from approximately 55-60 years onward, while other etiologies were relatively more frequent at younger ages. Late-onset dementia incidence (≥65 years) was substantially higher than early-onset dementia (<65 years) (130.9 vs. 6.3 per 100,000). Provincial age-standardized rates varied from 4.7 to 137.7 per 100,000, and were strongly associated with care access metrics. Between 2016 and 2022, age-standardized incidence increased significantly (p<0.001); however, capture fractions of 6 to 12% relative to regional cohorts and a 45% attenuation of the temporal coefficient after adjustment for registry maturation.

CONCLUSIONS: This study provides the first nationwide characterization of registry-based dementia certification incidence in Argentina. Distinct age-, sex-, and etiology-specific patterns highlight different epidemiological scenarios for early- and late-onset dementia. Because these estimates reflect administrative certification rather than clinical disease onset and are subject to differential ascertainment, they should be interpreted as a lower bound of true incidence; nonetheless, they constitute a feasible and informative surveillance approach for countries lacking national clinical registries and can support health system planning and prevention strategies.},
}

@article {pmid42461977,
year = {2026},
author = {Zhu, C and Song, L and Mao, S and Li, K and Lin, X},
title = {Receptor-Ligand-Mediated Anchoring of Polyphenol Quantum Dots to Membrane Fragments for Precision Delivery in Alzheimer's Disease Therapy.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c10322},
pmid = {42461977},
issn = {1944-8252},
abstract = {Polyphenol-based carbon dots (PCDs) hold great promise for Alzheimer's disease (AD) treatment owing to their inherent antioxidant activity, ultrasmall size, and favorable blood-brain barrier (BBB) permeability. Nevertheless, rapid immune clearance and poor lesion targeting severely hinder their clinical translation. Conventional cell membrane coating is poorly compatible with ultrasmall PCDs, causing incomplete encapsulation, active site masking, and membrane protein inactivation. Herein, we fabricated a novel biomimetic nanostructure (MQCM) by anchoring mannose-modified quercetin nanodots (MQNDs) onto BV2 cell membrane fragments (CMFs) via specific mannose-CD206 receptor-ligand interactions. This unique binding strategy endowed MQCM with a high anchoring efficiency (84.3%) and improved structural stability. Distinct from conventional nonspecific membrane coating that shields active sites and impairs nanoparticle functionality, this design avoids such drawbacks and completely preserves the intrinsic bioactivity of MQNDs and membrane proteins. The optimized MQCM displays high BBB permeability (42.35%), precise BV2 targeting, and lesion-responsive drug release. BV2-derived CMFs prolong blood circulation and lesion retention of MQNDs, while the released MQNDs exert multiple anti-AD effects by regulating ROS homeostasis, inhibiting Aβ fibrillation, and promoting Aβ autophagy. Collectively, this integrated biomimetic system offers a precise AD therapeutic strategy and advances the clinical translation of PCD-based nanomedicines.},
}

@article {pmid42462262,
year = {2026},
author = {Liang, S and Lapane, KL and Ott, BR and Tjia, J and Baek, J and Yuan, Y and Alcusky, M},
title = {Comparing Effectiveness of Antidepressants for Nursing Home Residents With Dementias and Depressive Symptoms.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70582},
pmid = {42462262},
issn = {1532-5415},
support = {5R01AG068450/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) are frequently accompanied by depressive symptoms, which may accelerate cognitive decline and increase mortality. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly prescribed, yet comparative effectiveness evidence in nursing home residents with ADRD is scarce.

METHODS: We conducted a retrospective cohort study using linked CMS data (2011-2018) of long-stay nursing home residents aged ≥ 65 years with ADRD and baseline depressive symptoms who newly initiated an SSRI or SNRI. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9; self-report or observed) at baseline and 60-120 days after initiation. Outcomes were the change in PHQ-9 scores (continuous) and clinically meaningful improvement. Analyses used overlap propensity score and inverse probability of censoring weighted linear and log-binomial models with generalized estimating equations to account for clustering of nursing home residents. Intention-to-treat (ITT) analyses, as-treated, and subgroup analyses were conducted.

RESULTS: Among 19,397 SSRI initiators and 2581 SNRI initiators, 66.9% had mild depressive symptoms at baseline. Median time from initiation to follow-up assessment was 85 days. In ITT analyses, mean PHQ-9 change was -2.38 for SSRIs and -2.24 for SNRIs (adjusted difference: -0.15; 95% CI, -0.42 to 0.11); clinically meaningful improvement occurred in 55.2% versus 56.9% (risk difference: -1.57; 95% CI, -3.66 to 0.52). As-treated analyses yielded similar results, and findings were consistent across subgroups defined by baseline depression severity, cognitive function, dementia type, and sensitivity analyses.

CONCLUSIONS: SSRIs and SNRIs were similarly effective for depressive symptoms in nursing home residents with ADRD. Given this and modest improvement rates, antidepressant selection should be individualized, emphasizing safety and resident characteristics. Additional research is needed to inform the decision to treat or not to treat, specific medication selection, and when to stop treatment in this population.},
}

@article {pmid42462283,
year = {2026},
author = {Meng, W and Yang, Q and Xu, J and Huang, Y and Wang, C and Song, Q and Song, L and Bian, J and Ma, Q and Ma, A and Yin, R},
title = {Identifying sex-specific sub-phenotypes of Alzheimer's disease progression using longitudinal electronic health records.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106391},
doi = {10.1016/j.ebiom.2026.106391},
pmid = {42462283},
issn = {2352-3964},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a complex neurodegenerative disorder, with women comprising nearly two-thirds of individuals with AD. However, sex-specific heterogeneity in AD progression remains insufficiently understood. A data-driven approach is needed to characterise such heterogeneity from longitudinal electronic health records (EHRs).

METHODS: We developed a deep learning-based framework to uncover sex-specific AD sub-phenotypes using longitudinal EHRs from OneFlorida+ Clinical Research Consortium. We constructed temporal representations of these EHRs and employed an autoencoder architecture to generate latent embeddings, followed by clustering to derive sex-specific sub-phenotypes with associated progression patterns. We also performed statistical and survival analyses to unravel the characteristics of our identified sub-phenotypes.

FINDINGS: From 1665 individuals with AD (961 females, 704 males), we identified five major sex-specific sub-phenotypes of AD with distinct progression pathways and comorbidity patterns. Female-dominant sub-phenotypes presented later AD onset, longer disease duration, and enrichment of respiratory and neurological disorders. Male-dominant sub-phenotypes exhibited earlier onset, shorter duration, and higher prevalence of endocrine and metabolic conditions. Survival analysis showed significant differences in time to AD onset across sub-phenotypes.

INTERPRETATION: Our findings revealed distinct disease trajectories and comorbidity patterns between male- and female-dominant subgroups with AD. This study provides insight into sex-specific AD progression and demonstrates a data-driven framework for characterising disease heterogeneity using longitudinal EHRs.

FUNDING: This study was supported by grants from the Florida Department of Health, the Centers for Disease Control and Prevention, the National Institute of Environmental Health Sciences, and the NIHNational Center for Advancing Translational Sciences.},
}

@article {pmid42462317,
year = {2026},
author = {Ban, Y and Miao, W and Jin, X and Chen, S and Lou, X and Wu, JL and Li, N},
title = {The underappreciated diversity of functional pigments in red yeast rice revealed by an integrated multi-engine mining strategy (IMMS).},
journal = {Food chemistry},
volume = {525},
number = {Pt 1},
pages = {150424},
doi = {10.1016/j.foodchem.2026.150424},
pmid = {42462317},
issn = {1873-7072},
abstract = {Red yeast rice (RYR) is a popular functional food, while its functional components remain severely understudied. This study developed an integrated multi-engine mining strategy (IMMS) ingeniously combining feature-based molecular networking, building blocks-based molecular networking, SIRIUS, PEAKS, and BUDDY to comprehensively analyze RYR components. Employing IMMS, 219 pigments (208 red, 6 orange, 5 yellow) and 104 peptides were first identified, including 185 potential new pigments, with red and yellow pigments showing higher contents. Notably, red pigments demonstrated optimal plasma exposure and brain distribution in rats after oral RYR. Bioactivity analysis first revealed that six typical pigments, especially red, suppressed oxidative stress and neuroinflammation related to Alzheimer's disease in L-Glu-induced HT-22 cells and LPS-induced BV-2 cells, potentially via the Keap1-Nrf2 and IDO1 pathways, respectively. These findings significantly expanded the pigment diversity and RYR components, facilitating the discovery of functional components and providing a foundation for RYR's development as an anti-Alzheimer's functional food.},
}

@article {pmid42462433,
year = {2026},
author = {Bernardes, LMM and Marquez, AS and do Prado Mascarenhas, FNA and de Freitas, LF and Ferreira, DC and Malta, SM and Moreira, AS and Mendonça, TP and Bernardo de Sousa, JN and Silva, ÍF and Correia, LIV and Martins, MM and Ferreira, RB and Zhu, A and Zhang, H and Adebiyi, O and Leung, AK and Espindola, FS and Leite, ML and Ueira-Vieira, C and Mendes-Silva, AP},
title = {Acetonic extract of Saskatoon berry attenuates amyloid-associated neurotoxicity in cellular and Drosophila melanogaster Alzheimer's disease models.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {202},
number = {},
pages = {119774},
doi = {10.1016/j.biopha.2026.119774},
pmid = {42462433},
issn = {1950-6007},
abstract = {Saskatoon berry (Amelanchier alnifolia) is rich in polyphenols known to modulate oxidative stress and neuroinflammation, key mechanisms involved in Alzheimer's disease (AD), yet its neuroprotective potential in this context remains unexplored. Here, we investigated two Saskatoon berry extracts, acetonic and ethanolic, using integrated chemical, computational, cellular and in vivo approaches. Antioxidant activity was confirmed in multiple assays, with stronger radical scavenging and moderate reducing capacity. Chemical profiling revealed solvent-dependent differences in phenolic and flavonoid content. In neuroglial models, the ethanolic extract showed mild-cytotoxicity, whereas the acetonic extract exhibited a favorable safety profile. In an amyloid-beta-induced cellular model, the acetonic extract produced only modest effects on viability. Furthermore, fibroblasts assays showed increased total ATP under non-inflammatory conditions, whereas in the LPS-stimulated inflammatory model the extract increased mitochondrial membrane potential. In contrast, in vivo studies using Drosophila melanogaster AD models showed protective effects of the acetonic extract, including reduced ThT-reactive fluorescence and increased retinal thickness, while improved survival was observed in w[1118] flies. Gene expression analysis of flies' brain tissue showed altered expression of selected mitochondrial- and immune-related genes. The AD-like model showed increased expression of co1, nd1, tfam and dipt, which were significantly reduced following treatment. Overall, these findings identify Saskatoon berry as a novel natural source of bioactive compounds with anti-Alzheimer's potential and suggest that the in vivo protective effects may involve mitochondrial homeostasis and immune-related processes, warranting future mechanistic studies and neuronal-specific validation in more complex organisms.},
}

@article {pmid42462519,
year = {2026},
author = {Morsy, NA and El-Shiekh, RA and Ebrahium, MM and Srour, AM},
title = {Rational design and synthesis of dispiroindene-pyrrolidinedione scaffolds as multi-target directed ligands: potent AChE inhibitors with antioxidant activity and favorable biocompatibility in SH-SY5Y cells.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110245},
doi = {10.1016/j.bioorg.2026.110245},
pmid = {42462519},
issn = {1090-2120},
abstract = {Addressing the urgent need for multi-target therapies in Alzheimer's disease, we report the rational design and one-pot, multi-component synthesis of novel substituted dispiroindene-pyrrolidinedione scaffolds (4a-r). Systematic biological evaluation identified five lead compounds (4g, 4j, 4k, 4m, and 4p) with potent inhibitory activity. Derivative 4k emerged as the primary lead, exhibiting an IC50 for Acetylcholinesterase (AChE) of 2.58 ± 0.11 μM and a remarkable selectivity index of 15.71, significantly exceeding that of donepezil (4.37), the reference drug. Concurrently, the series demonstrated notable affinity for Butyrylcholinesterase (BChE), with several derivatives exhibiting submicromolar to low micromolar inhibition. Furthermore, these scaffolds demonstrated superior antioxidant potential; notably, compound 4p achieved an IC50 value of 25.23 ± 1.25 μM, demonstrating an approximate 5-fold increase in radical scavenging potency relative to ascorbic acid (128.20 μM). In vitro safety assays on SH-SY5Y human neuroblastoma cells confirmed excellent biocompatibility, with compound 4m displaying an IC50 of 125.00 ± 6.91 μM, nearly four times less toxic than donepezil (32.84 μM). Molecular docking validated these results, showing robust π-π stacking and halogen-based stabilization within the catalytic anionic site. These findings, supported by ADME profiles predicting high blood-brain barrier permeability, position the dispiroindene-pyrrolidinedione framework as a highly effective, low-toxicity, multi-functional candidate for the development of Alzheimer's disease therapeutics.},
}

@article {pmid42462634,
year = {2026},
author = {Wang, X and Tong, J and Wang, M and Du, B and Wang, H and Liu, H and Yang, X and Mu, R and Wang, K and Liu, X and Wang, Q},
title = {Amyloid-like nanofilm-decorated antifouling field effect transistor biosensor array for enhancing Alzheimer's disease diagnosis.},
journal = {Biosensors & bioelectronics},
volume = {312},
number = {},
pages = {119030},
doi = {10.1016/j.bios.2026.119030},
pmid = {42462634},
issn = {1873-4235},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder. Compared to the limited specificity of single-biomarker detection, the combined detection of multiple biomarkers can significantly improve the accuracy of AD diagnosis. In this study, a field-effect transistor (FET) biosensor array integrating four independently functionalized regions was fabricated by modifying carbon nanotube (CNT) surfaces with amyloid bovine serum albumin (AL-BSA) nanofilm as an antifouling layer, enabling the simultaneous detection of multiple tau proteins. The proposed FET biosensor exhibited excellent anti-fouling performance while maintaining high sensitivity, with detection limits as low as 3.3 fg/mL, 0.17 fg/mL, 0.02 fg/mL, and 2.5 fg/mL for p-tau181, p-tau217, p-tau231, and t-tau, respectively. Evaluation of 35 clinical serum samples indicated that p-tau181 outperformed the other three tau proteins as an AD diagnostic biomarker. By further incorporating a support vector machine (SVM)-based machine learning algorithm and employing multi-biomarker co-detection, the accuracy of AD diagnosis can be improved to nearly 100%. This study provides a novel strategy for array FET biosensors with high clinical application potential for the precise detection of AD.},
}

@article {pmid42462667,
year = {2026},
author = {Yang, F and Chen, Y and Yan, Y and Zhao, R and Deng, L and Tian, D and Wang, Q and Xie, M},
title = {RVG-functionalized microglial membrane-coated cerium-gallic acid metal-organic frameworks for multi-target Alzheimer's therapy.},
journal = {Journal of colloid and interface science},
volume = {724},
number = {Pt 2},
pages = {141133},
doi = {10.1016/j.jcis.2026.141133},
pmid = {42462667},
issn = {1095-7103},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by aberrant β-amyloid (Aβ) aggregation, oxidative stress, neuroinflammation, and disrupted metal ion homeostasis, which limit the efficacy of conventional single-target therapies. To address these intertwined pathological processes, we developed a multifunctional nanotherapeutic platform based on a cerium-gallic acid bio-metal-organic framework (CeGA-MOF). Reversible Ce[3+]/Ce[4+] redox cycling enables efficient reactive oxygen species (ROS) scavenging, while gallic acid serves as both an organic ligand and metal chelator, inhibiting metal ion-mediated Aβ aggregation and alleviating oxidative stress-associated neurotoxicity, along with its intrinsic anti-inflammatory activity. To enhance in vivo stability and brain delivery, CeGA-MOF was coated with microglial membranes and functionalized with rabies virus glycoprotein (RVG) peptide, yielding a biomimetic nanosystem, CeGA-MOF/B/R. The microglial membrane provides immune evasion and inflammation-guided targeting, while RVG facilitates blood-brain barrier penetration. In vitro, CeGA-MOF/B/R effectively chelates Cu[2+], Zn[2+], and Fe[3+], suppresses metal ion-induced Aβ aggregation, and protects neurons. In APP/PS1 transgenic mice, it reduced cerebral Aβ, promoted anti-inflammatory microglial polarization, and improved learning and memory, highlighting its potential as a biomimetic nanoplatform for synergistic AD therapy.},
}

@article {pmid42463036,
year = {2026},
author = {Cheng, M and Zheng, X and Wei, YD and Ge, JF},
title = {Role of Abca7-related microglial responses in linking type 2 diabetes mellitus to Alzheimer's Disease progression: Evidence from single-cell transcriptomic analysis and experimental validation in animal and cell models.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179152},
doi = {10.1016/j.ejphar.2026.179152},
pmid = {42463036},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share overlapping pathological mechanisms characterized by neuroinflammation and metabolic dysfunction, yet the underlying mechanisms remain elusive. In this study, we aimed to investigate the potential involvement of Abca7 in the microglial responses linking AD and T2DM. Single-cell RNA sequencing (scRNA-seq) data from the hippocampi of db/db and db/m mice were analyzed to characterize cellular heterogeneity. To validate the bioinformatic findings, an AD mouse model was established by a single intracerebroventricular injection of Aβ1-42. Behavioral performances were observed, and the protein expression of Abca7 and typical neuropathological features of AD were detected. In parallel, in vitro studies were conducted using BV2 microglial cells exposed to Aβ1-42 following Abca7 knockdown. The scRNA-seq analysis revealed significant alterations in endothelial cells, microglia, and oligodendrocytes in db/db mice. Microglia emerged as central regulators of neuroinflammatory responses, with Abca7 identified as a hub gene linked to both T2DM and AD pathology. Consistently, the expression of Abca7 in the hippocampus of AD mice was markedly elevated and positively correlated with the cognitive impairments and Aβ/Tau pathology. Moreover, the knockdown of Abca7 could protect BV2 cells against Aβ-induced injuries and hyperactivation which could be partly ascribed to the suppression of NF-κB signaling and oxidative stress. Overall, these results suggest Abca7 may play a linking role in the microglial response between T2DM and AD, which is partly supported by in vivo and in vitro results of its effect on the hyperactivation of microglia in AD-like pathologies.},
}

@article {pmid42463181,
year = {2026},
author = {Kuznetsov, AV},
title = {Predicting biological age using an accumulated neurotoxicity biomarker for amyloid Beta oligomers.},
journal = {Mathematical medicine and biology : a journal of the IMA},
volume = {},
number = {},
pages = {},
doi = {10.1093/imammb/dqag005},
pmid = {42463181},
issn = {1477-8602},
abstract = {This study proposes using accumulated neurotoxicity, defined as the time integral of Aβ oligomer concentration, as a biomarker for neuronal aging. A relationship between biological age and accumulated neurotoxicity is proposed. Numerical analysis guided the development of a new analytical solution linking the biological and calendar ages of neurons. The effects of Aβ monomer and oligomer half-lives-key indicators of proteolytic efficiency-on biological age are examined. Both constant and age-dependent (exponentially increasing) half-life scenarios are considered. The findings indicate that increasing the half-life of Aβ monomers and oligomers with age accelerates biological aging. Reducing Aβ monomer production is shown to slow biological aging, with a linear relationship established between these two quantities. Additionally, biological age is found to depend linearly on the half-deposition time of Aβ oligomers into senile plaques. The model demonstrates that biological age is irreversible, providing a theoretical explanation for why plaque-clearing therapies cannot reverse established cognitive impairment. The model also demonstrates that biological age is path-dependent rather than state-dependent.},
}

@article {pmid42463287,
year = {2026},
author = {Maass, A and Garcia-Garcia, B and Behrenbruch, N and Schumann-Werner, B and Molloy, EN and Schwarck, S and Rullmann, M and Hochkeppler, A and Fischer, L and Büchel, AT and Bernal, J and Vockert, N and Incesoy, EI and Glanz, W and Butryn, M and Schulze, P and Baldauf, K and Stephens, AW and Schildan, A and Patt, M and Behnisch, G and Morgado, B and Esselmann, H and Seidenbecher, CI and Schott, BH and Wiltfang, J and Barthel, H and Sabri, O and Kreissl, MC and Düzel, E},
title = {Associations of [[18]F]PI-2620 Binding with Memory and Phosphorylated Tau 217 in Cognitively Unimpaired Older Adults.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.271927},
pmid = {42463287},
issn = {1535-5667},
abstract = {[[18]F]PI-2620 is a second-generation tau PET tracer that may detect early tau accumulation in aging. We investigated whether temporal lobe [[18]F]PI-2620 binding is associated with age, sex, genetic Alzheimer disease (AD) risk, plasma biomarkers of AD (plasma phosphorylated tau 217 [p-tau217], Aβ1-42/Aβ1-40), astrogliosis (glial fibrillary acidic protein), and domain-specific cognition in cognitively unimpaired (CU) older adults. Methods: In this study, 166 CU older adults (mean age, 72 ± 7 y; females, 46%; apolipoprotein ϵ4 [APOE4] carriers, 23%) and 13 young adults underwent extensive cognitive testing, blood sampling, MRI, and dynamic [[18]F]PI-2620 PET (0-60 min postinjection). Associations of regional [[18]F]PI-2620 distribution volume ratio (DVR) with age, sex, APOE4 genotype, and plasma biomarkers were examined using region-of-interest and voxelwise analyses. Additional imaging markers of age-related pathology included hippocampal volume, medial temporal lobe thickness, white matter (WM) hyperintensities, perivascular spaces, and hippocampal perfusion (R1-derived maps). Associations among temporal lobe DVR, other imaging markers, and domain-specific cognitive performance (from factor analysis) were tested. Results: In older adults, temporal [[18]F]PI-2620 binding was higher in women (β = 0.543, P < 0.001) and APOE4 carriers (β = 0.395, P = 0.030) and was positively associated with plasma p-tau217 (β = 0.22, P = 0.008). Voxelwise analyses showed age-related increases in basal ganglia signal, whereas WM signal was higher in younger adults. In a multiple regression model, higher temporal DVR (β = -0.36, P = 0.003) and lower hippocampal volume (β = 0.22, P = 0.007) predicted worse episodic memory and, together with demographic factors, explained approximately 30% of the variance. Conclusion: Temporal [[18]F]PI-2620 binding is associated with genetic AD risk, plasma p-tau217, female sex, and episodic memory deficits in CU older adults, supporting its sensitivity to early tau pathology, while highlighting the need to consider potential WM binding.},
}

@article {pmid42463411,
year = {2026},
author = {Shi, Y and Liao, X and Yu, G},
title = {Advances in Tricyclic Compounds for the Treatment of Alzheimer's Disease.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70384},
doi = {10.1002/cmdc.70384},
pmid = {42463411},
issn = {1860-7187},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Structure-Activity Relationship ; Animals ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Structure ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder involving interconnected pathological pathways, including cholinergic dysfunction, Aβ deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and dysregulation of metal ion homeostasis. Recently, the "one drug, one target" paradigm has faced certain clinical limitations, driving a paradigm shift toward multi-target therapeutic strategies. In this context, tricyclic scaffolds, characterized by rigid fused-ring skeletons, excellent structural tunability, and favorable neuropharmacological properties, have emerged as promising scaffolds for developing multi-target AD therapeutics. These molecules can interact with multiple AD-related targets through stable π-π stacking and hydrophobic interactions. Some tricyclic scaffolds, such as tetrahydrocarbolines, share structural similarity with endogenous neurotransmitters, suggesting potential involvement in modulating cognitive and mood-related pathways, along with favorable BBB permeability and neuro-compatibility. Accordingly, this review begins by outlining the distinct pathological mechanisms underlying AD, followed by a summary of recent progress on tricyclic compounds, encompassing both single-target and multi-target-directed molecules, with an emphasis on structure-activity relationships and mechanisms of action, aiming to offer new insights and strategies for combating this devastating disease.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
Structure-Activity Relationship
Animals
*Cholinesterase Inhibitors/chemistry/pharmacology
Molecular Structure
Oxidative Stress/drug effects

@article {pmid42463545,
year = {2026},
author = {Trares, K and Duman, D and Beyer, L and Michaelian, JC and Stocker, H and Holleczek, B and Beyreuther, K and Schöttker, B and Gerwert, K and Brenner, H},
title = {Predictive value of plasma p-tau217 for Alzheimer's dementia compared to other blood-based biomarkers.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42463545},
issn = {1757-4684},
abstract = {Phosphorylated-tau (p-tau217) is a promising blood-based biomarker for Alzheimer's dementia (AD) in clinical settings. However, research from prospective cohort studies is sparse. We measured plasma p-tau217 levels in baseline blood samples of 779 participants in a population-based cohort of older adults followed over 17 years. Associations with AD were assessed and compared to those with previous measurements of p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Comparisons to the amyloid beta (Aβ) misfolding biomarker were performed in a subgroup analysis. P-tau217, NfL and GFAP showed strong associations with AD risk, especially within the first 9 years of follow-up, outperforming p-tau181. Over the later years of follow-up, the predictive accuracy of p-tau217 was significantly reduced. In contrast, the Aβ misfolding biomarker demonstrated superior performance especially as a preclinical indicator of the risk of AD many years before diagnosis. The combination of p-tau217 with NfL, GFAP, basic demographic and genetic information, as well as the misfolding biomarker yielded an AUC 0.86 for AD diagnoses over the entire 17-year follow-up period.},
}

@article {pmid42463666,
year = {2026},
author = {Bjørnholm, KD and Li, H and Del Gaudio, F and Mocci, G and Shao, W and Baldisseri, E and Rao, SB and Lindblad, C and Fletcher-Sandersjöö, A and Vázquez-Liébanas, E and Pietilä, R and Muhl, L and Jiang, R and Kalantzi, C and Cheung, J and Jin, S and Svensson, M and Lesnik Oberstein, SAJ and Syvänen, S and Mäe, MA and Torp, R and Lendahl, U and Karlström, H and Thelin, EP and Nilsson, P and Vanlandewijck, M},
title = {Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer's, CADASIL, and Traumatic Brain Injury.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42463666},
issn = {2041-1723},
mesh = {Animals ; *Microglia/metabolism/pathology ; *Alzheimer Disease/genetics/pathology/metabolism ; Disease Models, Animal ; Mice ; Humans ; *Brain Injuries, Traumatic/genetics/pathology/metabolism ; *CADASIL/genetics/pathology/metabolism ; Transcriptome ; Mice, Transgenic ; Male ; Brain/blood supply/pathology/metabolism ; Single-Cell Analysis ; },
abstract = {The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.},
}

Animals
*Microglia/metabolism/pathology
*Alzheimer Disease/genetics/pathology/metabolism
Disease Models, Animal
Mice
Humans
*Brain Injuries, Traumatic/genetics/pathology/metabolism
*CADASIL/genetics/pathology/metabolism
Transcriptome
Mice, Transgenic
Male
Brain/blood supply/pathology/metabolism
Single-Cell Analysis

@article {pmid42463670,
year = {2026},
author = {Anwer, D and A, A and Marchi, A and Kerkhoven, E and Polster, A},
title = {Network-based discovery of regulatory drivers of cognitive decline in alzheimer's disease.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42463670},
issn = {2731-6068},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, yet its transcriptional regulatory architecture remains poorly understood. Here, we model sample-specific gene regulatory networks (GRNs) from dorsolateral prefrontal cortex transcriptomes of 87 individuals with AD and 67 non-cognitively impaired (NCI) controls and use a machine learning classifier to detect consistent disease-specific network features. This sample-specific network approach captures inter-individual variation in transcriptional regulation and revealed 22 key transcription factor-gene regulations that distinguish AD from NCI with 96% weighted accuracy. The key transcription factor-gene interactions were enriched in pathways central to AD pathology, including synaptic signalling, mitochondrial function, proteostasis, and neuroinflammation. Network analysis uncovered significant differences in regulatory connectivity between AD and controls, with ZNF225, ZNF849, and ZNF548 emerging as AD-specific regulatory hubs. Moreover, several key regulatory edges showed significant correlations with longitudinal cognitive decline, supporting their clinical relevance. Our findings highlight pervasive transcriptional dysregulation in AD, emphasizing sample-specific GRN modelling's value in uncovering regulatory mechanisms.},
}

@article {pmid42463907,
year = {2026},
author = {Yang, D and Guo, W and Wang, B},
title = {The Exercise-CTSS-AD Axis: a novel framework for understanding exercise-induced neuroprotection in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42463907},
issn = {1573-7365},
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; Animals ; *Cathepsins/metabolism ; *Neuroprotection/physiology ; *Exercise/physiology ; Blood-Brain Barrier/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Disease-modifying therapies for Alzheimer's disease (AD) targeting amyloid-β and tau have consistently failed, highlighting the urgent need for innovative therapeutic strategies. Cathepsin S (CTSS), a lysosomal cysteine protease upregulated in AD, functions as a "multifaceted disruptor" that interconnects neuroinflammation, blood-brain barrier (BBB) dysfunction, and Aβ metabolic dysregulation. Although exercise is a validated non-pharmacological intervention that mitigates AD pathology, its multi-target molecular mechanisms remain elusive. Here, we propose and substantiate the "Exercise-CTSS-AD Axis" hypothesis, positing that exercise confers neuroprotection by suppressing CTSS through synergistic anti-inflammatory, anti-aging, and metabolic regulatory pathways. Exercise-induced myokines and clearance of senescent cells inhibit CTSS transcription, while AMPK-TFEB axis activation enhances lysosomal function to repress CTSS enzymatic activity. This systemic CTSS suppression preserves BBB integrity, ameliorates microglia-driven neuroinflammation, and restores Aβ homeostasis by reducing production and enhancing clearance. Our framework provides a unifying molecular explanation for the pleiotropic benefits of exercise, positions CTSS as a quantifiable biomarker for personalized exercise regimens, and supports an innovative combinatorial strategy: "Exercise + low-dose CTSS inhibitors" as a disease-modifying therapy for AD.},
}

*Alzheimer Disease/metabolism/therapy
Humans
Animals
*Cathepsins/metabolism
*Neuroprotection/physiology
*Exercise/physiology
Blood-Brain Barrier/metabolism
Amyloid beta-Peptides/metabolism