@article {pmid42283695,
year = {2026},
author = {El Mammeri, N and Hong, M},
title = {Structures and Dynamics of Tau Assemblies from Solid-State NMR.},
journal = {Accounts of chemical research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.accounts.6c00208},
pmid = {42283695},
issn = {1520-4898},
abstract = {ConspectusAggregation of the microtubule-associated protein tau into β-sheet fibrils is a hallmark of many neurodegenerative diseases. Understanding the molecular mechanism of tau aggregation requires elucidating the structure and dynamics of fibrillar tau as the end product of aggregation, membrane-bound tau involved in nucleation and intercellular transmission of the aggregates, and microtubule-bound tau as the physiological state of the protein. Using solid-state NMR spectroscopy, we have obtained detailed information about these tau assemblies. Full-length tau fibrils formed in the presence of heparin adopt homogeneous structures that depend on the number of microtubule-binding repeats and that differ from ex vivo tau fibril structures. Phospho-mimetic mutations allowed heparin-free fibrillization, with mutation of the PHF1 epitope yielding a three-layered rigid core that mimics the fold of four-repeat (4R) tau in tauopathies. This three-layered structure is also adopted by other post-translational modification (PTM) mutants, indicating that tau's PTM code contains redundancy and dominance. In all tau fibrils, the rigid core represents only a fifth of the protein. Truncation of the disordered regions accelerated fibrillization, but the fibril fold is sensitive to temperature, pH, and ionic condition of the environment. In a short tau construct, acidic pH stabilized a flat-ribbon dimer structure, whereas neutral pH stabilized the twisted C-shaped fold of Alzheimer's disease (AD) tau. The reproducible in vitro reconstruction of AD-fold tau opens the path for studying small-molecule binding to AD tau for developing diagnostics and therapeutics. However, seeding experiments indicate that full-length tau adopting the AD fold lacks seeding potency; therefore, the rigid core structure alone does not ensure prion-like propagation of pathological tau. Instead, specific fuzzy coat dynamics may be required for serial amplification of tau aggregates. An essential property to replicate is likely the fuzzy coat dynamics. Solid-state NMR data show that tau dynamics depends on PTMs, and the most dynamic segments in three-layered tau lie in the proline-rich region, suggesting that separation of this region from the rigid core may be important for prion-like propagation of tau aggregates. Cholesterol-rich high-curvature lipid membranes alone induce tau fibrils and allow their insertion into the membrane, supporting the model that lipid membranes are involved in the nucleation and transmission of tau aggregates. Finally, solid-state NMR data show that the highest-affinity microtubule-binding domain of tau is the R' segment that is N-terminal to the PHF1 epitope, suggesting that stabilizing this segment may inhibit aggregation. These solid-state NMR data of multiple types of tau assemblies have provided numerous insights into the structures and dynamics of tau in pathology and physiology, advancing the reconstruction of the aggregation mechanism of tau in neurodegeneration.},
}

@article {pmid42283996,
year = {2026},
author = {Totuk, O},
title = {Amyloid-Related Imaging Abnormalities in Anti-amyloid Therapy: Clinical Implications of Kinetics for Safer Use and Risk Stratification.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {42283996},
issn = {1179-1918},
abstract = {Anti-amyloid monoclonal antibodies have emerged as disease-modifying therapies for Alzheimer's disease. However, their broader clinical adoption is limited by amyloid-related imaging abnormalities, a key safety concern. Traditionally viewed as an unavoidable and dose-dependent adverse effect, amyloid-related imaging abnormalities often lead to treatment interruption or the exclusion of high-risk patients from therapy. Emerging evidence now suggests that amyloid-related imaging abnormalities may instead reflect a transient modifiable cerebrovascular response, primarily influenced by the kinetics of amyloid clearance rather than the absolute magnitude of amyloid removal. Recent data from titration-based dosing strategies demonstrate that gradual amyloid mobilization can significantly reduce the incidence of amyloid-related imaging abnormalities without compromising amyloid positron emission tomography responses or downstream biomarkers. This kinetic perspective may support a more nuanced re-evaluation of patient groups previously deemed unsuitable for therapy, including APOE ε4 carriers, individuals with cerebral microbleeds, and patients on antithrombotic treatment. In this Current Opinion, we propose a pragmatic clinical framework that integrates amyloid clearance kinetics, magnetic resonance imaging-based risk stratification, and individualized protocols for treatment interruption and re-challenge. By reframing amyloid-related imaging abnormalities as a modifiable clinical decision-making challenge rather than an inherent toxicity, anti-amyloid therapies may be optimized for safer use; however, whether such approaches can enable broader and more inclusive treatment strategies remains to be established in prospective studies, particularly in high-risk populations.},
}

@article {pmid42284103,
year = {2026},
author = {Rahman, A and Hayes, EH and Adams, DJ},
title = {Mass Spectrometry-Based Screening Reveals Inhibitors of Cholesterol 25-Hydroxylase.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.6c00385},
pmid = {42284103},
issn = {1554-8937},
abstract = {Cholesterol 25-hydroxylase (CH25H) metabolizes cholesterol to 25-hydroxycholestrol (25HC) and plays a pathological role in osteoarthritis, Alzheimer's Disease, and other diseases. As an ER-resident transmembrane diiron lipid oxidase, CH25H remains a challenging enzyme to study, and no small molecule inhibitors of CH25H are available. As a first step toward developing CH25H inhibitors, we established a mass spectrometry-based cellular assay monitoring CH25H-mediated production of 25HC. Screening of this assay across a focused library of over 100 small molecules containing either an iron-coordinating moiety or a sterane ring system revealed three potent inhibitors of cellular CH25H activity (U73343, Ciclopirox, and phenanthroline). We additionally developed a secondary assay of CH25H function monitoring a transcriptional response confirmed to result from 25HC production. Finally, U73343 but not the iron-binding hits showed strong selectivity versus related diiron lipid oxidases. Overall, our work establishes a series of cell-based assays monitoring CH25H function and nominates first-in-class cell-active inhibitors of this disease-relevant enzyme.},
}

@article {pmid42284208,
year = {2026},
author = {Lawlis, NH and Northey, JM and Rattray, B and D'Cunha, NM},
title = {Exploring the perceptions, barriers, and enablers of physical activity for people with younger onset dementia and care partners through thematic analysis.},
journal = {Disability and rehabilitation},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/09638288.2026.2685087},
pmid = {42284208},
issn = {1464-5165},
abstract = {PURPOSE: People with younger onset dementia experience distinct lifestyle, disease, and funding circumstances. Given the holistic benefits of physical activity, we aim to explore people with younger onset dementia and care partner's perceptions of physical activity.

MATERIALS AND METHODS: Ten people with younger onset dementia (female = 4; aged 51-66) and nine care partners (female = 8, aged 55-67) participated in semi-structured interviews. Data were analysed using reflexive thematic analysis and reported according to the COREQ guidelines.

RESULTS: Five overarching themes were identified: 1) Safe participation in physical activity. Care partners expressed concerns for safe exercise participation, requiring activity modification with disease progression. 2) Social inclusion and community participation. People sought group-based and dementia inclusive physical activities to provide social support. 3) The impact of a dementia diagnosis on physical activity and wellbeing. Physical activity can mitigate the loss of sense of self and independence experienced post-diagnosis. 4) There is a need to overcome systemic and accessibility challenges, such as limitations in transport accessibility. 5) The role of tailored activity design.

CONCLUSIONS: Safety and transport accessibility are key barriers to physical activity for people with younger onset dementia. Group-based, dementia-inclusive, physical activity tailored for people with younger onset dementia may be effective in providing support.},
}

@article {pmid42284526,
year = {2026},
author = {Ramamurthy, A and Mondal, K and Klauda, JB},
title = {CDK5-p25 Peptide Inhibitor Samples an Intrinsically Disordered Ensemble in Solution.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.6c01887},
pmid = {42284526},
issn = {1520-5207},
abstract = {The 24-residue peptide p5 (KEAFWDRCLSVINLMSSKMLQINA) selectively inhibits the pathological CDK5-p25 complex implicated in Alzheimer's disease and other neurodegenerative disorders, yet the structural basis for this selectivity remains poorly understood. In this study, replica exchange with solute tempering (REST2) molecular dynamics simulations with explicit solvent were performed over 350 ns using the CHARMM36m force field to extensively characterize the conformational landscape of p5 in aqueous solution at physiological temperature. Gaussian Mixture Variational Autoencoder (GMVAE) clustering identifies three dominant conformational states: a compact disordered state, an extended disordered state, and a partially β-structured state featuring a transient antiparallel β-hairpin between residues 5-8 (WDRC) and 16-19 (SSKM). The small free energy differences between states (ΔΔG < 0.35 kcal/mol) enable rapid nanosecond-time scale interconversion, and multiple structural metrics are consistent with p5 exhibiting the hallmarks of an intrinsically disordered peptide in solution. Temperature-dependent free energy profiles confirm that the low-energy conformational basin is robust across a wide temperature range, validating the physiological relevance of the sampled ensemble. The absence of stable helical structure in the unbound state, combined with the peptide's backbone flexibility and transient β-strand propensity, supports a coupled folding-and-binding mechanism upon CDK5 engagement. These findings provide a structural framework for understanding p5's selective inhibition of CDK5-p25 and lay the groundwork for future simulations of p5-CDK5 complexes and the design of optimized therapeutic CDK5 inhibitors.},
}

@article {pmid42284535,
year = {2026},
author = {Caunca, M and Gutierrez, S and Wheeler, K and Braskie, MN and Torres, J and Yaffe, K},
title = {Race and Ethnicity, Hypertension, and Neuroimaging Markers of Brain Aging: A Causal Mediation Analysis in the HABS-HD Study.},
journal = {Neurology},
volume = {107},
number = {1},
pages = {e218164},
doi = {10.1212/WNL.0000000000218164},
pmid = {42284535},
issn = {1526-632X},
mesh = {Humans ; *Hypertension/ethnology/diagnostic imaging/epidemiology ; Female ; Male ; *Brain/diagnostic imaging/pathology ; *Aging ; Hispanic or Latino ; Neuroimaging ; Middle Aged ; Aged ; Black or African American ; White People ; Magnetic Resonance Imaging ; White Matter/diagnostic imaging ; Mediation Analysis ; Cohort Studies ; White ; },
abstract = {BACKGROUND AND OBJECTIVES: The mechanisms underlying racial/ethnic differences in dementia incidence and pathology are multifactorial, and hypertension represents an actionable target for reducing these differences. We aimed to estimate the extent to which controlling for hypertension mediates racial/ethnic inequities in neuroimaging markers of brain aging.

METHODS: The Health and Aging Brain Study-Health Disparities cohort is a highly phenotyped, racially and ethnically diverse cohort of cognitive aging. We used marginal structural models with inverse probability weights to estimate total and controlled direct effects of race/ethnicity, hypertension, and systolic blood pressure (SBP) at baseline, with neuroimaging markers measured on average 2 years later. Neuroimaging markers of brain aging were measured at the 2-year follow-up.

RESULTS: Among Black and Hispanic participants with any neuroimaging data at the second visit (overall N = 1,347), 68% and 71% were women, 75% and 67% had hypertension, and the mean age was 61 and 63 years, respectively. Black and Hispanic participants had greater white matter hyperintensity volume (WMHV) compared with non-Hispanic White (NHW) participants (n = 1,333, β [95% CI]: Black 2.08 [1.68-2.59], Hispanic 0.99 [0.91-1.08]). After analytically setting hypertension status to absent, Black-NHW inequities in WMHV were attenuated (β [95% CI]: 1.3 [1.01-1.65]). Black participants had lower amyloid deposition compared with NHW participants (n = 679, β [95% CI]: -0.29 [-0.46 to -0.12]), but analytically controlling for hypertension did not appreciably change estimates. Compared with NHW participants, Hispanic participants had lower Alzheimer disease meta-region of interest cortical thickness (n = 1,005, β [95% CI]: -0.20 [-0.34 to -0.07]), but neither hypertension nor SBP significantly mediated this difference. Medial temporal lobe tau-PET standardized uptake value ratio did not significantly differ in Black or Hispanic participants compared with NHW participants (n = 408).

DISCUSSION: Black-NHW inequities in subclinical cerebral small vessel disease may be mitigated by population-level efforts to reduce hypertension prevalence. Future studies should extend this work to examine clinical outcomes.},
}

Humans
*Hypertension/ethnology/diagnostic imaging/epidemiology
Female
Male
*Brain/diagnostic imaging/pathology
*Aging
Hispanic or Latino
Neuroimaging
Middle Aged
Aged
Black or African American
White People
Magnetic Resonance Imaging
White Matter/diagnostic imaging
Mediation Analysis
Cohort Studies
White

@article {pmid42276614,
year = {2026},
author = {Karthikeyan, K and Velmurugan, G and Upadhyay, R and Sevanan, M and Chinnathambi, S},
title = {Glutamate and glutamine metabolism in neurodegenerative diseases.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {1-24},
doi = {10.1016/bs.irn.2026.01.008},
pmid = {42276614},
issn = {2162-5514},
mesh = {Humans ; *Glutamic Acid/metabolism ; *Glutamine/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; },
abstract = {Glutamate is known as the most important excitatory neurotransmitter in brain. Glutamate and glutamine recycling is very essential to maintain the nitrogen metabolism. Despite of its major functions, its dysregulation is a basic pathology which is common to neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS). Amyloid-β and Tau in AD disrupt glutamate uptake and the glutamate-glutamine cycle, accelerating synaptic failure, whereas loss of astrocytic EAAT2 in ALS generates unrelenting excitotoxicity and motor neuron demise. Toxic α-synuclein aggregation in PD exacerbates dopamine-glutamate imbalance through destabilizing corticostriatal transmission. This review explores on the key mechanisms by which glutamate impairment leads to the pathogenies of neurogenerative disorders and also about current medications like amantadine, memantine, and riluzole which are glutamate antagonists, are shown to partially alleviative but cannot halt the advancement of the disease. One of the potential targets for disease-modifying treatments could be the receptor modulation, astrocytic function, and elimination of excess glutamate.},
}

Humans
*Glutamic Acid/metabolism
*Glutamine/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy
Animals

@article {pmid42276615,
year = {2026},
author = {Jain, V and Bharti, S},
title = {Environmental toxins, PFAS exposure, and brain metabolism: A new angle in Alzheimer's disease pathophysiology.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {107-144},
doi = {10.1016/bs.irn.2026.01.011},
pmid = {42276615},
issn = {2162-5514},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complicated cause and effect, usually associated with amyloid-β plaques, tau pathology, and neuroinflammation. Recent research indicates that changes in brain energy metabolism play a crucial role in the progression of AD. Additionally, persistent environmental toxins, particularly per- and polyfluoroalkyl substances (PFAS), have attracted considerable attention due to their widespread occurrence, ability to accumulate in living organisms, and neurotoxic effects. This chapter explores the connection between PFAS exposure and metabolic dysfunction in the brain as a potential new factor in the etiology of Alzheimer's disease. This study explored the potential impacts of PFAS on insulin signaling, lipid homeostasis, glucose metabolism, mitochondrial dynamics, and brain energy supply. The epidemiological associations between PFAS exposure and cognitive impairment are also examined, along with the mechanisms underlying oxidative stress, neuroinflammation, and dysregulation of metabolic systems. Finally, prevention, management, therapeutic approaches, and the research gap in PFAS-induced neurotoxicity are explored. Findings from this study emphasize the need to incorporate environmental toxicology into the Alzheimer's disease metabolic model for the sake of future treatment and preventive efforts.},
}

@article {pmid42276616,
year = {2026},
author = {Zucchi, I and Cocola, C and Pelucchi, P and Mazzaccaro, D and Nano, G and Palizban, M and Porta, G and Reinbold, RA},
title = {TMEM230 and mitochondrial regulation in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {145-185},
doi = {10.1016/bs.irn.2026.02.002},
pmid = {42276616},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Membrane Proteins/metabolism ; *Mitochondria/metabolism ; Animals ; *Endoplasmic Reticulum/metabolism ; Mitochondria Associated Membranes ; },
abstract = {Aging is associated with an attrition of cell subcellular components of the endomembrane system due to long-term exposure to environmental stresses or physical/chemical insults. Tissue morphology physiology and function are strongly dependent on the linked dynamic activities of the endomembrane of organelles of the endomembrane system (ES). This is especially true for nervous tissue and the brain where ES components must interact over long (neurite) distances for proper synapse functions. As the endoplasmic reticulum (ER) is the primary organelle responsible for generating plasma membrane and subcellular membrane components, dysregulation of the ER has a significant role in nervous tissue physiology and diseases in which membrane function is critical, such as in age associated Alzheimer's Disease (AD). Understanding why the ER fails to respond effectively to stress may provide a promising platform for developing antiaging treatments. In this review we characterizegene pathways induced by the transmembrane (TMEM) protein, TMEM230 in the ER in Alzheimer's disease (AD). TMEM230 upregulates oxidative phosphorylation and mitochondria pathways associated cell metabolism. High levels of expression of TMEM230 associated with AD, due chronic inflammation drives hyperoxidation leading to aberrant structural changes in the tethering of the mitochondria and ER membrane and consequently, intra-organelle calcium balance. Sustained elevated levels of expression of TMEM230 leads to catastrophic oxidative stress and irreversible mitochondria damage as seen in some AD patients. Our studies support that Parkinson's Disease and Huntington's Disease may be similarly driven by chronic high levels TMEM230 which results in decoupling of ER-mitochondrial regulation.},
}

Humans
*Alzheimer Disease/metabolism
*Membrane Proteins/metabolism
*Mitochondria/metabolism
Animals
*Endoplasmic Reticulum/metabolism
Mitochondria Associated Membranes

@article {pmid42276617,
year = {2026},
author = {Vijayalakshmi, P and Alex, AM and Muthupandian, S and Desai, D and Jayaprakashvel, M and Singh, SK and Selvaraj, C},
title = {Mitochondrial rescue in Alzheimer's disease: Exploring marine-derived compounds for brain metabolism regulation.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {187-213},
doi = {10.1016/bs.irn.2026.02.003},
pmid = {42276617},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Mitochondria/metabolism/drug effects ; Animals ; *Brain/metabolism/drug effects ; *Neuroprotective Agents/pharmacology ; *Aquatic Organisms ; },
abstract = {Alzheimer Disease (AD) is a progressive neurodegenerative condition because of its cognitive impairment, synaptic impairment and loss of neurons. Mitochondrial dysfunction has become one of the key factors of disease development and progression and one of the several pathological characteristics of AD. The mitochondrial cascade hypothesis suggests that amyloid-β and tau pathology depend on age-related mitochondrial impairment, which is an earlier and faster process and provokes neurodegeneration. Mitochondria play critical roles in metabolism of neuronal energy, maintenance of calcium and regulation of reactive oxygen species (ROS); their dysfunction leads to bioenergetic impairment, oxidative stress, and synaptic failure. Marine ecosystems constitute an unexampled source of bioactive therapeutic-related compounds of structural diversity. Marine-derived compounds (MDCs) such as polysaccharides, oligosaccharides, polyphenols, lipids, alkaloids and peptides have antioxidant, anti-inflammatory, and neuroprotective effects. Recent reports indicate that MDCs can salvage mitochondrial performance by increasing biogenesis, restoring dynamics (fusion fission balance), modulating metabolism and improving mitochondrial quality control. The compounds also control metabolism of the brain affecting the use of glucose, lipid metabolism, and synthesis of neurotransmitters. This chapter clearly discusses the insights of marine-derived compounds as a mitochondrial rescue in AD. We stress their chemical heterogeneity, biologic activity and mode of action including the regulation of signaling pathways, e.g. AMPK, PI3K/Akt, MAPK, and SIRT1. We also talk about their effects on synaptic plasticity, neuronal survival and cognitive function. Lastly, we have also find the research gaps, research challenges, and perspectives and highlight the necessity of translational research, better bioavailability, and sustainable harvesting plans. Marine-derived compounds as a group are one of the brightest prospects in AD therapeutics by providing innovative methods to restore the state of mitochondria and control the metabolism in the brain.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Mitochondria/metabolism/drug effects
Animals
*Brain/metabolism/drug effects
*Neuroprotective Agents/pharmacology
*Aquatic Organisms

@article {pmid42276618,
year = {2026},
author = {Saini, V and Singh, S and Kumar, R and Shahadab, M and Jha, HC},
title = {Circadian rhythm, metabolic stress, and Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {215-240},
doi = {10.1016/bs.irn.2026.05.004},
pmid = {42276618},
issn = {2162-5514},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Beyond hereditary factors related to an individual's genetics, acquired traits are becoming increasingly common, including lifestyle changes such as diet and pathogenic infections. This brings about the involvement of metabolic stress and gut-brain axis dysfunction in the progression of AD. Recent studies have revealed that circadian rhythms not only regulate brain energy metabolism but also orchestrate changes in gut microbiota, inducing neurological modulations. Gut-derived metabolites and microbial signals can modulate host circadian gene expression, thereby influencing neuroinflammation. Metabolic stresses, characterized by impaired glucose utilization, mitochondrial dysfunction, and oxidative stress, exacerbate this cycle through systemic inflammation and gut dysbiosis. Additionally, dietary patterns and timing, such as time-restricted feeding, have been known to benefit both the circadian clock and gut-brain axes, thereby reducing neuroinflammation and improving cognitive outcomes. Therefore, this chapter synthesizes the emerging evidence on the interconnected roles of circadian rhythm, gut microbiota, and metabolic stresses in AD pathogenesis. It highlights the mechanistic insights into how chronobiology and nutrition can be leveraged to restore gut-brain metabolic homeostasis, offering innovative strategies for early intervention of Alzheimer's disease.},
}

@article {pmid42276619,
year = {2026},
author = {Upadhyay, R and Santhosh, S and Malathi, R and Kumari, PS and Vijayanand, S and Sevanan, M},
title = {Starved synapses: Gut microbiome dysbiosis and its role in Alzheimer's glucose impairment.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {241-264},
doi = {10.1016/bs.irn.2026.01.010},
pmid = {42276619},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology ; Animals ; *Glucose/metabolism ; *Dysbiosis/metabolism ; *Gastrointestinal Microbiome/physiology ; *Blood-Brain Barrier/metabolism ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognised as a multifactorial disorder driven by metabolic, microbial, and neuroinflammatory imbalances. The study of the research results proposes that gut dysbiosis and impaired brain glucose metabolism are closely interrelated through the gut-brain metabolism axis. Changes in the intestinal microbiome may disrupt insulin sensitivity, cause systemic inflammation, and disrupt the blood-brain barrier, worsening neuronal glucose deficits and facilitating amyloid-β (Aβ) aggregation and tau phosphorylation. Alongside, neurodegenerative cascades are further enhanced by neuronal metabolic reprogramming, characterised by decreased glucose uptake, dysfunctional glycolytic enzymes, and oxidative stress. Short-chain fatty acids (SCFAs) are mainly butyrate, which have a neuroprotective effect in regulating inflammation and gut integrity, and dysbiosis causes increased pro-inflammatory cytokines and endotoxin leakage. This two-way communication network provides new therapeutic opportunities, such as probiotics, prebiotics, nutritional control, and metabolic reprogramming interventions, to regain homeostasis and prevent the advancement of AD.},
}

Humans
*Alzheimer Disease/metabolism/microbiology
Animals
*Glucose/metabolism
*Dysbiosis/metabolism
*Gastrointestinal Microbiome/physiology
*Blood-Brain Barrier/metabolism
*Brain/metabolism

@article {pmid42276620,
year = {2026},
author = {Shenoy, A and Eva, TA and Palanivel, V and Salkar, A and Gupta, VB and Chitranshi, N and Graham, SL and Gupta, V and Basavarajappa, D},
title = {Invisible threats of microplastics induced toxicity: Oxidative and inflammatory pathways in the CNS and retina.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {25-47},
doi = {10.1016/bs.irn.2026.01.003},
pmid = {42276620},
issn = {2162-5514},
mesh = {Humans ; Animals ; *Oxidative Stress/drug effects ; *Microplastics/toxicity ; *Neuroinflammatory Diseases/chemically induced/metabolism ; *Retina/drug effects/metabolism ; *Inflammation/chemically induced/metabolism ; *Central Nervous System/drug effects/metabolism ; Blood-Retinal Barrier/drug effects/metabolism ; },
abstract = {The global spread of microplastics has become a serious public health concern. Once thought to be inert, microplastics are now recognized as biologically active agents capable of accumulating in the body and causing toxic effects across organ systems. This review summarizes current evidence on their oxidative and inflammatory effects in the central nervous system (CNS) and the eye. Studies show that microplastics can cross biological barriers such as the blood-brain barrier (BBB) and blood-retinal barrier (BRB), where they are taken up by cells, impair mitochondria, and trigger inflammation. Microplastics have been found in cerebrospinal fluid, brain tissue, and ocular structures, raising concern about their link to neurodegenerative and retinal diseases, including Alzheimer's, Parkinson's, macular degeneration, and other disorders. Mechanistic data indicate activation of NF-κB and TGF-β1 pathways, promotion of protein aggregation, and disruption of neural signaling. In the eye, microplastics have been linked to oxidative stress, corneal thinning, and photoreceptor damage. However, human studies are limited due to challenges in detecting tiny particles and lack of microplastic-free controls. Research is further hindered by inconsistent definitions, particle diversity, and non-physiological exposure models. We highlight the need for standardized methods, multi-omics tools, and long-term studies to better understand exposure impacts. Given the rise in neurological and ocular diseases, clarifying the role of microplastics is essential for effective public health strategies.},
}

Humans
Animals
*Oxidative Stress/drug effects
*Microplastics/toxicity
*Neuroinflammatory Diseases/chemically induced/metabolism
*Retina/drug effects/metabolism
*Inflammation/chemically induced/metabolism
*Central Nervous System/drug effects/metabolism
Blood-Retinal Barrier/drug effects/metabolism

@article {pmid42276621,
year = {2026},
author = {Medeiros, CMDS and da Conceição, RSV and Mendes, MKA and de Jesus, JR and Lopes Júnior, CA},
title = {From metals to mitochondria: Linking trace elements to energy crisis in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {265-315},
doi = {10.1016/bs.irn.2026.05.003},
pmid = {42276621},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Mitochondria/metabolism ; *Energy Metabolism/physiology ; *Trace Elements/metabolism ; *Metals/metabolism ; Animals ; Oxidative Stress/physiology ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder and the most common cause of dementia, with a high incidence in the global population, especially in the elderly. AD presents a complex pathogenesis including protein misfolding and aggregation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and on. Currently, the imbalance of essential metals has been associated with AD pathology. Although trace elements such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) are vital for physiological processes in the brain, their dyshomeostasis, whether due to deficiency or excess, mainly impairs energy metabolism by increasing the production of free radicals (e.g., ROS), resulting in oxidative stress and, subsequent mitochondrial dysfunction. Excess metals impair the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) in mitochondria. Thus, metal ions are closely linked to the mitochondrial energy-transducing capacity and redox homeostasis. The brain is highly susceptible and sensitive to metal-mediated metabolic crisis, leading to neuronal dysfunction, a key factor in the progression and severity of AD. Traditional treatments for AD pathology are based on acetylcholinesterase inhibitors and anti-amyloid approaches, but metal chelation has shown potential in reversing the clinical condition of the disease. Herein, we discuss the contribution of metal imbalance to the metabolic energy impairment of the brain in AD, highlighting its relationship with mitochondrial dysfunction. Some therapeutic approaches involving restoration of metal ion homeostasis are discussed.},
}

Humans
*Alzheimer Disease/metabolism
*Mitochondria/metabolism
*Energy Metabolism/physiology
*Trace Elements/metabolism
*Metals/metabolism
Animals
Oxidative Stress/physiology
*Brain/metabolism

@article {pmid42276622,
year = {2026},
author = {Malviya, S and Saha, D and Kamble, A and Singh, DR and Sundaram, SM and Devanathan, V},
title = {Neurovascular coupling and energy substrate delivery in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {317-338},
doi = {10.1016/bs.irn.2026.05.001},
pmid = {42276622},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology ; Animals ; *Energy Metabolism/physiology ; *Neurovascular Coupling/physiology ; *Brain/metabolism ; *Blood-Brain Barrier/metabolism ; Cerebrovascular Circulation/physiology ; Glucose/metabolism ; },
abstract = {The brain has exceptionally high metabolic demands and depends on a continuous supply of oxygen and glucose to maintain neuronal activity and cognitive function. Despite accounting for only about 2 % of body weight, it consumes more than 20 % of the body's energy. This demand is met through tightly regulated cerebral blood flow mediated by neurovascular coupling (NVC), a process that links neuronal activity with local vascular responses. The cellular components responsible for this regulation including neurons, astrocytes, endothelial cells, pericytes, and vascular smooth muscle cells form the neurovascular unit (NVU), which maintains blood brain barrier (BBB) integrity, metabolic homeostasis, and efficient substrate delivery. Increasing evidence suggests that disruption of neurovascular and metabolic regulation is an early and critical contributor to Alzheimer's disease (AD). Impairment of NVU function leads to reduced cerebral blood flow, endothelial dysfunction, pericyte loss, and breakdown of the BBB. These vascular changes compromise the delivery of oxygen and glucose, resulting in cerebral hypometabolism that often precedes classical pathological hallmarks such as amyloid-β plaques and tau neurofibrillary tangles. Alterations in glucose transport across the BBB, particularly reduced expression of the GLUT1 transporter, further exacerbate neuronal energy deficits. Disturbances in lactate metabolism and mitochondrial dysfunction also contribute to oxidative stress and progressive neurodegeneration. Understanding the interaction between neurovascular dysfunction, impaired brain metabolism, and AD pathology provides important insight into disease progression. Therapeutic strategies aimed at restoring vascular function, improving metabolic substrate delivery, and enhancing neuronal energy metabolism may offer promising avenues for early intervention in AD.},
}

Humans
*Alzheimer Disease/metabolism/physiopathology
Animals
*Energy Metabolism/physiology
*Neurovascular Coupling/physiology
*Brain/metabolism
*Blood-Brain Barrier/metabolism
Cerebrovascular Circulation/physiology
Glucose/metabolism

@article {pmid42276623,
year = {2026},
author = {Atasever, E and Turgut, Ş and Andican, G and Çakatay, U},
title = {Redox bioenergetics of neuronal senescence in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {49-74},
doi = {10.1016/bs.irn.2026.05.002},
pmid = {42276623},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Oxidation-Reduction ; Animals ; *Neurons/metabolism/pathology ; *Energy Metabolism/physiology ; Oxidative Stress/physiology ; *Mitochondria/metabolism ; *Cellular Senescence/physiology ; Reactive Oxygen Species/metabolism ; *Aging/metabolism ; },
abstract = {Neuronal aging is a key but often overlooked part of Alzheimer's disease. It links age-related loss of cellular energy to long-lasting problems in neuronal function. Even though neurons don't usually divide, ongoing stressors like oxidative damage, mitochondrial dysfunction, and problems with protein handling can make them appear old. This is seen as lasting DNA damage, calcium imbalance, and the release of substances that cause inflammation. These changes are closely tied to loss of balance in cell energy and redox function. Mitochondria, which make most neurons' energy, are both a main source and a target for reactive oxygen species (ROS). Long-term redox imbalance damages energy production, lowers NAD[+], and disrupts SIRT1 regulation. Eventually, this leads to energy failure and loss of synaptic function. In AD, excessive ROS production and redox imbalances interact with amyloid-β toxicity, tau hyperphosphorylation, and metal ion disturbances. This convergence increases mitochondrial damage and fragmentation. When mitophagy is impaired, dysfunctional mitochondria are not removed, leading to ROS accumulation that further damages cellular structures and reinforces oxidative stress. This forms a self-perpetuating cycle that accelerates neuronal aging and neurodegeneration. Notably, research shows that energy failure and redox imbalance often precede the formation of amyloid plaques and tangles, suggesting that these mechanisms may initiate disease onset. This chapter reviews core mechanisms underlying redox signaling and neuronal senescence. It details how altered mitochondrial function disrupts neuronal energy homeostasis and triggers a cascade of molecular events that underlie Alzheimer's disease. The proposed framework connects redox failure, cellular senescence, and neurodegeneration as interdependent drivers of disease progression.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Oxidation-Reduction
Animals
*Neurons/metabolism/pathology
*Energy Metabolism/physiology
Oxidative Stress/physiology
*Mitochondria/metabolism
*Cellular Senescence/physiology
Reactive Oxygen Species/metabolism
*Aging/metabolism

@article {pmid42276756,
year = {2026},
author = {Özütemiz, C and Ahmadi, R and Folkertsma, M and Lunos, S and Pillai, AP and Mantyh, WG and Cai, D and Streib, C},
title = {Comparison of SWI with T2* in the Diagnosis of Cerebral Amyloid Angiopathy Using ARIA Scoring and Boston Criteria 2.0 at 7T MRI.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9472},
pmid = {42276756},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: 7T-MRI enables detection of subtle hemorrhagic biomarkers associated with cerebral amyloid angiopathy (CAA). However, the relative performance of T2* compared with susceptibility-weighted imaging (SWI), as well as the applicability of Boston Criteria 2.0 at 7T, remains uncertain. This study evaluated diagnostic agreement between T2* and SWI, interobserver variability, and the utility of the Boston Criteria 2.0 at 7T-MRI and characterized the prevalence of emerging imaging biomarkers, such as the intragyral hemorrhage sign (IGHS).

MATERIALS AND METHODS: In this retrospective study, 130 examinations from 111 patients referred for 7T-MRI between 2022 and 2025 for transient focal neurologic deficits, cognitive impairment, suspected CAA, or Alzheimer's disease were analyzed. Two experienced neuroradiologists independently evaluated T2* and SWI sequences using ARIA-based categorical scoring for intracerebral parenchymal hemorrhage (IPH), cortical/subcortical microbleeds (C/SC-MB), deep microbleeds (D-MB), cortical superficial siderosis (cSS), and IGHS. Discrepancies were resolved by consensus. Boston Criteria 2.0 classifications were assigned by a vascular neurologist. Intersequence and interobserver agreement were assessed, and associations between imaging markers and Boston classifications were analyzed.

RESULTS: Interobserver agreement of neuroradiologists was high across both sequences, with almost perfect agreement for IPH, C/SC-MB, D-MB, and cSS (κ = .85-1.00). T2* and SWI demonstrated almost perfect agreement for IPH, C/SC-MB, D-MB, and cSS (κ = .90-1.00) and substantial agreement for IGHS (κ = .62). Almost perfect agreement was observed between Boston scores based on SWI and T2* (κ = .92). IGHS was observed in about 24% and 41% cases with a positive Boston score with T2* and SWI, respectively. Among 81 patients with at least one hemorrhagic marker, 35 (45%) were excluded from CAA due to D-MBs detection despite radiologic features suggestive of CAA.

CONCLUSIONS: T2* and SWI provide comparable diagnostic performance for CAA-related hemorrhagic markers and almost perfect agreement regarding the Boston Criteria at 7T. Interobserver agreement was high across all sequences, supporting the reproducibility of ARIA-based scoring at 7T. Boston Criteria 2.0 are applicable at 7T; however, improved detection of deep microbleeds may lead to false-negative classifications. Updated diagnostic frameworks tailored to 7T-MRI, including potential incorporation of IGHS, may be warranted.},
}

@article {pmid42276904,
year = {2026},
author = {Launay, A and Baudouin, A and Gonthier, C and Brachet, M and Matysiak, A and Vanneste, S and Taconnat, L},
title = {Development of a new episodic memory assessment tool (NEM): Preliminary data and clinical perspectives.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2026.04.011},
pmid = {42276904},
issn = {0035-3787},
abstract = {The present study aimed to test the discriminating power, reliability, and validity of a new episodic memory assessment tool (NEM). NEM was designed to be more ecological than current tests of episodic memory, based on incidental encoding and a deepened assessment of recall. The encoded material is a short video involving a choice procedure to encourage participant immersion. The delayed recall phase is guided by a semi-directive interview. Preliminary data were collected from 199 cognitively unimpaired participants aged 18 to 91, as well as from 35 older adults with cognitive impairment (18 patients with mild cognitive impairment and 17 patients with Alzheimer's disease). The results show that NEM exhibits good internal consistency and inter-rater agreement. NEM performance is sensitive to the effects of age and can discriminate between pathological and normal ageing. NEM offers an alternative to existing tools for a more ecological assessment of episodic memory, enabling better investigation of the formation of episodic memories in everyday life.},
}

@article {pmid42277155,
year = {2026},
author = {Wang, L and Knox, S and Lawson, AB and Mollalo, A},
title = {Agricultural pesticide use and Alzheimer's disease dementia prevalence across US counties in a mixed supervised-unsupervised analysis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55678-4},
pmid = {42277155},
issn = {2045-2322},
abstract = {Agricultural pesticide use represents one of the most geographically patterned environmental systems, yet most prior research has focused largely on individual compounds rather than correlated exposure regimes. We conducted a cross-sectional analysis using modeled pesticide application intensity and Alzheimer's Disease (AD) dementia prevalence at the county-level across the United States. Stability-based Elastic Net screening and clustering were used to identify exposure groupings, and associations with AD prevalence were estimated using adjusted regression models. Out of 462 total pesticides screened, 112 demonstrated high selection stability and were grouped into 25 exposure clusters. Twenty clusters were significantly associated with AD dementia prevalence (p<0.05). The strongest positive associations were observed for a soil fumigation/nematicide system, an herbicide-dominant vegetation control regime, and a neuroactive insecticide system. Neuroactive insecticides and soil-intensive treatment systems were disproportionately represented among positively associated clusters, whereas systems dominated by phenoxy- and photosystem II inhibiting herbicides were more frequently aligned with inverse gradients. The fully adjusted model explained 59% of between-county variance (baseline R[2] = 0.44). Findings suggest that pesticide mixtures are associated with geographic heterogeneity in AD dementia prevalence and warrant higher-resolution, longitudinal investigation.},
}

@article {pmid42277209,
year = {2026},
author = {Maisto, N and Ciufolini, G and Dashtiani, S and Casoli, L and Di Venere, A and Carbone, M and Mango, D},
title = {Amyloid-beta fibrils as active contributors to synaptic dysfunction in Alzheimer's disease.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {42277209},
issn = {1745-7254},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid-beta (Aβ) aggregates, in the form of fibrils and plaques. While it has largely been stated that Aβ oligomers are the main toxic species, significant evidence indicates that fibrils may also be relevant to AD pathogenesis. Notably, evidence indicates that while fibrils, through direct interaction with neuronal membranes, contribute to synaptic dysfunction and cellular damage, no direct evidence between fibrils and their impact on neuronal functions, including plasticity, was investigated. This study inquired into the impact of Aβ fibrils complex on neuronal function and membrane integrity, shedding light on their contribution to synaptic defects. Aβ fibrils were generated from Aβ1-42 oligomers, and their effects were evaluated on synaptic plasticity in ex vivo hippocampal slices from both female and male mice. Compared to Aβ1-42 oligomers, fibrils induced more severe damage in synaptic plasticity, emphasizing their potent neurotoxicity effect underlying cognitive decline. Additionally, using a liposomal model to examine fibril-membrane interactions, it was observed that Aβ fibrils are able to affect membrane fluidity compared to the Aβ1-42 oligomeric species, indicating that the size and aggregation state of Aβ fibrils are crucial for their toxicity. These findings challenge the view that oligomers are the primary toxic species in AD, showing that Aβ fibrils also play an active role in cellular dysfunction, promoting a synaptic dysfunction correlated to the cognitive impairment observed in AD.},
}

@article {pmid42277328,
year = {2026},
author = {Andrade, K and Lejeune, FX and Houmani, N and Yabouri, R and Thiebaut de Schotten, M and Pacella, V},
title = {Error unawareness as a driver of cognitive decline in individuals at risk for Alzheimer's disease.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10461-z},
pmid = {42277328},
issn = {2399-3642},
abstract = {Anosognosia, or unawareness of one's deficits, predicts faster clinical progression in Alzheimer's disease (AD), though its mechanisms remain unclear. We investigated five-year trajectories of response awareness and error-monitoring efficiency using second-order judgments from an annual word recognition memory task in cognitively unimpaired individuals at risk for AD from the INSIGHT-preAD cohort. Participants were divided into three groups according to amyloid status at baseline (positive, A + ; negative, A-) and clinical progression (controls, CTRL A+ or A-; and progressors, PROG). Task accuracy declined in PROG, while CTRL A+ showed continued learning, and CTRL A- remained accurate. Inefficient error-monitoring predicted subsequent performance decline in the PROG, with a strong interaction between accuracy and error-monitoring already at baseline. This effect was primarily driven by error unawareness. These findings provide first evidence that error unawareness - a core feature of anosognosia - may foster cognitive decline through the disruption of error-feedback learning mechanisms, potentially accelerating AD progression.},
}

@article {pmid42277407,
year = {2026},
author = {Park, KY and Nam, GE and Han, K and Jung, JH and Yoo, JE and Lee, CW and Kang, SH and Kim, CK and Shin, DW},
title = {Association between blood pressure and risk of ischemic stroke among individuals with dementia: A nationwide cohort study.},
journal = {Hypertension research : official journal of the Japanese Society of Hypertension},
volume = {},
number = {},
pages = {},
pmid = {42277407},
issn = {1348-4214},
abstract = {Prior research has established a positive correlation between blood pressure (BP) and ischemic stroke in the general population; however, this association has not been investigated in dementia patients. A population-based cohort of 73,130 individuals with newly diagnosed dementia who underwent a Korean national health checkup after diagnosis was followed up until the end of 2019. Individuals were classified according to their systolic (SBP) and diastolic BP (DBP) during health checkups. Multivariable Cox proportional hazards regression was performed, calculating the hazard ratios (HRs) and 95% confidence intervals (CIs) for incident ischemic stroke. During a mean follow-up of 3.6 years, 4446 (6.1%) patients developed ischemic stroke. In all-cause dementia patients, the risk of ischemic stroke increased after SBP/DBP exceeded 130/90 mmHg compared with SBP 120-129 mmHg and DBP 70-79 mmHg (reference) (both P for trend <0.001). Similar trends were observed in patients with Alzheimer's disease and vascular dementia. In particular, SBP/DBP ≥ 140/90 mmHg and SBP 100-109 mmHg were associated with incrementally higher risks of ischemic stroke and a decreased risk of Alzheimer's disease, respectively (both P for trend <0.001). The positive linear association of SBP and DBP with ischemic stroke in all-cause dementia remained after stratification by sex and antihypertensive medication use, and the association between SBP and ischemic stroke was greater among younger individuals (40-79 years old). In conclusion, both SBP and DBP showed positive linear relationships with the risk of incident ischemic stroke in dementia patients. Achievement of the target BP may be important for stroke prevention in individuals with dementia.},
}

@article {pmid42277464,
year = {2026},
author = {},
title = {Microglia at a key inflection point in Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42277464},
issn = {1546-170X},
}

@article {pmid42277578,
year = {2026},
author = {Stevens, DA and Alm, K and Bakker, A and Kamath, V and Manning, KJ and Rebok, GW and Rosenberg, PB and Nowrangi, MA},
title = {Diffusion Tensor Imaging Correlates of Financial Capacity Instrument-Short Form Completion Time in Mild Cognitive Impairment.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20250087},
doi = {10.1176/appi.neuropsych.20250087},
pmid = {42277578},
issn = {1545-7222},
abstract = {OBJECTIVE: The capacity to complete financial tasks accurately and efficiently is fundamental to financial independence; however, early declines in the progression of Alzheimer's disease may contribute to personal financial loss, risk for elder abuse, and increased caregiver burden. Slower performance on measures of financial capacity may reflect early disease-related changes, foreshadowing subsequent cognitive decline. The authors investigated the relationship between the time needed to complete financial tasks and white matter tract diffusion characteristics among older individuals with or without mild cognitive impairment (MCI).

METHODS: Fifteen participants with MCI and 15 healthy control participants completed diffusion MRI scans, a neuropsychological assessment, and the Financial Capacity Instrument-Short Form (FCI-SF). In analyses of data adjusted for demographic characteristics, Geriatric Depression Scale scores, and FCI-SF total score, the authors used diffusion tensor imaging to investigate correlations between the time needed to complete financial tasks and diffusion characteristics of white matter tracts terminating in the angular and fusiform gyri.

RESULTS: FCI-SF completion times were significantly prolonged among participants with MCI compared with healthy control participants. The two groups did not significantly differ in diffusion metrics across the selected white matter tracts. FCI-SF total completion time was significantly correlated with multiple diffusion metrics in the arcuate, vertical occipital, and inferior longitudinal fasciculi of individuals with MCI.

CONCLUSIONS: Completion time measures of the FCI-SF may reflect early disease-related changes in white matter tracts implicated in reading and arithmetic performance.},
}

@article {pmid42277629,
year = {2026},
author = {Chang, Y and Li, H and Liu, X and Li, X and Liu, J and Song, J and Fu, H and Xu, X and Wang, Y and Wang, Q and Ren, N and Chen, J and Deng, X and Zhang, X and Zuo, L and Zhou, B and Sun, X and Li, Z and Cao, Y and Wu, R and Jia, J and Qian, H and Wang, R},
title = {Lecanemab Reduces Neuropsychiatric Symptoms and Related Regional Brain Amyloid Load in Early Alzheimer's Disease: A Preliminary Prospective Study.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {6},
pages = {e70974},
doi = {10.1002/cns.70974},
pmid = {42277629},
issn = {1755-5949},
support = {82371999//the National Natural Science Foundation of China/ ; 2021ZD0201804//the Ministry of Science and Technology of the People's Republic of China/ ; 24BJZ14//Health Special Research Projects/ ; //Novel Medical Technologies and Innovative Services of Chinese PLA General Hospital/ ; },
abstract = {AIM: This prospective study examined whether lecanemab was associated with changes in neuropsychiatric symptoms (NPS) and investigated their associations with cerebral amyloid burden in patients with early-stage Alzheimer's disease (AD).

METHODS: Fourteen eligible participants underwent amyloid positron emission tomography, magnetic resonance imaging, and neuropsychological assessments at baseline and following 6 months of lecanemab treatment. Neuropsychological assessments included the Clinical Dementia Rating, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Hamilton Depression Rating Scale, Hamilton Anxiety Scale (HAMA), and Neuropsychiatric Inventory (NPI).

RESULTS: MMSE and MoCA remained stable, while amyloid burden decreased after 6 months of treatment (p < 0.05). HAMA, total NPI score, and NPI sub-scores for psychosis, hyperactivity, and apathy were also decreased (p < 0.05). Improvements in NPS were associated with lower amyloid burden in the hippocampus, amygdala, thalamus, inferior frontal gyrus (IFG), and anterior cingulate gyrus. These clinical improvements were associated with increased fractal dimension in the middle cingulate cortex and decreased sulcal depth in the IFG.

CONCLUSIONS: These findings suggest that, in early AD, lecanemab treatment may be associated with benefits beyond cognitive stabilization, including possible improvement in NPS, which may relate to amyloid clearance and structural changes in relevant brain regions.},
}

@article {pmid42277669,
year = {2026},
author = {Boz, S and Dagdemir, AN and Oztorun, HS and Kocaismail, Z and Dogrul, RT and Oguz, EF and Erdogan, K and Yılmaz, B and Efe, FK and Erten, R and Demirel, E and Eken, G and Silay, K},
title = {Does resolvin D2 reflect cognitive impairment in older adults? A clinical and biomarker analysis.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07817-9},
pmid = {42277669},
issn = {1471-2318},
support = {2729//Yıldırım Beyazıt Üniversitesi BAP/ ; },
abstract = {BACKGROUND: Alzheimer's disease is a progressive neurodegenerative disorder with an unclear etiology, in which inflammation and impaired resolution pathways may play a role. This study investigated the relationship between serum Resolvin D2 levels and cognitive status in individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease.

METHODS: In this cross-sectional study, 165 adults aged ≥ 65 years who attended a tertiary geriatric clinic between 2022 and 2025 were classified as cognitively normal, mild cognitive impairment, or Alzheimer's disease. Demographic, clinical, laboratory, and comprehensive geriatric assessment data were collected. Serum Resolvin D2 levels were measured using ELISA and analyzed in relation to cognitive status. Logistic regression and ROC curve analyses were performed to evaluate the potential diagnostic value of Resolvin D2.

RESULTS: Resolvin D2 levels did not differ significantly among cognitive status groups. In multivariate analyses, Resolvin D2 was not an independent predictor of dementia or cognitive impairment. ROC curve analyses demonstrated limited diagnostic performance of Resolvin D2 compared with established clinical and laboratory indicators. These findings suggest that serum Resolvin D2 levels may have limited utility as a standalone biomarker, although their role within neuroinflammatory and resolution pathways warrants further investigation.

CONCLUSION: Serum Resolvin D2 levels have limited ability to distinguish older adults with cognitive impairment or dementia from cognitively normal individuals. In contrast, S-MMSE, Lawton IADL scores, and comorbidity burden remain independent predictors of cognitive status. While Resolvin D2 shows anti-inflammatory and pro-resolving effects in experimental models, its value as a standalone biomarker for cognitive decline appears limited. Larger, prospective, multi-biomarker studies are needed to clarify its role.},
}

@article {pmid42277828,
year = {2026},
author = {Liu, L and Li, JH and Bai, YD and Wang, YJ and Bu, XL},
title = {Meningeal lymphatic dysfunction in Alzheimer's disease: molecular mechanisms, clinical implications, and future perspectives.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00962-0},
pmid = {42277828},
issn = {1750-1326},
support = {No. U22A20294//National Science Foundation of China/ ; No. CSTB2023NSCQ-JQX0019//Natural Science Foundation of Chongqing Municipality/ ; },
abstract = {The meningeal lymphatic system has recently emerged as a critical regulator of brain homeostasis, facilitating cerebrospinal fluid drainage, metabolic waste clearance, and immune cell trafficking. Accumulating evidence now implicates meningeal lymphatic dysfunction as a pivotal contributor to the pathogenesis of Alzheimer's disease (AD). This review critically evaluates current neuroimaging techniques for assessing meningeal lymphatic function in humans, highlighting their technical limitations in capturing dynamic pathological changes specific to AD. We summarize recent advances demonstrating that meningeal lymphatic impairment exacerbates key AD hallmarks-including amyloid-β (Aβ) and tau deposition, neuroimmune dysregulation, and myelin degradation-collectively accelerating disease progression. Building on these insights, we systematically analyse emerging therapeutic strategies aimed at enhancing meningeal lymphatic function, such as pharmacological approaches (e.g., vascular endothelial growth factor C (VEGF-C)-mediated lymphangiogenesis), physical interventions (e.g., transcranial photobiomodulation), and surgical techniques (e.g., cervical lymphaticovenous anastomosis). However, significant challenges remain, including the scarcity of direct human evidence linking meningeal lymphatic dysfunction to AD and the lack of standardized, noninvasive assessment tools. To address these gaps, we propose future fundamental and clinical research directions for meningeal lymphatic vessels and AD. By bridging mechanistic insights with translational applications, this review highlights the role of the meningeal lymphatic system as a promising yet underexplored target for AD modification.},
}

@article {pmid42277961,
year = {2026},
author = {Bonnar, O and Saadi, F and Sanchez-Mico, MV and Hanlin, LH and Vom Eigen, KA and Mumbi, N and Bacskai, BJ and Greenberg, SM and Holtzman, DM and van Veluw, SJ},
title = {Longitudinal multiphoton imaging of cerebral amyloid angiopathy in response to anti-ApoE4 immunotherapy in mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00957-x},
pmid = {42277961},
issn = {1750-1326},
support = {P01 AG078106/GF/NIH HHS/United States ; A2022051S//BrightFocus Foundation grant/ ; },
abstract = {BACKGROUND: There are no available treatments to halt or slow the progression of cerebral amyloid angiopathy (CAA), a disease neuropathologically characterized by the deposition of amyloid-β (Aβ) within the walls of the cerebrovasculature. Recently a novel therapeutic strategy has been described, targeting non-lipidated ApoE4 that co-deposits with Aβ, resulting in lower levels of Aβ across the brain. To understand the therapeutic potential for patients with CAA, we sought to determine if this global reduction in Aβ deposits corresponds to the active removal of existing aggregates in the vasculature and if so, whether this may improve vascular function over time.

METHODS: Cranial windows were implanted in 9-10-month-old 5xFAD mice expressing human APOE4 to facilitate chronic, unanesthetized imaging using in vivo multiphoton microscopy. Mice were treated weekly with anti-ApoE4 immunotherapy (HAE-4) or control IgG (50 mg/kg). Parenchymal and vascular Aβ burden as well as vascular function were measured in vivo before and during treatment. Post-mortem brains were assessed for CAA, parenchymal Aβ plaques and iron deposits. In a separate study, 5xFAD mice were treated with weekly HAE-4 or control IgG with the same doses of antibodies from 8 to 10 months of age in the absence of cranial windows.

RESULTS: Treatment with HAE-4 resulted in reduction of total Aβ plaque area post-mortem in mice and shrinkage of existing smaller plaques imaged with in vivo multiphoton microscopy. Vascular fibrillar Aβ under the cranial window conversely increased over time either with or without HAE-4 treatment and there was no treatment-associated improvement in vascular function in cortical arterioles in the areas measured in vivo. There was no evidence of hemorrhagic events linked to treatment, however there was significant immune cell activation. In 5xFAD mice treated without a cranial window, there was a reduction in plaques and CAA as previously described in HAE-4 vs. control treated mice.

CONCLUSIONS: Anti-ApoE4 immunotherapy, as shown previously, decreased the overall amount of Aβ. It also appeared to remove some existing plaque Aβ without measurable effects on vascular fibrillar Aβ deposits or vascular function in areas measured in vivo under a cranial window. The absence of treatment-associated hemorrhagic events may offer a comparative advantage relative to anti-Aβ immunotherapy.},
}

@article {pmid42278193,
year = {2026},
author = {Lourenço, KA and Dos Santos, MV and Araujo, AC and Guiguer, EL and Curi, R and Rocha, MG and Monteiro, ES and Yanaguizawa Junior, JL and Pithon-Curi, T and Quesada, K and de Abreu, LC and Marcondes, CO and Barbalho, SM and Valenti, VE and Miglino, MA},
title = {From Toxin to Therapy: Biomedical Applications of Bee Venom in Cancer, Diabetes, and Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114661},
pmid = {42278193},
issn = {1422-0067},
mesh = {Humans ; *Bee Venoms/therapeutic use/pharmacology/chemistry ; Animals ; *Neurodegenerative Diseases/drug therapy ; *Neoplasms/drug therapy ; *Diabetes Mellitus/drug therapy ; },
abstract = {Apitherapy is a complementary therapeutic approach based on the use of bee-derived products, particularly bee venom (BV), also known as apitoxin. Bee venom is a complex mixture of biologically active compounds, including peptides, enzymes, and biogenic amines, that exhibit diverse pharmacological activities. Major bioactive constituents such as melittin, apamin, adolapin, and phospholipase A2 have attracted increasing scientific interest due to their anti-inflammatory, antioxidant, antimicrobial, analgesic, and immunomodulatory properties. This review provides a comprehensive overview of the biological effects and therapeutic potential of bee venom in the management of chronic diseases, particularly diabetes, cancer, and neurological disorders. Evidence from experimental and clinical studies suggests that BV and its components can modulate multiple molecular pathways associated with oxidative stress, inflammation, apoptosis, and immune responses. These mechanisms contribute to potential benefits in glycemic control, tumor suppression, neuroprotection, and pain management. Additionally, bee venom has been investigated for its capacity to influence signaling pathways involved in cellular proliferation and survival, highlighting its potential as a complementary strategy in the treatment of complex diseases such as neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Despite these promising therapeutic effects, the clinical use of BV remains limited due to safety concerns, particularly the risk of allergic reactions, systemic toxicity, and anaphylaxis. Recent advances in drug delivery systems and nanotechnology may help improve the safety and efficacy of BV-based therapies by enabling targeted delivery and controlled dosing. Overall, bee venom represents a promising source of bioactive compounds with potential applications in translational and integrative medicine; however, further well-designed clinical trials and mechanistic studies are necessary to establish its safety, efficacy, and long-term therapeutic value.},
}

Humans
*Bee Venoms/therapeutic use/pharmacology/chemistry
Animals
*Neurodegenerative Diseases/drug therapy
*Neoplasms/drug therapy
*Diabetes Mellitus/drug therapy

@article {pmid42278253,
year = {2026},
author = {Park, MN and Kim, HW and Hong, JH and Kim, JK and Lee, SB and Baek, HS and Kwak, S and Kwon, YJ and Park, K and Jeon, J and Heo, NH and Lee, SH and Cho, J and Kim, S},
title = {Functional Pathological Features and Molecular Markers in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114720},
pmid = {42278253},
issn = {1422-0067},
support = {RS-2024-00439078//National Research Foundation of Korea/ ; RS-2024-00405401//National Research Foundation of Korea/ ; RS-2023-00249115//National Research Foundation of Korea/ ; RS-2025-25430279//National Research Foundation of Korea/ ; RS-2023-00246208//National Research Foundation of Korea/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Biomarkers/metabolism ; Animals ; Microglia/metabolism/pathology ; Blood-Brain Barrier/metabolism/pathology ; Neurons/metabolism/pathology ; Neuroinflammatory Diseases/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder defined not only by amyloid-β plaques and tau pathology but also by several interacting processes that drive disease progression. These include neuroinflammation, neuronal cell death, synaptic dysfunction, blood-brain barrier (BBB) breakdown, and myelin and axonal damage. Together, they lead to neuronal loss and cognitive decline. In this review, we present a cell-centered framework linking these processes with key molecular markers. Neuroinflammation is driven by activated microglia and astrocytes and is associated with markers such as Iba1, CD68, GFAP, and C3, along with cytokines including IL-1β and TNF-α. Neuronal cell death occurs through apoptosis, ferroptosis, pyroptosis, and necroptosis, with markers such as caspase-3, GPX4, GSDMD, and MLKL. Synaptic dysfunction is reflected by reduced synaptic proteins, including synaptophysin and PSD-95. BBB breakdown increases permeability and reduces clearance of toxic molecules. Myelin and axonal damage, associated with MBP and NfL, disrupt neural connectivity. These processes are dynamically interconnected and may contribute differently across disease stages. This integrated cell-centered and systems-level framework provides insight into AD progression while highlighting potential biomarkers and therapeutic targets for diagnosis, disease monitoring, and therapeutic intervention.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Biomarkers/metabolism
Animals
Microglia/metabolism/pathology
Blood-Brain Barrier/metabolism/pathology
Neurons/metabolism/pathology
Neuroinflammatory Diseases/metabolism/pathology

@article {pmid42278287,
year = {2026},
author = {Gao, R and Lyu, C and Gu, Y and Hao, R and Wang, C and Li, X},
title = {Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114756},
pmid = {42278287},
issn = {1422-0067},
support = {42275197//National Natural Science Foundation of China/ ; TJWJ2023XK007//Key Projects of Tianjin Municipal Health Commission/ ; TJYXZDXK-3-017C//Key Discipline of Geriatrics in Tianjin Municipality/ ; TJYXZDXK-065B//Tianjin Key Medical Discipline Construction Project/ ; 25JCQNJC00780//Tianjin Science and Technology Plan Project/ ; TA-10207 PRC//Tianjin Center for Health and Meteorology Multidisciplinary Innovation, Building a Climate Change Early Warning System for the Aged - Climate change and aged care research and modeling firm/ ; },
abstract = {Alzheimer's disease (AD) is characterized not only by neuronal dysfunction but also by profound remodeling of the brain microenvironment, including immune-glial activation and metabolic dysregulation. Increasing evidence also implicates neurosteroid-related pathways in AD and dementia. Nobiletin has shown neuroprotective effects in AD-related models, but its upstream human targets and mechanism-based translational relevance remain insufficiently defined. Here, we integrated multi-omics analyses, interpretable machine learning, causal inference, structural modeling, and experimental validation to identify candidate nobiletin-associated molecular nodes in AD. HSD17B1 consistently emerged as a central AD-associated candidate across multiple analytical layers and showed reproducible discriminatory performance in independent validation cohorts. SHAP analysis further identified HSD17B1 as a major contributor to the optimal predictive model, while Mendelian randomization supported a protective association between genetically increased HSD17B1 expression and AD risk. Immune infiltration, single-cell, and spatial transcriptomic analyses linked HSD17B1 to glia-associated remodeling and regionally heterogeneous expression patterns in AD. Molecular docking and molecular dynamics simulations supported the structural feasibility of nobiletin binding to HSD17B1, and in an Aβ1-42-induced SH-SY5Y cell model, nobiletin increased HSD17B1 expression at both the mRNA and protein levels. Together, these findings support HSD17B1 as an AD-associated and nobiletin-responsive candidate molecular node, highlight a potential connection between nobiletin and neurosteroid-related regulation, and provide an integrated framework for target prioritization and validation in AD.},
}

@article {pmid42278308,
year = {2026},
author = {Khalil, MH},
title = {Humanised Environmental Enrichment: Spatial Effects of Cities and Buildings on Adult Hippocampal Neurogenesis in Humans.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114779},
pmid = {42278308},
issn = {1422-0067},
support = {N/A//Gates Cambridge Trust/ ; },
abstract = {Adult hippocampal neurogenesis persists throughout the human lifespan, yet declines in Alzheimer's disease and major depression, associated in part with reduced brain-derived neurotrophic factor (BDNF) levels. For rodents, environmental enrichment, dichotomised primarily as physical activity and spatial complexity, robustly promotes adult hippocampal neurogenesis, but no framework has translated these findings to human environments. This review is the first to synthesise evidence across the full translational pathway, arguing that spatial complexity and physically active navigation in neighbourhoods and buildings constitute a humanised form of environmental enrichment. It proposes that standard indoor environments may represent a functionally impoverished condition for the human hippocampus, paralleling standard laboratory caging. An applied model is presented, mapping built environment features onto the neurobiological mechanisms regulating adult hippocampal neurogenesis, with BDNF as the central translatable biomarker linking environmental exposures to neurogenic outcomes. A methodological roadmap for future empirical validation is also outlined. This framework repositions the built environment as a modifiable determinant of adult hippocampal neurogenesis in humans, with implications for mitigating the risk of depression, cognitive impairment, and Alzheimer's disease.},
}

@article {pmid42278322,
year = {2026},
author = {Adewuyi, EO and Auta, A and Ossai, CI and Anyaegbu, CC and Nguyen, TTH and Rahman, MR and Stephan, BCM and Tessema, GA and Nyholt, DR and Pereira, G},
title = {Genome-Wide and Locus-Level Analyses Reveal Modest, Heterogeneous Genetic Sharing Between Alzheimer's Disease and Myasthenia Gravis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114792},
pmid = {42278322},
issn = {1422-0067},
support = {GNT2025837//National Health and Medical Research Council/ ; },
mesh = {*Myasthenia Gravis/genetics ; Humans ; *Genome-Wide Association Study ; *Alzheimer Disease/genetics ; Polymorphism, Single Nucleotide ; *Genetic Predisposition to Disease ; Major Histocompatibility Complex/genetics ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder, whereas myasthenia gravis (MG) is an autoimmune neuromuscular disease. Despite their distinct clinical manifestations, both disorders involve immune dysregulation and cholinergic dysfunction, and epidemiological evidence for an association remains inconclusive. Here, we investigated the genetic architecture underlying the AD-MG relationship using large-scale European-ancestry genome-wide association study (GWAS) data, including early- and late-onset MG, within a multi-resolution analytical framework. Genome-wide analyses indicated modest polygenic overlap between AD and MG, supported by nominally significant and directionally consistent correlations across datasets, SNPeffect concordance in the primary GWAS, and robust gene-level overlap. Evidence for genome-wide correlation was weaker and non-significant across AD-MG subtypes. Local genetic correlation analyses revealed that shared AD-MG signals were largely locus-specific and heterogeneous, with regions showing both concordant and discordant effects, particularly across MG subtypes. Subtype-specific analyses indicated broader and more heterogeneous overlap for AD-late-onset MG, including both major histocompatibility complex (MHC) and non-MHC loci, whereas AD-early-onset MG showed more restricted patterns largely confined to the MHC. Cross-trait meta-analysis and colocalisation further refined these findings, identifying a limited number of loci with evidence of shared AD-MG association, while most regions were consistent with distinct causal variants. A chromosome 16 locus showed the most consistent shared cross-trait AD-MG signal across multiple analytical frameworks. Mendelian randomisation analyses provided no evidence of a causal effect of AD liability on MG and yielded only suggestive, and inconclusive evidence for the reverse direction. Gene-level and expression-informed analyses prioritised immune-related genes, as well as regulators of transcription, chromatin organisation, and synaptic processes, without implying concordant causal variants across traits. Tissue and pathway analyses suggested shared immune involvement, with differential emphasis on innate immune processes in AD and adaptive immune pathways in MG. Notably, heterogeneity of effects within the MHC and across loci suggests that overlap reflects a complex, context-dependent architecture rather than a uniform immune-driven signal. Overall, our findings indicate that the AD-MG relationship is characterised by modest genome-wide polygenic overlap, substantial locus-specific heterogeneity, and partial convergence on immune-related genetic architecture, rather than a uniformly shared mechanism.},
}

*Myasthenia Gravis/genetics
Humans
*Genome-Wide Association Study
*Alzheimer Disease/genetics
Polymorphism, Single Nucleotide
*Genetic Predisposition to Disease
Major Histocompatibility Complex/genetics

@article {pmid42278353,
year = {2026},
author = {Cipriano, GL and Anchesi, I and Raffaele, I and Astorino, MF and Minuti, A and Calabrò, M and Crisafulli, C},
title = {Neuroinflammation and Secretase Regulation in Alzheimer's Disease: From Molecular Cross-Talk to Multi-Target Therapeutics.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114824},
pmid = {42278353},
issn = {1422-0067},
support = {RRC-2026-23688274//Ministero della Salute/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition, neurofibrillary tau tangles, synaptic dysfunction, and progressive cognitive decline. AD is increasingly recognized as a condition in which chronic neuroinflammation actively shifts amyloid precursor protein (APP) processing toward the amyloidogenic pathway, driving Aβ production and accumulation rather than merely accompanying amyloid deposition. In this review, we examine the molecular cross-talk between inflammatory signalling and secretase regulation, highlighting how pro-inflammatory mediators promote amyloidogenic processing and contribute to downstream synaptic dysfunction. We discuss the major pathways linking glial activation to aberrant APP cleavage, including STAT3-dependent BACE1 upregulation, immune-mediated modulation of γ-secretase through IFITM3, and activation of the C/EBPβ/δ-secretase axis, which connects inflammatory stress to both amyloid and tau pathology. We further address the contribution of epigenetic mechanisms, particularly microRNA-mediated derepression of BACE1 and suppression of ADAM10, as well as SIRT3-related impairment of Aβ clearance. These interconnected processes establish a feed-forward pathogenic network in which neuroinflammation amplifies secretase imbalance, amyloidogenesis, and synaptic vulnerability. Finally, we discuss emerging multi-target therapeutic strategies aimed at modulating inflammatory signalling, restoring non-amyloidogenic APP processing, and preserving proteostatic and synaptic resilience. Collectively, this framework supports the view that targeting the inflammatory control of secretase activity may represent a biologically relevant strategy for disease modification in AD.},
}

@article {pmid42278362,
year = {2026},
author = {Malenchini, M and Beretti, F and Gatti, M and Bertucci, E and Del Toro, E and Maraldi, T},
title = {Stem Cell-Derived Extracellular Vesicles Ameliorate the Neuron Mitochondrial Damage Induced by ROS-, LPS-Exposure: In Vitro Model of Neuron, Microglia, and Astrocyte Triple Co-Culture.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114834},
pmid = {42278362},
issn = {1422-0067},
mesh = {*Lipopolysaccharides/toxicity ; *Neurons/metabolism/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Microglia/metabolism/drug effects ; *Reactive Oxygen Species/metabolism ; *Extracellular Vesicles/metabolism ; Coculture Techniques ; *Astrocytes/metabolism/drug effects/cytology ; Animals ; Humans ; Oxidative Stress/drug effects ; Hydrogen Peroxide ; Cell Survival/drug effects ; Cells, Cultured ; },
abstract = {Oxidative stress causes brain damage contributing to neurodegenerative and vascular diseases. In Alzheimer's disease (AD), elevated oxidative stress and mitochondrial damage are closely linked to misfolded protein accumulation. ROS also plays a major role in ischemic brain injury, particularly during reperfusion, impairing the blood-brain barrier and highlighting the association between vascular pathology and AD. To investigate perturbations in brain cells occurring in mixed dementia (AD combined with vascular dementia components), we used a triple culture system comprising neurons, astrocytes, and microglia and induced neuronal injury by combining LPS and H2O2 exposures. Cell viability assays revealed that neuronal death occurred mainly through apoptosis and DNA damage. In neurons and astrocytes exposed to LPS+H2O2, the expression of NADPH oxidase isoform 2, a major source of ROS, increased, along with FOXO3 and SOD2, a key mitochondrial ROS scavenger. Indeed, these changes were accompanied by altered mitochondrial morphology and integrity, as well as reduced neurite extension and thickness. The treatment with extracellular vesicles (EVs) derived from amniotic fluid stem cells was tested due to their rich content of antioxidant molecules. Interestingly, EVs reversed the negative effects of LPS+H2O2, suggesting the protective role against neuronal injury in vitro may be mediated by the EV-cargo.},
}

*Lipopolysaccharides/toxicity
*Neurons/metabolism/drug effects
*Mitochondria/metabolism/drug effects/pathology
*Microglia/metabolism/drug effects
*Reactive Oxygen Species/metabolism
*Extracellular Vesicles/metabolism
Coculture Techniques
*Astrocytes/metabolism/drug effects/cytology
Animals
Humans
Oxidative Stress/drug effects
Hydrogen Peroxide
Cell Survival/drug effects
Cells, Cultured

@article {pmid42278365,
year = {2026},
author = {Pinta-Castro, A and Michel-Ureña, G and Pérez-González, AP and De Anda-Jáuregui, G and Hernández-Lemus, E},
title = {Canonical Pathways Rewiring in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114835},
pmid = {42278365},
issn = {1422-0067},
support = {904078//Secretaría de Ciencia Tecnología e Innovación/ ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the simultaneous disruption of interconnected molecular pathways, yet the structural mechanisms underlying this transcriptional disintegration remain poorly characterized. To address this, we constructed condition-specific gene co-expression networks from DLPFC bulk RNA-seq data, using a mutual-information (MI) framework with infomap community partitioning. Functional enrichment of network communities via Ingenuity Pathway Analysis (IPA) identified GABAergic signaling, SNARE complex assembly, Synaptogenesis, and neurexin and neuroligin interactions as significantly overrepresented pathways. Integration of node degree with condition-specific average expression revealed coordinated topological centralization of key synaptic genes-including NRXN2, LRRTM1, DLGAP3, and SHANK1-alongside a widespread transcriptional downregulation in GABAergic and Synaptogenesis modules. A shortest-path analysis revealed a consistent expansion of intra-pathway distances across all evaluated canonical pathways in AD, a pattern statistically consistent with reduced local co-expression cohesion. These findings reframe Late-Onset Alzheimer's Disease (LOAD) as an active structural-rewiring process, in which the observed topological centralization pattern seems to be consistent with a consolidation of co-expression around synaptic components, though we cannot exclude that shifts in cellular composition contribute to this signal in bulk RNA-seq data.},
}

@article {pmid42278457,
year = {2026},
author = {Chang, YB and Baleja, JD},
title = {The Role of the Ketogenic Diet in Modulating Biochemical Pathophysiology in Psychiatric and Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114932},
pmid = {42278457},
issn = {1422-0067},
abstract = {The ketogenic diet, a high-fat and low-carbohydrate diet, has potential therapeutic effects on various neurological and psychiatric disorders. The diet shifts the body's energy production in the form of adenosine triphosphate from using glucose to fats. The increased fatty acid β-oxidation results in the production of ketone bodies. This metabolic adaptation changes cellular bioenergetics, especially in the brain, which is highly reliant on energy metabolism. Schizophrenia, a psychotic disorder, and bipolar disorder, a mood disorder, are distinct psychiatric illnesses that can both involve disturbances in mood, cognition, and perception. These disturbances differ in prominence and clinical significance between the two conditions. Although the underlying mechanisms behind each disorder vary, they share some common pathophysiology, such as imbalances in the neurotransmitter system, mitochondrial dysfunction, and oxidative stress. Alzheimer's disease, a neurodegenerative disorder marked by progressive cognitive decline, shares similar cellular disruptions, along with additional pathological features such as neuroinflammation and neuronal death. Recent studies suggest that the ketogenic diet may exert therapeutic effects by modulating underlying biochemical pathways. Its ability to reduce oxidative stress, improve mitochondrial function, and stabilize neurotransmitter balance may help alleviate symptoms and potentially slow disease progression.},
}

@article {pmid42278468,
year = {2026},
author = {Piekarczyk, N and Berezka, P and Domkowicz, K and Myślińska, D and Kaczor, JJ},
title = {Vitamin D3 and Dimethyl Fumarate Partially Restore Neurotrophic Signaling Without Altering Mitochondrial Integrity in the STZ-Induced Model of Sporadic AD.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114940},
pmid = {42278468},
issn = {1422-0067},
support = {531-D080-D248-25//Faculty of Biology/ ; },
abstract = {Alzheimer's disease (AD) is characterized by impaired neurotrophic support, oxidative stress, and metabolic dysfunction. Using the intracerebroventricular streptozotocin (ICV-STZ) rat model of sporadic AD, we investigated whether vitamin D3 (VitD3) and dimethyl fumarate (DMF), administered alone or in combination, modulate hippocampal neurotrophin-related signaling and redox balance. Animals were assigned to SHAM, STZ, VITD, DMF, and COMBO groups, representing control, ICV-STZ, VitD3-treated ICV-STZ, DMF-treated ICV-STZ, and combined VitD3 + DMF-treated ICV-STZ animals, respectively. Hippocampal neurotrophin processing (proBDNF and mature BDNF), downstream signaling (Akt and pAkt), IGF-1 content, mitochondrial oxoglutarate dehydrogenase (OGDH) content, citrate synthase (CS) activity, and glutathione peroxidase (GPx) activity were assessed. STZ administration showed a trend toward reduced mature BDNF content compared with the SHAM group (p = 0.07), whereas combined VitD3 and DMF treatment significantly increased mature BDNF content compared with the STZ group. The mature BDNF/proBDNF ratio was reduced in the STZ group compared with the SHAM group and tended to be higher in the COMBO group compared with the STZ group (p = 0.09). proBDNF content remained unchanged. IGF-1, pTrkB, total Akt, and pAkt content did not differ significantly between groups. The pAkt/Akt ratio showed a trend toward reduction in the STZ group compared with SHAM group (p = 0.09). GPx activity increased in the STZ group, while CS activity and OGDH content were not significantly altered. These findings indicate that STZ-induced neurodegeneration is characterized by redox-associated uncoupling of neurotrophic signaling rather than mitochondrial disruption. Combined VitD3 and DMF treatment partially modulated neurotrophic signaling, supporting a limited but measurable neuroprotective effect.},
}

@article {pmid42278498,
year = {2026},
author = {Ramírez-Expósito, MJ and Cueto-Ureña, C and Martínez-Martos, JM},
title = {Calcitonin Gene-Related Peptide (CGRP): Biology, Signaling, Pathophysiological Roles, and Therapeutic Applications.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114973},
pmid = {42278498},
issn = {1422-0067},
mesh = {Humans ; *Calcitonin Gene-Related Peptide/metabolism/genetics/chemistry ; Animals ; *Signal Transduction ; Receptors, Calcitonin Gene-Related Peptide/metabolism ; Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use/pharmacology ; },
abstract = {The calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide belonging to the calcitonin family, discovered as a product of alternative splicing of the calcitonin gene. CGRP has emerged as a pleiotropic signaling molecule with widespread distribution in the central and peripheral nervous systems, particularly within primary sensory neurons. This narrative review synthesizes current knowledge on the CGRP system, integrating recent advances in its molecular structure, gene organization, and post-translational processing with high-resolution structural insights into its heterodimeric receptor complex (CLR-RAMP1) obtained through cryo-electron microscopy. We also include long-term safety data on anti-CGRP monoclonal antibodies, emerging cardiovascular risk signals, and novel therapeutic applications in vestibular migraine and pediatric populations. The intracellular signaling cascades activated by CGRP, including the canonical cAMP-PKA pathway, MAP kinase activation, and context-dependent calcium signaling, are discussed in relation to its diverse physiological functions. These encompass vasodilation, nociception modulation, neurogenic inflammation, gastrointestinal motility, bone metabolism, tissue regeneration, and energy homeostasis. The central role of CGRP in migraine pathophysiology is examined to understand the development of targeted therapies. The current pharmacological landscape is reviewed, including the evolution of small-molecule CGRP receptor antagonists (gepants) through three generations and the four approved monoclonal antibodies targeting CGRP or its receptor, with comparative analysis of their efficacy, safety profiles, and clinical positioning. Beyond migraine, emerging and predominantly preclinical roles of the CGRP system are discussed in chronic pain, osteoarthritis, cardiovascular diseases, sepsis, cancer (particularly bone metastases and tumor microenvironment immunomodulation), and neurodegenerative disorders such as Alzheimer's disease. In these areas, the available evidence remains heterogeneous and, in most cases, is not yet sufficient to support clinical translation. Finally, future directions are discussed, including the development of stable CGRP analogs, allosteric modulators, and the potential expansion of therapeutic applications into oncology, intensive care medicine, and neuroprotection.},
}

Humans
*Calcitonin Gene-Related Peptide/metabolism/genetics/chemistry
Animals
*Signal Transduction
Receptors, Calcitonin Gene-Related Peptide/metabolism
Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use/pharmacology

@article {pmid42278509,
year = {2026},
author = {Jelińska, J and Józwiak, M and Szeleszczuk, Ł and Sikora, K and Kamysz, W and Kleczkowska, P and Gackowski, M and Grodner, B},
title = {BPC-157 and Its Novel Hybrid Analogs as Inhibitors of Acetylcholinesterase.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114984},
pmid = {42278509},
issn = {1422-0067},
abstract = {Acetylcholinesterase (AChE) inhibition remains a key therapeutic strategy in the management of neurodegenerative disorders such as Alzheimer's disease. In this study, the inhibitory potential of the gastric pentadecapeptide BPC-157 and two newly designed hybrid analogs, CIARA-1 and CIARA-2, was investigated for the first time. The hybrid peptides were rationally designed by combining a BPC-157-derived fragment with an arginine-containing C-terminal sequence to enhance interactions with the enzyme's active and peripheral binding sites. Enzyme kinetics were evaluated using a modified Ellman assay, and inhibition parameters were determined through Lineweaver-Burk analysis. All tested compounds exhibited a competitive mechanism of inhibition, as evidenced by increased Michaelis-Menten constant (Km) values with unchanged maximum velocity (Vmax), indicating competition with the substrate at the catalytic site of AChE. Among the tested compounds, CIARA-1 demonstrated the highest inhibitory potency, reflected by the lowest inhibition constant (Ki = 0.24 mM) and IC50 value (2.52 mM), followed by CIARA-2 (Ki = 0.29 mM; IC50 = 2.73 mM) and BPC-157 (Ki = 0.48 mM; IC50 = 2.80 mM). These findings were consistent with molecular modeling predictions, supporting stronger binding interactions for CIARA-1. Despite significantly lower potency compared to clinically used AChE inhibitors, the studied peptides represent a promising scaffold for further optimization. Overall, this work demonstrates that BPC-157 and its hybrid analogs act as reversible competitive AChE inhibitors, with enhanced activity observed for structurally modified derivatives. The results highlight the potential of peptide-based hybrid molecules as multifunctional candidates in the development of novel therapeutics targeting cholinergic dysfunction.},
}

@article {pmid42278518,
year = {2026},
author = {Ricci, S and Benuzzi, M and Fazzina, M and Cacialli, P},
title = {ZL006 Treatment Reduces Inflammation, Oxidative Stress, and Brain Aβ1-42 Accumulation and Rescues the Loss of PSD95 Synaptic Marker in Familial Alzheimer's Disease-Associated psen1-Deficient Zebrafish Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114992},
pmid = {42278518},
issn = {1422-0067},
support = {Cacialli-RFO2024//the Italian Ministry of University and Research (MIUR)/ ; },
abstract = {Familial Alzheimer's disease (FAD) is a rare form of Alzheimer's. FAD is mainly caused by one or multiple mutations in the genes encoding for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), with the majority occurring in PSEN1. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for FAD. Recently, ZL006 (Med Chem Express cat. Number HY-100456) was shown to reduce over-produced nitric oxide and oxidative stress in ischemic stroke and could protect neurons against Aβ1-42-induced neurotoxicity (in vitro study). With this in mind, we tested ZL006 at different doses (10 μM, 25 μM, 50 μM and 100 μM) in zebrafish embryo injected with ctrl-MO and psen1-MO, investigating the effects on pathological phenotype in vivo. We showed that ZL006 exposure suppresses inflammation, oxidative stress and accumulation of Aβ1-42 in psen1-MO. In conclusion, our study showed that ZL006 was able to ameliorate the pathological phenotype of psen1-morphant zebrafish embryos, supporting its potential as a candidate for further investigations in the context of FAD treatment.},
}

@article {pmid42278520,
year = {2026},
author = {Kassenova, A and Svirin, E and Sitdikova, K and Chaprov, K and Tsoy, A and Munter, J and Nurzhanov, A and Kuznetsova, M and Veremeyko, T and Deykin, A and Ponomarev, E and Strekalova, T and Askarova, S},
title = {Effects of Wheat Malt Extract on Molecular and Behavioral Markers in Aged APP/PS1 and Wild-Type Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114994},
pmid = {42278520},
issn = {1422-0067},
support = {AP23485236//Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; Ref. No. 201223FD8829//The Faculty Development Competitive Research Grant Program, Nazarbayev Fund, Nazarbayev University/ ; FFSG-2024-0020//Scientific state assignment to the Centre for Collective Use IPAC RAS/ ; FZWG-2024-0003//The Scientific state assignment/ ; 101007642EU//The Marie Skłodowska-Curie PhytoApp within the European Union's Horizon 2020 research and innovation program (H2020-MSCA-RISE-2020)/ ; 101086453EU//The Marie Skłodowska-Curie Aqua-Synapse project within the European Union's Horizon 2020 research and innovation program (H2020-MSCA-RISE-2020)/ ; },
abstract = {Growing evidence suggests an important pathogenetic role of brain-specific gangliosides in the mechanisms underlying Alzheimer's disease (AD), the most common form of dementia. Nutritional strategies targeting ganglioside sialylation-for example, through agglutinin-mediated modulation-have therefore attracted increasing research interest. In particular, wheat malt extract (WME), a food-derived source of wheat germ agglutinin (WGA) with high affinity for gangliosides, may influence molecular pathways involved in AD pathogenesis. Twelve-month-old female APPswe/PS1E9 transgenic mice, a model of AD, and wild-type (WT) littermates received WME or tap water for three weeks. Behavioral performance was subsequently assessed. Amyloid plaque burden and astrocyte activation were evaluated using Congo red staining and GFAP immunoreactivity, respectively. Gene expression of selected AD markers in the brain was quantified by RT-qPCR. Aged WT mice exhibited robust, region-specific molecular responses to WME, including upregulation of activity-dependent and synaptic plasticity genes (Arc, Egr1, Bdnf, Syp), enhancement of metabolic and insulin-related signaling (Pgc1a, Sirt1, Igf1r, Irs2), increased Cldn5 expression, and reduced pro-inflammatory Il1β expression. APP/PS1 mice exhibited limited response to WME, suggesting more persistent transcriptional signatures of synaptic impairment, metabolic dysregulation, and neuroinflammation than in WT mice. We found no significant effects of WME treatment on amyloid plaque density and behavior in APP/PS1 mice. No effects on astrocyte activation were observed in either group. These findings demonstrate that dietary WME counteracts abnormal behaviors and molecular changes in neuron plasticity, metabolic, and vascular markers under conditions of normal aging but fails to improve the hallmarks of AD pathology. This highlights the potential of WGA-containing nutrients as a preventive nutritional approach targeting pathogenic mechanisms of aging and, potentially, AD pathology.},
}

@article {pmid42278527,
year = {2026},
author = {Lazarut-Nistor, A and Sibianu, M and Slevin, M},
title = {CRP Is a Key Indicator of Rheumatoid Arthritis-Associated Vascular Injury and Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27115001},
pmid = {42278527},
issn = {1422-0067},
mesh = {Humans ; *Arthritis, Rheumatoid/complications/metabolism ; Biomarkers/metabolism ; *C-Reactive Protein/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/etiology ; *Vascular System Injuries/metabolism/etiology ; },
abstract = {Systemic inflammation plays a pivotal role in the progression of rheumatoid arthritis (RA) and its associated comorbidities, ranging from cardiovascular (CV) disease to neurodegenerative conditions such as Alzheimer's disease (AD). This narrative review examines the molecular cross-talk linking these pathologies, with a specific focus on the distinction between pentameric C-reactive protein (pCRP) and its proinflammatory monomeric form (mCRP). We discuss evidence suggesting that mCRP is not merely a passive marker but also an active driver of endothelial dysfunction, atherosclerosis, and synovial inflammation. This review further explores the connections among inflammatory biomarkers, blood vessel integrity, and neurodegeneration, detailing how persistent cytokine elevation (IL-6, TNF-α) and vascular injury contribute to cerebral small vessel disease (cSVD) and cognitive decline, with neurofilament light chain (NfL) serving as a key biomarker of neuroaxonal injury. Additionally, we address the neurobiology of pain in RA, highlighting the mechanisms of central sensitization (CS) and neuroimmune signalling that sustain pain-independent joint swelling. This evidence indicates that understanding the dynamic connection between CRP isoforms and neuronal markers should offer new insights for risk stratification and suggests that targeting mCRP may provide a novel therapeutic avenue to mitigate both articular and extra-articular manifestations of RA.},
}

Humans
*Arthritis, Rheumatoid/complications/metabolism
Biomarkers/metabolism
*C-Reactive Protein/metabolism
Animals
*Neurodegenerative Diseases/metabolism/etiology
*Vascular System Injuries/metabolism/etiology

@article {pmid42278544,
year = {2026},
author = {Wang, X and Rong, Z and Xue, F},
title = {Multi-Dimensional Transcriptomics Reveals the Prominent Role of Neuroinflammation in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27115020},
pmid = {42278544},
issn = {1422-0067},
support = {SC1032511980070//Zhejiang Wanli University/ ; 20231023//Ministry of Industry and Information Technology/ ; 81301404//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's Disease (AD), the most common form of dementia, is pathologically defined by extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tangles (NFTs), accompanied by chronic neuroinflammation. Recent advances in single-cell RNA sequencing (scRNA-seq/snRNA-seq) and spatial transcriptomics have provided unprecedented resolution for unraveling the cellular and molecular landscape of neuroinflammation in AD. While scRNA-seq enables high-throughput profiling of cellular heterogeneity across brain regions, spatial transcriptomics preserves tissue architecture to map cell-type-specific gene expression within its anatomical context. This review synthesizes the neuroinflammatory mechanisms of AD, outlines the technical evolution and comparative capabilities of single-cell and spatial omics platforms, including resolution, throughput, and compatibility with multiple sample types, and critically evaluates findings from studies in both animal models and human brain tissues. These approaches have revealed state-specific transitions in microglia and astrocytes, including shifts in transcriptional programs, metabolic reprogramming, and pro-inflammatory polarization across disease stages. Notably, spatial transcriptomic analyses demonstrate pronounced regional heterogeneity: periplaque microenvironments exhibit distinct immune-cell compositions and gene expression signatures. Collectively, these omics technologies are redefining the cellular basis of AD progression and hold the potential to impact the discovery of early diagnostic biomarkers and precision therapeutic targets.},
}

@article {pmid42278547,
year = {2026},
author = {Pastén-Castrejón, NJ and Martínez-Orozco, H and Gutiérrez-Silerio, GY and Hernández-Montiel, HL and Maya-Arteaga, JP and Poblano-Paez, I and García-Solís, P and Díaz-Miranda, SY},
title = {Hippocampal, Microglial, Morphological, and Amyloid Profiles Following Thiamine Pyrophosphate Treatment in 3xTg-AD Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27115022},
pmid = {42278547},
issn = {1422-0067},
mesh = {Animals ; *Microglia/metabolism/drug effects/pathology ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; *Thiamine Pyrophosphate/pharmacology ; Mice, Transgenic ; *Hippocampus/metabolism/drug effects/pathology ; Female ; Mice ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and chronic neuroinflammation, with microglia playing a central role in its pathogenesis. Alterations in microglial metabolism have been proposed to contribute to AD-related inflammatory responses and reduced Aβ clearance, suggesting that thiamine-dependent pathways may be relevant in this context. Thiamine pyrophosphate (TPP), the active form of vitamin B1, is essential for glucose metabolism and mitochondrial function; however, its association with microglial changes in AD remains unclear. In this study, 9-month-old female triple-transgenic AD (3xTg-AD) mice and non-transgenic controls (NoTg) received TPP (2.0 mg/mL) or saline as a vehicle for six weeks via osmotic pumps. Nesting, a hippocampus-dependent behavioral test, as well analyses of Aβ burden, microglial morphology, and the expression of genes related to metabolic and immune pathways were evaluated. Differences in nesting behavior between experimental groups were observed, but TPP treatment was not associated with an evident change in 3xTg-AD mice. In the subiculum and CA1 regions of the hippocampus of female 3xTg-AD mice exposed to TPP, a lower Aβ burden was observed, and morphological variations in microglia were detected in both groups (3xTg-AD and NoTg). Additionally, in the brain of the TPP-treated group, some changes in mRNA gene expression were recorded. Together, these findings describe hippocampal microglial and amyloid profiles following TPP treatment in 3xTg-AD mice and provide a basis for further investigation of thiamine-dependent pathways in AD-related neuroinflammatory contexts.},
}

Animals
*Microglia/metabolism/drug effects/pathology
*Alzheimer Disease/drug therapy/metabolism/pathology/genetics
*Thiamine Pyrophosphate/pharmacology
Mice, Transgenic
*Hippocampus/metabolism/drug effects/pathology
Female
Mice
*Amyloid beta-Peptides/metabolism
Disease Models, Animal

@article {pmid42278566,
year = {2026},
author = {Velázquez de Castro-Bono, A and Castro-Luna, G and Guil-Guerrero, JL},
title = {Beyond the Amyloid Hypothesis: Systemic Drivers, CNS-PNS Crosstalk, and the Future of Alzheimer's Disease Therapeutics.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27115042},
pmid = {42278566},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy/pathology ; Animals ; *Amyloid beta-Peptides/metabolism ; *Central Nervous System/metabolism ; *Peripheral Nervous System/metabolism ; tau Proteins/metabolism ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is undergoing a profound paradigm shift, transitioning from a localized, monolithic proteinopathy into a complex, multisystem disorder. This critical review synthesizes recent mechanistic, translational, and clinical insights to dismantle the traditional linear amyloid cascade hypothesis. We explore the synergistic interplay between amyloid-β (Aβ) and tau propagation, positioning chronic neuroinflammation, endolysosomal failure, and metabolic starvation-often framed as "Type 3 Diabetes"-as fundamental disease drivers. Crucially, we highlight the emerging biological bridge of CNS-PNS crosstalk, where central neurodegeneration and peripheral neuropathies are linked by systemic immune activation and microbiota-gut-brain axis dysbiosis. The recent validation of disease-modifying therapies (DMTs) confirms Aβ clearance as a viable pharmacological target; however, the marginal clinical gains and severe radiological risks, such as Amyloid-Related Imaging Abnormalities (ARIA), expose the profound limitations of monotherapy. Ultimately, we argue that isolated amyloid clearance is merely an induction phase. The future of AD therapeutics mandates a sequential combination approach-pairing early plaque debulking with lifelong metabolic and neuroimmune maintenance. Supported by scalable fluid biomarkers (e.g., plasma p-tau217) and the expanded ATN(I) framework, the field must embrace proactive precision medicine and inclusive clinical trial designs to successfully transform AD into a manageable chronic condition.},
}

Humans
*Alzheimer Disease/metabolism/therapy/pathology
Animals
*Amyloid beta-Peptides/metabolism
*Central Nervous System/metabolism
*Peripheral Nervous System/metabolism
tau Proteins/metabolism
Brain/metabolism

@article {pmid42278574,
year = {2026},
author = {Mazzeo, P and Vietri, M and Tecce, N and Delizia, A and Remondelli, V and Ciaglia, T and Di Dio, A and Corletti, L and Pizzuti, CG and Pepe, G and Stabile, E and Correale, M and Campiglia, P and Miranda, MR and Tecce, MF and Vestuto, V},
title = {SGLT2 Inhibitors in Alzheimer's Disease: Biochemical Insights and Therapeutic Potential.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27115051},
pmid = {42278574},
issn = {1422-0067},
abstract = {Sodium-glucose cotransporter-2 (SGLT2) inhibitors, initially developed as antidiabetic agents, have recently gained attention for their potential role in modulating processes relevant to Alzheimer's disease (AD). Preclinical studies suggest that they may influence key mechanisms involved in AD. However, available clinical studies, mainly retrospective and focused on diabetic populations, provide insufficient clarity on whether these effects extend to broader, non-diabetic groups. The heterogeneity of neurodegenerative diseases, which differ in inflammatory and proteotoxic mechanisms, further highlights the need for disease-specific investigations. This review examines mechanistic pathways through which SGLT2 inhibition may influence AD progression and evaluates current clinical evidence, aiming to identify key knowledge gaps and guide future research. This review summarises the latest evidence from the literature, focusing on preclinical experiments, translational studies and early clinical observations. The search focused on pathways related to microglial and astrocytic activation, oxidative stress, metabolic remodeling, neuronal survival, and amyloid and tau dynamics. Accumulating data indicate that SGLT2 inhibitors exert multifaceted actions relevant to AD pathology, including reduced neuroinflammation and oxidative stress, improved mitochondrial and insulin signaling, as well as decreased amyloid deposition and tau hyperphosphorylation. Additionally, SGLT2 inhibition may improve cerebrovascular perfusion and blood-brain barrier stability, potentially supporting cognitive function. Nonetheless, major challenges remain, including variable blood-brain barrier permeability and heterogeneous experimental responses. SGLT2 inhibitors represent a promising pleiotropic class of compounds with potential disease-modifying effects in AD. Their capacity to target metabolic, inflammatory, and proteotoxic pathways makes them attractive candidates for neurodegenerative therapy. Further studies are required to clarify biochemical pathways and validate clinical efficacy.},
}

@article {pmid42278575,
year = {2026},
author = {Lucy, TT and Mamun-Or-Rashid, ANM and Lee, DC and Lefterov, I and Koldamova, R and Fitz, NF},
title = {Integration of Transcriptional Signatures from Brain Tissue and Plasma Extracellular Vesicles of a Preclinical Tauopathy Mouse Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27115050},
pmid = {42278575},
issn = {1422-0067},
support = {R01 AG075992//NIH Common Fund/ ; R01 AG077636/AG/NIA NIH HHS/United States ; R01 AG075069/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Extracellular Vesicles/metabolism/genetics ; Mice ; *Tauopathies/genetics/metabolism/pathology ; *Brain/metabolism/pathology ; Disease Models, Animal ; Gene Expression Profiling ; *Transcriptome ; RNA, Untranslated/genetics ; MicroRNAs/genetics ; Mice, Transgenic ; RNA, Circular/genetics ; Microglia/metabolism ; Gene Expression Regulation ; },
abstract = {Tauopathies, including Alzheimer's disease, involve progressive neurodegeneration and sustained neuroinflammation. We present a multi-compartment transcriptomic atlas of 9.6-month-old PS19 tauopathy mice compared with wild-type (WT) controls (n = 8/group), profiling cortical mRNA, cortical non-coding RNA (ncRNA), and plasma small extracellular vesicle (pEV) ncRNA. In the PS19 cortex, mRNA sequencing identified 917 differentially expressed genes (DEGs), with microglial deconvolution revealing an association toward disease-associated microglia (DAM) gene signature and downregulation of genes involved in oxidative phosphorylation and cholesterol biosynthesis relative to WT. Cortical ncRNA profiling identified 466 differentially expressed ncRNAs, primarily circular RNAs (circRNAs; n = 331). In pEVs, 822 ncRNAs were differentially abundant, of which 657 circRNAs were identified in PS19 compared to WT mice. Cross-compartment integration suggest that pEV miRNA gene targets functionally mirrored genes involved in the brain's inflammatory and metabolic failure. We identified a preliminary candidate signature of 33 ncRNAs, including miR-5114 (up in brain, down in pEV), circ_0008242 and circ_0002153 (up in brain and pEV), and circ_0007688 (down in brain and pEV), differentially enriched across both brain and periphery in PS19 compared to WT mice. These results suggest that the pEV non-coding landscape may partially reflect central tau-mediated changes in the brain transcriptional response. This study identifies circRNAs as the most numerically perturbed ncRNA class and provides a foundation for potential peripheral indicators of central brain tau pathology.},
}

Animals
*Extracellular Vesicles/metabolism/genetics
Mice
*Tauopathies/genetics/metabolism/pathology
*Brain/metabolism/pathology
Disease Models, Animal
Gene Expression Profiling
*Transcriptome
RNA, Untranslated/genetics
MicroRNAs/genetics
Mice, Transgenic
RNA, Circular/genetics
Microglia/metabolism
Gene Expression Regulation

@article {pmid42278664,
year = {2026},
author = {Segmen, H and Yildiz, M},
title = {A Multi-Locus and Machine Learning-Based Assessment of SNCA Variants in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27115143},
pmid = {42278664},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/genetics ; *alpha-Synuclein/genetics ; *Polymorphism, Single Nucleotide/genetics ; Female ; *Machine Learning ; *Genetic Predisposition to Disease ; Case-Control Studies ; Male ; Linkage Disequilibrium ; Aged ; Haplotypes ; Genotype ; Alleles ; Aged, 80 and over ; },
abstract = {This study investigates the role of single nucleotide polymorphisms (SNPs) in the SNCA gene, encoding alpha-synuclein, in Alzheimer's disease (AD). A case-control study was conducted including 95 AD patients and 97 healthy controls. Four SNCA polymorphisms (rs2583988, rs2619363, rs2619364, rs10005233) were analyzed using logistic regression, haplotype estimation, genotype combination analysis, and Random Forest modeling. Significant associations were identified for rs2583988, rs2619364, and rs2619363, while rs10005233 showed no association. The rs2583988 C allele and rs2619364 G allele were more frequent in patients, suggesting increased disease risk. Linkage disequilibrium analysis revealed weak correlations (low r[2]), indicating largely independent genetic effects. Multivariate logistic regression showed that clinical parameters, rather than genetic variants, were independently associated with AD. Multi-locus genotype analysis demonstrated that specific SNP combinations were linked to increased disease risk. Firth regression confirmed associations in low-frequency genotypes. The outcomes derived from the Random Forest methodology were classified as exploratory and not as proof of clinical predictive utility, attributed to the limited sample size, the absence of external validation, and the educational imbalance. Ordinal logistic regression indicated no association between SNCA variants and cognitive severity, while education had a protective effect. The selected SNCA variants showed exploratory associations with AD in this cohort; however, they failed to maintain their validity as independent predictors in multivariate logistic regression analysis. Before drawing any conclusions regarding screening or risk stratification, these findings require independent replication, correction for multiple testing and functional validation.},
}

Humans
*Alzheimer Disease/genetics
*alpha-Synuclein/genetics
*Polymorphism, Single Nucleotide/genetics
Female
*Machine Learning
*Genetic Predisposition to Disease
Case-Control Studies
Male
Linkage Disequilibrium
Aged
Haplotypes
Genotype
Alleles
Aged, 80 and over

@article {pmid42279024,
year = {2026},
author = {Baiamonte, L and Tarantino, D and Lodico, M and Bellante, G and Migliazzo, C and Allegra, P and Maniscalco, L and Piccoli, T and Vanacore, N and Matranga, D and Salemi, G},
title = {Air Pollution and Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Journal of clinical medicine},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/jcm15114163},
pmid = {42279024},
issn = {2077-0383},
abstract = {Background/Objectives: Alzheimer's disease (AD) is the most common cause of dementia. Among the various factors associated with the risk of AD, growing attention in recent years has focused on environmental influences, particularly air pollution. The association between air pollutants and AD remains inconclusive due to heterogeneity in available studies. Given these gaps, we performed a systematic review on the topic. Methods: We systematically searched Pubmed, Embase and Scopus. Retrieved records underwent screening by title and abstract and then in full text. We included studies quantitatively exploring the association between exposure to air pollutants and risk of AD. We performed a meta-analysis to identify a pooled estimate of the impact of each pollutant on the probability of developing AD. Results: We retrieved 1081 records and included 27 studies. We found a significant association between PM2.5 levels and AD risk (HR 1.74, 95%CI 1.36-2.23). Our data did not support a relevant role for the other pollutants we analyzed (for PM10 HR = 1.35, 95%CI: 0.86-2.11; for NO2 HR = 1.34, 95%CI 0.96-1.86; and for O3 HR = 1.03, 95%CI 0.68-1.57). Conclusions: PM2.5 emerged as the pollutant most strongly and consistently associated with an increased risk of AD. This robust and statistically significant association underscores the potential neurotoxic effects of fine particulate matter. For other pollutants, a clear role was not found. These results should be interpreted with caution, due to high heterogeneity in the definition of AD in the included studies (in most cases, a clinical definition was used). More research will be needed in the future.},
}

@article {pmid42279176,
year = {2026},
author = {Wang, X and Wei, C},
title = {Network Meta-Analysis of Cognitive Impairment and miRNA Expression in Alzheimer's Disease Patients with Hearing Loss: A Systematic Review and Cross-Validation.},
journal = {Journal of clinical medicine},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/jcm15114315},
pmid = {42279176},
issn = {2077-0383},
abstract = {Background: Age-related hearing loss (HL) is a significant independent risk factor for Alzheimer's disease (AD), yet the molecular mechanisms underlying this comorbidity and the comparative efficacy of hearing interventions for cognitive outcomes remain unclear. This study aims to integrate clinical evidence and molecular data to address these gaps. Objective: The objective of this study was to conduct a systematic review and network meta-analysis (NMA) in order to: (1) compare the effects of hearing interventions on cognitive function in AD patients; (2) identify and rank key microRNAs (miRNAs) associated with AD-HL comorbidity; (3) explore heterogeneity sources; and (4) cross-validate findings with internal clinical sequencing data. Methods: We systematically searched PubMed, Web of Science, Embase, and the Cochrane Library, with a cut-off date of May 2024. Included studies involved AD patients with/without HL, reporting cognitive scores (MoCA, MMSE, and AVLT) or miRNA expression data. An NMA was performed to rank interventions (cochlear implants-CIs, hearing aids-HAs, and no intervention-NI) and miRNAs using surface under the cumulative ranking (SUCRA) curves. Heterogeneity was assessed via subgroup analysis and meta-regression. Pooled miRNA expression results were cross-validated against an internal clinical sequencing dataset (LC-P20240110033, n = 16) using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Results: Twelve studies (2137 patients) were included. HL was significantly associated with worse cognitive function (MoCA: SMD = -0.82, 95% CI: -1.15 to -0.49; AVLT delayed recall: SMD = -1.12, 95% CI: -1.56 to -0.68). NMA revealed that the CI group (SUCRA = 0.89) was superior to the HA group (SUCRA = 0.62) and NI (SUCRA = 0.09) for preserving MoCA scores. Among the nine differentially expressed miRNAs identified in exploratory synthesis, three met strict quantitative criteria for NMA (reported in ≥2 independent studies with comparable quantification and variance data); hsa-miR-6875-5p was the most consistent biomarker (pooled FC = 1.52, 95% CI: 1.04-2.23), showing excellent agreement with sequencing data (FC = 3.29; ICC = 0.82, 95% CI: 0.67-0.91). Heterogeneity was significantly influenced by the miRNA detection platform (p = 0.04) and HL severity (p = 0.03). Conclusions: This study demonstrates that HL exacerbates cognitive decline in AD in a dose-dependent manner. Cochlear implants may offer superior cognitive protection compared to hearing aids. The consistently dysregulated hsa-miR-6875-5p emerges as a hypothesis-generating cross-modal biomarker, bridging clinical observation and molecular pathology in AD-HL comorbidity.},
}

@article {pmid42279785,
year = {2026},
author = {Zhao, J and Zhou, L and Liu, Y and Yang, Z and Ban, F and Zhang, Y},
title = {Comprehensive Extraction of Shrimp Head Lipids and Peptides from Litopenaeus vannamei: Evaluation of Neuroprotective Potential and Constituent Analysis.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/foods15111999},
pmid = {42279785},
issn = {2304-8158},
support = {2025A1515010941//Guangdong Provincial Natural Science Foundation/ ; 2024A1515110066//Guangdong Provincial Natural Science Foundation/ ; KCXFZ20240903093925033//the Sustainable Development Program of Shenzhen Science and Technology Major Program/ ; 2025KCJS_057//Guangdong Provincial Graduate Student Course Construction Project/ ; 2025060//Shenzhen Kunpeng Youth Innovation Project/ ; 2024ZDZX2086//Special Project in Key Fields of Guangdong Provincial Higher Education Institutions/ ; 2024B01265//Zhanjiang Science and Technology Plan Projects/ ; GDOU2025092//Guangdong Provincial College Student Innovation & Entrepreneurship Training Project/ ; },
abstract = {The increasing prevalence of Alzheimer's disease has created a substantial and urgent need for brain-healthy functional foods. The processing of Pacific white shrimp (Litopenaeus vannamei) generates considerable amounts of head waste, which is rich in bioactive compounds, including lipids and peptides, holding great promise for the development of nutraceuticals to support human brain health. However, traditional extraction methods are time-consuming and inefficient in fully utilizing these compounds. This study aimed to explore the functional properties of these shrimp head-derived ingredients using "one-step" three-phase partitioning (TPP) followed by successive proteolysis. The extracted polar lipid (PL-SH), protein (P-SH) and proteolytic peptidic product (Pep-SH) from shrimp heads were screened for their antioxidant, neuroprotective, and anti-neuroinflammatory activities. Antioxidant activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS[+]), and hydroxyl free radical scavenging assays, all of which revealed strong antioxidant potential for all three products. Neuroprotective activities were assessed using HT-22 mouse hippocampal neuronal cells challenged with Aβ25-35, and anti-neuroinflammatory activities were evaluated using BV-2 microglial cells stimulated with lipopolysaccharide (LPS). The results suggested that both PL-SH and Pep-SH exerted protective effects against Aβ25-35-induced cell damage under the tested conditions, and PL-SH also reduced nitric oxide (NO) production induced by LPS, indicating potential anti-neuroinflammatory activity. However, further studies with additional biomarkers (e.g., ROS, apoptosis markers, and cytokines) are required to confirm these effects. The lipid composition of PL-SH was further characterized by thin-layer chromatography and LC-MS/MS-based lipidomics, revealing various classes of phospholipids. Furthermore, analysis of the molecular weight distribution and sequences of peptides in Pep-SH revealed peptide sizes ranging from 70 to 1700 Da and a high degree of homology to known antioxidant and neuroprotective peptide sequences. These findings suggest that lipids and peptides from Pacific white shrimp heads possess valuable functional properties, supporting their potential use in the development of functional foods for neuroprotection and anti-neuroinflammation.},
}

@article {pmid42280440,
year = {2026},
author = {Rahman, M and Akter, K and Rani, A and Park, MN and Kim, B},
title = {Herbal Neurotherapeutics for Cognitive Disorders: Integrative Mechanisms Linking Neurotransmitter Systems, Neurodegeneration, and the Gut-Brain Axis.},
journal = {Nutrients},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/nu18111796},
pmid = {42280440},
issn = {2072-6643},
support = {RS-2020-NR049559//National Research Foundation of Korea (NRF) grant/ ; RS-2020-NR054734//Basic Science Research Program through the National Research Foundation of Korea (NRF),/ ; },
abstract = {Cognitive disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, depression, and vascular dementia, are associated with dysregulation of neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, and γ-aminobutyric acid (GABA). These disorders are increasingly recognized as multifactorial conditions involving oxidative stress, neuroinflammation, mitochondrial dysfunction, synaptic impairment, blood-brain barrier disruption, metabolic imbalance, and gut-brain axis dysregulation. Current pharmacological therapies may provide symptomatic relief; however, their clinical benefits are often limited and associated with adverse effects. Herbal medicines have gained increasing attention as potential complementary approaches for cognitive support and neuroprotection. Preclinical evidence and emerging clinical studies suggest that herbal bioactive compounds may exert neuroprotective effects through antioxidants, anti-inflammatory, and neurotransmitter-modulating mechanisms. Medicinal herbs such as Bacopa monnieri, Withania somnifera, Ginkgo biloba, Glycyrrhiza glabra, Moringa oleifera, and ginseng have shown potential cognitive benefits in experimental models and selected human studies. Advanced delivery systems, including nanoparticles and phytosomes, may further improve the bioavailability and brain-targeting efficiency of herbal compounds. However, current clinical evidence remains heterogeneous and limited by insufficient standardization, small sample sizes, and short study durations. Further large-scale clinical studies and standardized safety assessments are essential before herbal neurotherapeutics can be widely applied in cognitive and neurological disorders.},
}

@article {pmid42280655,
year = {2026},
author = {Koyama, S and Pham, L and Murakawa, Y and Ogawa, Y and Terauchi, K and Davis, K},
title = {Unlocking the Power of Plant-Derived Natural Products: Therapeutic Benefits for Cognitive Health and Neuropsychiatric Symptoms in Dementia-Related Diseases.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/plants15111619},
pmid = {42280655},
issn = {2223-7747},
abstract = {Dementia, including Alzheimer's disease (AD), represents one of the most pressing public health challenges of the 21st century, affecting more than 55 million individuals worldwide, with projections reaching 139 million by 2050. Current pharmacological treatments offer limited efficacy and significant side effects, driving intense interest in plant-derived natural products as both preventive and therapeutic agents. This review synthesizes preclinical and clinical evidence for key phytochemical classes, including polyphenols, phenolic acids, flavonoids, terpenoids, and alkaloids, in the context of dementia and age-related cognitive decline. Molecular mechanisms are examined in detail, including effects on antioxidant defense and redox homeostasis, suppression of neuroinflammation, and enhancement of synaptic plasticity and neurotransmission. Despite promising preclinical and epidemiological evidence, most clinical trials remain limited in scale and duration and provide mixed results on the efficacy of using phytochemicals for cognitive health. Among the compounds with the most consistent clinical support are the ginkgo diterpene extract EGb 761, saffron carotenoids, curcumin, and rosmarinic acid. A dedicated section addresses the emerging evidence for aromatherapy as a non-pharmacological intervention for behavioral and cognitive symptoms of dementia. Future directions include strategies to improve bioavailability of phytochemicals, the utilization of aromatherapy together with oral supplements, and the need for larger randomized controlled trials using well-characterized and reproducibly manufactured formulations and purified active compounds. Priority areas for future investigation include resolving pharmacokinetic barriers to central nervous system (CNS) delivery, standardizing herbal product composition, and conducting adequately designed clinical trials in well-defined patient populations.},
}

@article {pmid42281255,
year = {2026},
author = {Luo, Z and Yang, J},
title = {The Role of the IL-33/ST2 Axis in Nervous System Development and Diseases.},
journal = {Immunology and cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1111/imcb.70138},
pmid = {42281255},
issn = {1440-1711},
support = {51355093//Guangdong Pharmaceutical University/ ; },
abstract = {Interleukin (IL)-33, a cytokine belonging to the IL-1 family, is produced in various tissues, including the nervous system. As a nuclear-stored alarmin protein, IL-33 is released under cell stress or damage, triggering immune responses through its receptor complex, composed of ST2L and the IL-1 receptor accessory protein (IL-1RAcP). The receptors for IL-33 are expressed in various cell types within the nervous system, including neurons, astrocytes, and microglia, and play a crucial role in neurodevelopment and the pathogenesis of neurological diseases. In neurodevelopment, IL-33 promotes microglial metabolic adaptation and phagocytosis via the IL-33/ST2/Akt axis, modulates glial function to affect neural circuit maturation, and influences oligodendrocyte differentiation. In neurological disorders, IL-33 exerts context-dependent regulatory effects in the nervous system through modulation of myeloid and T-cell responses, maintenance of barrier integrity, promotion of tissue repair, and regulation of neuroimmune homeostasis. In acute CNS injuries such as ischemic stroke and traumatic brain injury, IL-33 is generally associated with anti-inflammatory polarization and enhanced repair, although circulating levels may also reflect injury severity. In chronic neurodegenerative diseases including Alzheimer's and Parkinson's disease, IL-33 is implicated in amyloid-β clearance, remyelination, glymphatic function, and neuroprotection, while dysregulation of the IL-33/sST2 axis correlates with disease progression. In contrast, IL-33 may facilitate tumor progression in glioma. Emerging evidence also supports IL-33 and sST2 as potential biomarkers for diagnosis and prognosis in CNS disorders.},
}

@article {pmid42281258,
year = {2026},
author = {Yin, WL and Peng, L and Zhang, JH and Huang, XL and Yin, WG},
title = {Hyperlipid-Related Alzheimer's Disease: Potential Role of CircUCK2/miR-24-3p/p38 Axis in Neuronal Damage.},
journal = {Comprehensive Physiology},
volume = {16},
number = {3},
pages = {e70146},
doi = {10.1002/cph4.70146},
pmid = {42281258},
issn = {2040-4603},
support = {20190214//Qingyuan People's Hospital Medical Research Fund 2019/ ; },
mesh = {*Alzheimer Disease/metabolism/etiology/genetics/pathology ; Animals ; Humans ; *MicroRNAs/metabolism/genetics ; *Hyperlipidemias/complications/metabolism ; *p38 Mitogen-Activated Protein Kinases/metabolism/genetics ; Male ; *Neurons/metabolism/pathology ; Mice ; Female ; Aged ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; Signal Transduction ; },
abstract = {BACKGROUND: Accumulating empirical evidence underscores that hyperlipidemia may fuel the pathological progression of Alzheimer's disease (AD) by triggering inflammatory signaling cascades and promoting amyloid-β (Aβ) fibrillogenesis. The CircUCK2/miR-24-3p/p38 regulatory axis has been identified as a key molecular node in these biological processes, yet its specific functions in AD associated with abnormal lipid metabolism remain incompletely delineated.

METHODS: We recruited 50 AD patients and 50 healthy individuals from the Neurology Department of the Affiliated Hospital of the University of South China. Logistic regression analysis was employed to explore the correlation between blood lipid concentrations and AD susceptibility, while Pearson correlation analysis was used to assess the association between lipid levels and Aβ deposition. Dual-luciferase reporter assays confirmed the mutual regulatory relationships among CircUCK2, miR-24-3p, and p38. Additionally, we evaluated inflammatory responses, neuronal damage, and the activation status of p38. A hyperlipidemic mouse model was established to examine the expression levels of AD-related biomarkers.

RESULTS: Elevated blood lipid levels were closely correlated with increased AD risk and enhanced Aβ deposition. CircUCK2 was found to induce p38 phosphorylation by targeting miR-24-3p, thereby augmenting autophagic flux, mitigating inflammatory reactions, and suppressing apoptotic pathways in hyperlipidemic cells. Furthermore, p38 activation reduced the levels of pro-inflammatory mediators, downregulated the expression of Aβ42 and P-tau181, and improved learning and memory capabilities in mice.

CONCLUSION: Hyperlipidemia accelerates Aβ deposition and neuronal injury, potentially exacerbating AD progression. The CircUCK2/miR-24-3p/p38 signaling pathway may serve as a promising therapeutic target for AD intervention.},
}

*Alzheimer Disease/metabolism/etiology/genetics/pathology
Animals
Humans
*MicroRNAs/metabolism/genetics
*Hyperlipidemias/complications/metabolism
*p38 Mitogen-Activated Protein Kinases/metabolism/genetics
Male
*Neurons/metabolism/pathology
Mice
Female
Aged
Amyloid beta-Peptides/metabolism
Mice, Inbred C57BL
Signal Transduction

@article {pmid42281500,
year = {2026},
author = {Rashidi, SK and Dezfouli, MA and Khalili, H and Kiani, AKD},
title = {The role of gut microbiota in the neurobiology and treatment of Alzheimer's disease.},
journal = {General physiology and biophysics},
volume = {45},
number = {2},
pages = {129-151},
doi = {10.4149/gpb_2025042},
pmid = {42281500},
issn = {0231-5882},
mesh = {Humans ; *Alzheimer Disease/therapy/microbiology/physiopathology ; *Gastrointestinal Microbiome ; Animals ; *Brain/physiopathology ; Amyloid beta-Peptides/metabolism ; Probiotics/therapeutic use ; Fecal Microbiota Transplantation ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia in the elderly population and characterized by progressive cognitive decline. The major pathological features of AD are the accumulation of extracellular amyloid-beta protein as neuritic plaques and intracellular hyperphosphorylated tau protein as neurofibrillary tangles. Studies have shown that gut microbiota are involved in several central nervous system disorders through regulation of neurotransmitter production, blood-brain barrier permeability and immune responses. The gut microbiota establishes a two-way communication between the gut and the brain through neural, endocrine, and immune pathways, which play a role in various neurological diseases, including AD. Alterations in the composition and function of the gut microbiota may influence neuroinflammation, amyloid-beta accumulation, and tau pathology. Targeting the balance of the gut microbiota through probiotics, prebiotics, and fecal microbial transplantation could be promising therapeutic approach against neurodegeneration. Understanding the complex relationship between the gut microbiota and AD pathobiology could pave the way for novel preventive and therapeutic strategies. Here, we summarized advances in the role of gut microbiota in AD pathobiology and updated rising concerns from recent reports. Moreover, the possibility of applying the capability of the gut microbiota as a promising treatment against AD has been discussed in this review.},
}

Humans
*Alzheimer Disease/therapy/microbiology/physiopathology
*Gastrointestinal Microbiome
Animals
*Brain/physiopathology
Amyloid beta-Peptides/metabolism
Probiotics/therapeutic use
Fecal Microbiota Transplantation

@article {pmid42281759,
year = {2025},
author = {Foye, G and Foye, E and Walter, S and Ptomey, LT},
title = {Research should be conducted with us, not on us: Perspectives on Alzheimer's disease clinical trials for persons with Down syndrome.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {1},
number = {4},
pages = {},
pmid = {42281759},
issn = {2997-3805},
abstract = {Life expectancy for individuals with Down syndrome (DS) has increased significantly over the past 60 years, drawing greater attention to Alzheimer's disease (AD), now the leading cause of death in this population. Despite a lifetime AD risk as high as 90%, individuals with DS have been historically excluded from AD research, exacerbating already-existing significant gaps in prevention, diagnosis, and treatment strategies. Although recent clinical trials have begun to address this, challenges in recruitment and retention persist due to accessibility barriers, safety concerns, and limited prior engagement. Meaningful inclusion requires centering the voices of both individuals with DS and their caregivers to ensure that researchers provide accessible studies, communicate with respect, and share results, which will result in greater trust in research. This perspective offers personal reflections from an adult with DS, her caregiver, and two researchers, offering practical insights for designing inclusive, respectful, and person-centered clinical trials.},
}

@article {pmid42282019,
year = {2026},
author = {Restuccia, G and Ielo, A and Buono, VL and Quartarone, A and Bonanno, L},
title = {Biological plausibility of single-shell NODDI-DTI in non-demented older adults: associations with plasma biomarkers and follow-up cognition.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9423230/v1},
pmid = {42282019},
issn = {2693-5015},
abstract = {Background White matter (WM) degeneration is increasingly recognized as a major feature of aging and neurodegenerative disorders, such as Alzheimer's disease (AD). NODDI-DTI is a technique that allows the estimation of neurite density index (NDI) and orientation dispersion index (ODI) in white matter from single-shell diffusion tensor imaging. However, it should be interpreted as a tensor-derived approximation and biological support for these metrics is needed. This study aimed to provide multimodal evidence supporting the biological plausibility of NODDI-DTI estimates. Methods Demographic, clinical and single-shell DWI data from 42 older adults without dementia were obtained from the Alzheimer's Disease Neuroimaging Initiative database. We tested associations between NODDI-DTI metrics by performing (i) an exploratory voxel-wise analysis to characterize the spatial distribution and the percentage of statistically significant associations across the white matter (ii) and a tract-based analyses in a priori AD-vulnerable white matter tracts. Finally, we conducted longitudinal analyses to test whether baseline NODDI-DTI metrics and plasma biomarkers were associated with follow-up Montreal Cognitive Assessment (MoCA) performance. Results Among the investigated plasma biomarkers, pTau181 was the only biomarker showing widespread significant associations with diffusion metrics, with a substantially more extensive effect for NDI. In the tract-based analyses, higher plasma concentrations of pTau181 were associated mainly with lower NDI in the fornix, inferior fronto-occipital fasciculus and uncinate fasciculus. Higher plasma concentrations of NfL were associated with lower NDI in the fornix, together with opposite ODI effects in the splenium of the corpus callosum and uncinate fasciculus. In the subgroup with follow-up MoCA available, higher baseline ODI in the hippocampal cingulum and higher baseline pTau181 were both independently associated with worse cognitive performance. Conclusions These findings suggest that NODDI-DTI may represent a biologically plausible and clinically informative approach to study early WM microstructure, with potential prognostic relevance for subsequent cognitive performance, particularly when full multi-shell acquisitions are not feasible or not available.},
}

@article {pmid42282034,
year = {2026},
author = {Tanzi, R and Castro, R and Gavrilles, E and Choi, SH},
title = {Microglia regulate adult neurogenesis via interleukin-6 trans-signaling triggered by apoptotic progenitors.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9619714/v1},
pmid = {42282034},
issn = {2693-5015},
abstract = {In the adult hippocampus, neural progenitor cells (NPCs) proliferate before undergoing differentiation, maturation, and incorporation into the hippocampal neurocircuitry, where they contribute to diverse learning and memory processes that can be perturbed by injury, aging, and disease (1-10). Recent advances have identified microglia and interleukin-6 (IL-6) as regulators of adult hippocampal neurogenesis (AHN) (11). Despite these findings, the mechanism by which IL-6 signaling or microglia regulate neurogenesis has remained unclear. Here, we show that IL-6 trans signaling is triggered by microglial IL-6R shedding during efferocytosis, and that this mediates the transition from proliferation to neuronal differentiation in neighboring, healthy NPCs. We found that proliferating NPCs secrete IL-6 and that apoptotic NPCs are commonly found within clusters of proliferating NPCs. Next, we show that efferocytosis of apoptotic NPCs causes IL-6 receptor shedding by microglia and that IL-6 trans activation of NPCs leads to neuronal differentiation and maturation. Finally, we generated transgenic mice lacking IL-6R exclusively in microglia and found impaired neuronal maturation in the adult hippocampus and deficits in learning and memory in these mice. Our results reveal a molecular mechanism by which microglia regulate adult neurogenesis and contextualize myriad separate investigations into the role of microglia and IL-6 in neurogenesis. Our results position microglia not merely as passive responders to cell death but as active regulators of lineage specification and progenitor cell maturation within the neurogenic niche. The IL-6 trans signaling axis appears to function as a temporally gated checkpoint that coordinates niche refinement-balancing expansion with maturation and synchronizing neuronal development with microglial activation and quiescence. These results could be utilized to develop treatments in pathological contexts characterized by deficits in neurogenesis, such as Alzheimer's disease.},
}

@article {pmid42282051,
year = {2026},
author = {Vaithianathan, K},
title = {Cross-scale spatially-aware generative modeling of transcriptomic programs underlying neurodegenerative brain organization.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42282051},
issn = {2331-8422},
abstract = {Neurodegenerative disorders such as Alzheimer's disease exhibit highly organized patterns of regional brain vulnerability, yet the biological mechanisms underlying this spatial selectivity remain incompletely understood. Existing imaging-transcriptomic studies have largely relied on correlation-based analyses between gene expression and neuroimaging phenotypes, limiting their ability to model how molecular organization gives rise to neurodegeneration. Here, we introduce a cross-scale spatially-aware generative framework for modeling transcriptomic programs underlying cortical neurodegeneration. Regional transcriptomic profiles were derived from the Allen Human Brain Atlas using 910 landmark genes across 68 cortical regions. Neurodegenerative vulnerability maps were constructed from ADNI FreeSurfer cortical thickness measurements by computing regional cortical thinning differences between cognitively normal controls (NC = 926) and Alzheimer's disease subjects (AD = 426). A variational generative architecture was used to learn latent biological programs linking regional gene-expression organization to cortical degeneration while incorporating graph-based spatial smoothness regularization to preserve cortical organization. The proposed framework achieved strong prediction of regional neurodegenerative vulnerability, yielding an explained variance of 0.8604 and a significant spatial correlation between predicted and observed cortical degeneration profiles (r = 0.9439, p < 0.001). The learned latent representations revealed structured transcriptomic organization associated with distributed disease susceptibility. These findings demonstrate that biologically constrained generative modeling can bridge microscale molecular organization with macroscale neurodegeneration, providing a foundation for spatially-aware generative neurobiology and computational neuroscience.},
}

@article {pmid42282149,
year = {2026},
author = {Venkatesh, S and Zhang, S and Zhu, W and Morris, M and Mercurio, R and Berman, SB and Mathys, H and Olsen, AL and Shaaban, CE and Visweswaran, S and Lopez, OL and Cai, T and Hou, J and Xia, Z},
title = {Predicting the timing of first sustained cognitive worsening in Alzheimer's disease using real-world clinical data and machine learning.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.02.26354764},
pmid = {42282149},
abstract = {BACKGROUND: Cognitive assessments are sparsely documented in electronic health records (EHRs), limiting scalable detection of cognitive worsening in real-world clinical settings.

METHODS: We applied a deep neural network optimized for identifying clinical event timing from sparsely labeled gold-standard data (label-efficient incident phenotyping from longitudinal EHR , LATTE) to predict time-to-first sustained cognitive worsening in AD patients from a large healthcare system (2011-2022) with linkage to an AD Research Center registry in a subset. Sustained cognitive worsening was defined as cognitive decline persisting over ≥2 consecutive visits within 3 years. Separate LATTE models were trained with worsening labels from Clinical Dementia Rating (CDR), Mini-Mental Status Examination (MMSE), and Montreal Cognitive Assessment (MoCA) scores; semi-supervised learning scaled predictions to larger imputation cohorts lacking sufficient longitudinal scores. We evaluated model performance using average time-specific area under the receiver operating characteristic curve (AUC), area between curves (ABC), and Brier scores. To demonstrate clinical utility, we examined whether predicted time-to-worsening differentiated clinically meaningful patient subgroups using competing-risk Cox proportional hazards models accounting for death.

FINDINGS: The cohort comprised 27,614 AD patients (65% women, 91% non-Hispanic White, mean [SD] age at start of follow-up 78.76 [9.53] years). In gold-standard cohorts (n: CDR=632, MMSE=710, MoCA=752; remaining patients formed imputation cohorts), LATTE demonstrated robust predictive performance (average time-AUC: CDR 0.816, MMSE 0.694, MoCA 0.710; ABC: CDR 0.067, MMSE 0.293, MoCA 0.078; Brier score: CDR 0.252, MMSE 0.437, MoCA 0.295). APOE -ε4 carriers had shorter predicted time-to-worsening compared to non-carriers across all assessments in the imputation cohorts (HRs 1.241-1.376, all p <0.025), and k-means derived patient clusters showed differential time-to-worsening in the overall and imputation cohorts (HRs 0.777-0.908, all p <.001).

INTERPRETATION: LATTE enables scalable prediction of sustained cognitive worsening timing, differentiating clinically meaningful patient subgroups. This approach could improve AD clinical monitoring and decision-making in routine care and support targeted clinical trial enrichment.

EVIDENCE BEFORE THIS STUDY: The growing burden of Alzheimer's disease (AD) creates an urgent unmet need for pragmatic tools to monitor cognitive decline at the point of care and identify target patient populations for clinical trial recruitment. However, cognitive assessments are sparsely documented in electronic health records (EHRs), and fluctuating scores can obscure true worsening, whereas specialized fluid and neuroimaging biomarkers are rarely available outside research settings, limiting scalable real-world utility.

ADDED VALUE OF THIS STUDY: We applied a deep neural network algorithm optimized for identifying clinical event timing from sparsely labeled longitudinal EHR data (LATTE) to predict time-to-first sustained cognitive worsening across three complementary cognitive assessments in AD patients from a large healthcare system: the Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA). We defined sustained cognitive worsening as clinically meaningful decline (without improvement) persisting over ≥2 consecutive visits within 3 years. We trained LATTE on gold-standard cohorts with sparse outcome labels derived from longitudinal cognitive assessments, then leveraged a semi-supervised framework to scale predictions to larger imputation cohorts lacking gold-standard cognition outcome labels. The algorithm robustly predicted the timing of first sustained cognitive worsening, with CDR outperforming MMSE and MoCA. For orthogonal validation, predicted time-to-worsening differentiated clinically meaningful subgroups defined by APOE-ε4 carrier status and knowledge graph-guided patient clustering.

Scalable prediction of cognitive worsening from sparsely labeled EHR data could identify patients at higher risk of sustained cognitive worsening. In routine clinical practice, this could inform timely disease-modifying therapy initiation and care planning. Targeted enrichment of clinical trial populations with higher-risk patients could increase statistical power and reduce sample size requirements.},
}

@article {pmid42282181,
year = {2026},
author = {Rivera-Mindt, M and Savin, MJ and Guzman, V and Arentoft, A and Barragan, EV and Cubbellotti, S and Heuer, HW and Kubo Germano, K and Rosen, H and Jun Cho, S and Higuera, M and Sotelo, M and Ramirez, C and Culhane, JE and Margolis, A and Slaughter, A and Calcetas, A and Talavera, S and Vincaludo, K and DiBenedetto, J and Ayo, O and Cham, H and Rabinovici, GD and Boxer, AL and Byrd, DA},
title = {The BEYONDD Pilot Study: A Decentralized Community-Engaged Research Framework for Multimodal Characterization of Neurodegenerative Risk in a Multi-Ethnic, Midlife Cohort with Subjective Cognitive or Behavioral Complaints.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.01.26354636},
pmid = {42282181},
abstract = {INTRODUCTION: Alzheimer's disease and related dementias (AD/ADRD) pathology begin decades before diagnosis, yet scalable risk detection infrastructures for midlife adults remain limited. The Biomarker Evaluation of Young Onset Dementia from Diverse Populations (BEYONDD; R56AG075744) pilot study was designed to address this gap through a decentralized, community-engaged research (CER) model for neurodegenerative risk detection in midlife adults with subjective cognitive or behavioral complaints (sCBC).

METHODS: This cross-sectional pilot assessed the feasibility of CER-based digital recruitment and participant completion of remotely-acquired screening, cognitive, clinical, and phlebotomy assessments with support of Community Research Navigators (CRNs). Feasibility was evaluated using digital recruitment metrics, yield, retention, and geographic reach.

RESULTS: Our approach generated 1.8+ million advertisement impressions, 161,100 clicks, and 4,089 web-registrants. 2,117 individuals completed the online screener, exceeding the prespecified screening goal by 141%. We enrolled a multi-ethnic, midlife cohort of 579 participants (M age =51.6[6.5]; 75% female; 44% Latinx, 31% non-Latinx Black-American, and 26% all other race/ethnicities), exceeding the enrollment goal by 290%, and 476 participants completed the remote protocol (82% retention). Participants were recruited from 49 U.S. states, Puerto Rico, Australia, and Canada. CRN engagement was concentrated during study stage transitions.

DISCUSSION: BEYONDD's decentralized, CER-based screening infrastructure demonstrated wide geographic reach, strong early-stage engagement, and efficient recruitment among diverse midlife adults. These findings support the feasibility of scalable CER-based digital recruitment for decentralized early detection initiatives and AD/ADRD trials.},
}

@article {pmid42282182,
year = {2026},
author = {Fernandez-Lozano, S and Villeneuve, S and Collins, DL and , },
title = {Cardiovascular risk and hippocampal-cognitive coupling in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.01.26354601},
pmid = {42282182},
abstract = {INTRODUCTION: The Framingham Risk Score (FRS) indexes cardiovascular risk (CVR), but age-weighting may confound associations with brain and cognitive outcomes.

METHODS: In 923 amyloid-positive ADNI participants, we compared FRS against a Multiple Indicators Multiple Causes (MIMIC)-derived age-adjusted measure (CVR mimic) using sex-stratified linear mixed-effects (LME) and latent growth curve mediation (LGCM) models of hippocampal-to-ventricle ratio (HVR)- cognitive coupling.

RESULTS: FRS predicted hippocampal atrophy in all six LGCM models; CVR mimic in none of the six. HVR-cognitive coupling held in four of six FRS and four of six CVR mimic models. Indirect effects reached significance in four of six FRS and none of the six CVR mimic models. LME 3-way interactions (years × risk × HVR) survived FDR correction in all six FRS versus none of the six CVR mimic models.

DISCUSSION: FRS "effects" on hippocampal-cognitive decline largely reflect age-related variance. Age-adjusted measures complement FRS by isolating cardiovascular effects from aging.

RESEARCH IN CONTEXT: Systematic Review: The Framingham Risk Score (FRS) predicts brain atrophy and cognitive decline across cohorts [1-4]. Yet age dominates the FRS [5,6] and accounts for most of its predictive value in older adults [7,8], suggesting these associations may reflect age confounding. No prior study has compared FRS against an age-adjusted latent measure.Interpretation: FRS indirect effects on cognitive decline via hippocampal atrophy primarily reflect age-weighting; age is itself a legitimate vascular proxy [9]. Partialling out age (CVR mimic) nullified the cardiovascular-risk-to-hippocampal pathway, while HVR-cognitive coupling persisted, indicating coupling reflects neurodegeneration. Prior FRS-brain reports likely conflate age-driven and cardiovascular effects. Future Directions: Replication in independent aging cohorts with longitudinal cardiovascular measurement is needed. The MIMIC age-adjustment framework can be applied to any composite risk score where age confounding is a concern. Intervention trials should test whether cardiovascular management preserves hippocampal-cognitive coupling using age-adjusted endpoints rather than FRS.

HIGHLIGHTS: Age-adjusted cardiovascular risk does not accelerate hippocampal atrophyHippocampal-cognitive coupling persists regardless of how risk is measuredFRS-brain associations in elderly samples primarily reflect age-weightingA reverse pattern in amyloid-negative controls supports a cognitive reserve effectMIMIC-based age-adjustment generalizes to any age-confounded composite score.},
}

@article {pmid42282183,
year = {2026},
author = {Morillo, CA and Zheng, L and Ghanbarian, E and Khorsand, B and Glover, CM and Grill, JD and Sajjadi, SA and , and Ezzati, A},
title = {APOE and amyloid-tau pathology in cognitively unimpaired older adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.02.26354753},
pmid = {42282183},
abstract = {INTRODUCTION: APOE genotype shows well-established dose-dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized.

METHODS: We performed a cross-sectional analysis of harmonized multi-cohort ADSP-PHC data from 4,380 CU participants across 4 cohorts with APOE genotype, amyloid PET, and cognitive data from four domains of memory, language, executive, and visuospatial function, including a subset of 758 with tau PET imaging.

RESULTS: APOE ε4 showed a strong dose-dependent association with amyloid burden and amyloid positivity, with the highest levels observed among ε4 homozygotes. Associations between APOE and global tau burden were more modest and appeared to be driven mainly by ε4 homozygotes, while regional analyses showed localized APOE ε4-related associations in medial temporal regions. Independently, higher tau burden was associated with lower memory and language performance.

CONCLUSIONS: In CU older adults, APOE ε4 was most strongly associated with amyloid burden, with more modest associations observed for medial temporal tau burden.

HIGHLIGHTS: APOE ε4 showed dose-dependent associations with amyloid burden and age-related amyloid differencesAPOE-related global tau associations were modest, mainly in ε44 group, with stronger medial temporal effects among ε4 carriersHigher tau burden was associated with lower memory and language performance, regardless APOE status.

RESEARCH IN CONTEXT: Systematic review: The authors reviewed the literature using PubMed and Google Scholar to examine relationships among APOE genotype, amyloid pathology, tau pathology, and cognition in cognitively unimpaired individuals. Previous studies from A4, ADNI, A4/LEARN, and large multicohort tau PET datasets have consistently shown strong APOE-related effects on amyloid burden and more modest regional effects on tau. The present study extends this literature using a large harmonized ADSP-PHC dataset with amyloid PET, tau PET, and harmonized cognitive measures. Interpretation: The findings suggest that amyloid abnormalities remain the main pathological feature linked to APOE genotype in cognitively unimpaired individuals. APOE-related effects on tau were smaller and were concentrated mainly in medial temporal regions. APOE genotype was not consistently related to cognition, while higher tau burden was associated with lower memory and language performance. Future directions: These findings support the use of APOE genotype as a stratification factor in studies of cognitively unimpaired individuals. Longitudinal studies will be important to clarify how APOE-related differences in amyloid and regional tau burden evolve over time and whether they are linked to later cognitive decline and progression to Alzheimer's disease.},
}

@article {pmid42282194,
year = {2026},
author = {Lafille, J and Provenzano, F and , },
title = {A Three-Item Functional Screen for Multimodal Prognostic Triage in Mild Cognitive Impairment: Benchmarking Against Entorhinal Tau PET and Plasma p-tau217.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.01.26354584},
pmid = {42282194},
abstract = {IMPORTANCE: Broadening access to biomarker-informed risk stratification in mild cognitive impairment (MCI) has become even more critical to early assessment in Alzheimer disease given recent developments in regulatory approvals of disease-modifying therapies and advancements of blood-based biomarkers. This requires accessible approaches that can be deployed at scale to better differentiate the disease biology from the clinical progression risk prediction. While entorhinal tau positron emission tomography (PET) can refine near-term prognostic assessment, the cost and logistic burden of imaging limit broad clinical use.

OBJECTIVE: Evaluate whether a brief informant-reported screen derived from the Functional Activities Questionnaire (FAQ) could better stratify scalable biologically anchored prognostic information for 3-year progression from MCI to Alzheimer disease dementia. The primary study was designed around FAQ-derived screens performance relative to entorhinal tau PET standardized uptake value ratio (SUVR), plasma phosphorylated tau 217 (p-tau217) and Mini-Mental State Examination (MMSE) score. Secondary analyses evaluated the stable FAQ-derived screen selected for clinical risk separation, tau and amyloid PET biological context, additional plasma biomarkers, resource-use scenarios and sensitivity analyses around subgroups, calibration, decision-curve, survival, timing, early-progressor exclusions and endpoint-ascertainment IPW.

This retrospective secondary progression risk prediction study analyzed 350 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with a baseline clinical diagnosis of MCI at the tau PET anchor visit. All studies were conducted in cohorts with 3-year progression status known. The first primary benchmarking included 157 participants (including 32 progressors) for FAQ with entorhinal tau PET SUVR comparisons and 153 participants (including 31 progressors) for FAQ, entorhinal tau PET SUVR and MMSE comparisons. The second primary benchmarking was derived from a smaller UPENN plasma p-tau217 subset of 66 participants (including 13 progressors).

EXPOSURES: The FAQ-derived candidate screens were evaluated by leakage-controlled repeated nested cross-validation. The stable 3-item FAQ-derived screen selected was defined as any informant-reported difficulty in at least one of the three activities comprising finances/checkbook, shopping and games/hobbies ("Locked FAQ Trio"). The Locked FAQ Trio was compared against both biological and cognitive comparators: entorhinal tau PET SUVR, plasma p-tau217 and MMSE score. Amyloid PET status and Centiloid burden as well as plasma biomarkers paired per same-file plasma such as Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and a directionally adjusted 4- marker plasma composite were used for biology or exploratory context and not for defining the clinical endpoint.

MAIN OUTCOMES AND MEASURES: The primary binary endpoint was progression from baseline MCI at the tau PET anchor visit to Alzheimer disease dementia within 3 years. Model performance used the cross-validated area under the receiver operating characteristic curve (AUC), the difference in AUC (ΔAUC) was bootstrap 95% confidence intervals (CI) at the participant level with P values adjusted using the Benjamini-Hochberg (BH) procedure. Other measures included Brier scores, calibration summaries, survival discrimination and operating characteristics such as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and screen-positivity prevalence, while decision-curve analyses and resource-use scenarios remained exploratory.

RESULTS: A leakage-controlled nested cross-validation selection repeatedly identified a 3-item screen defined as any difficulty in at least one of the three following activities comprising finances/checkbook, shopping and games/hobbies (Locked FAQ Trio). In an independent 3-year progression benchmark analysis of base-covariate models, the Locked FAQ Trio showed higher numerical, directional but not statistically significant, discrimination than entorhinal tau PET among 157 participants including 32 progressors (AUC, 0.787 vs 0.780; ΔAUC, +0.007; 95% CI, -0.099 to 0.113; BH-adjusted P = 0.926) and was statistically significantly higher than MMSE score (AUC, 0.796 vs 0.637; ΔAUC, +0.159; 95% CI, 0.045 to 0.276; BH-adjusted P = 0.029). The Locked FAQ Trio was positive in 37.6% of participants and captured 27 of 32 progressors, showing sensitivity of 84.4%, specificity of 74.4%, PPV of 45.8%, and NPV of 94.9%. Progression within 3 years occurred in 45.8% of screen-positive participants versus 5.1% of screen-negative participants and the corresponding adjusted hazard ratio over full follow-up was 7.46. The screen was also associated with higher entorhinal tau burden and remained consistent across survival, timing-sensitive, amyloid and missingness analyses. A different 3-item FAQ-derived companion screen ("Companion FAQ Trio") was evaluated for sensitivity, it was defined as any impairment in at least one of the three activities comprising forms/papers, shopping and remembering appointments/medications/holidays. The Companion FAQ Trio was positive in 54.1% participants and captured 96.9% of progressors, with 36.5% of screen-positive progressing to dementia versus 1.4% of screen-negative.In a second primary benchmark analysis of a smaller matched plasma subset of 66 participants including 13 progressors, plasma p-tau217 showed the highest discrimination (AUC, 0.890) across all single predictors in a base-covariates model, compared with the Locked FAQ Trio (AUC, 0.749) and entorhinal tau PET SUVR (AUC, 0.798). A stratification study of the Locked FAQ Trio combined with p-tau217 showed separation of observed risk, differentiating lower and higher risk of progression per strata. Notably, none (0 of 31) of the participants in the lower risk cohort progressed and 64.3% (9 of 14) of participants in the higher risk cohort progressed. Nevertheless, 37.5% (3 of 8) of participants in the Locked FAQ Trio-negative/p-tau 217-high cohort progressed. This emphasizes that patients should not be excluded from further biomarker testing when clinical concern remains.

CONCLUSION: A brief 3-item stable FAQ-derived screen was identified as a compelling front-end additional layer to prognostic triage in MCI patients. This Locked FAQ Trio screen demonstrated a higher numerical discrimination than entorhinal tau PET SUVR in 3-year base-covariates prediction risk models. Plasma p-tau217 remained the strongest scalable predictor of progression to dementia in a smaller plasma subset. These findings reinforce that adding a brief functional screen to the staged prognosis assessment triage pathway can help prioritize and contextualize biomarker escalation, offering a scalable, deployable, and low burden solution to expand screening to a broader patient population.

KEY POINTS: Question: Can a low-burden brief informant-reported functional questionnaire support staged prognostic triage, before biomarker escalation, for near-term progression risk from mild cognitive impairment to Alzheimer disease dementia?Findings: In this progression risk prediction study of 350 individuals with mild cognitive impairment, a 3-item Functional Activities Questionnaire (FAQ) was identified as a stable early signal for progression risk using a leakage-controlled repeated nested cross-validation. The screen was defined as any impairment in at least one of the three activities comprising finances/checkbook, shopping and games/hobbies ("Locked FAQ Trio"). In an independent prognosis prediction study, the Locked FAQ Trio was numerically, but not statistically significantly, higher than entorhinal tau positron emission tomography (PET) standardized uptake value ratio (SUVR) and statistically significantly higher than Mini-Mental State Examination (MMSE) score. In a smaller plasma subset of 66 participants, plasma phosphorylated tau 217 (p-tau217) showed the highest discrimination and the Locked FAQ Trio combined with p-tau217 differentiated lower and higher risk of progression.Meaning: An informant-reported brief 3-item functional questionnaire can help to inform and prioritize biomarker testing. A selected Locked FAQ Trio showed a higher numerical discrimination than specialized entorhinal tau PET biomarker and contextualized plasma p-tau217 biomarker. The suggested staged framework starts with Locked FAQ Trio screen triage, then plasma p-tau217 refinement before selective confirmation disease pathology with cerebrospinal fluid biomarkers or amyloid PET and/or tau PET for staging or prognostic prediction.},
}

@article {pmid42282197,
year = {2026},
author = {Shao, Y and Yin, Y and Cheng, Y and McGeary, JE and Taveira, TH and Tsuang, DW and Logue, MW and Ayandeh, S and Ahmed, A and Zamrini, E and Zeng-Treitler, Q},
title = {Medication-Wide Association Study of Alzheimer's Disease and Related Dementias: Identifying Drug Candidates from Electronic Health Records through Explainable AI.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.02.26354752},
pmid = {42282197},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a leading cause of death and disability, and treatment options for Alzheimer's disease and related dementias (ADRD) remain limited. We applied a data-driven, mechanism-agnostic Medication-Wide Association Study Plus (MWAS+) framework to identify candidate medications associated with ADRD using longitudinal electronic health record data and explainable artificial intelligence (AI).

METHODS: We used Veterans Health Administration electronic health record data from January 1999 to May 2022. The initial study population comprised 8,424,715 Veterans aged 65 years or older. Cases were defined by ADRD-related diagnosis codes or ADRD-related medication prescriptions, and controls were free of ADRD diagnosis and ADRD-related medication use. After exclusions and matching on sex, race, age at first encounter, and duration of follow-up, the primary analytic cohort included 505,817 matched case-control pairs (1:1; 1,011,634 Veterans). Longitudinal features were extracted from historical data up to 1 year before the index date and aggregated into 1-year intervals. We developed an upgraded Hybrid Value-Aware Transformer (HVAT 2.0) to jointly learn from longitudinal and nonlongitudinal clinical data while incorporating numerical values associated with clinical concepts, including cumulative medication dose. To enhance interpretability, we applied a medication-specific impact score method to estimate model-derived associations between medication exposure and ADRD risk.

FINDINGS: The model demonstrated stable performance across data partitions, with area under the receiver operating characteristic curve values of 0.791 in the training set, 0.772 in the validation set, and 0.775 in the testing set. Metolazone and varenicline were identified as the top 2 candidate medications with negative impact scores, suggesting potentially protective associations with new-onset ADRD. The impact score was -0.196 per unit of cumulative dose for metolazone (1800 mg) and -0.134 per unit for varenicline (280 mg). Although individual-level impact scores varied, most exposed patients had negative scores, including 12,020 of 12,480 metolazone users (96%) and 8,341 of 8,786 varenicline users (95%).

IMPLICATIONS: This study demonstrates the feasibility of combining a medication-wide association framework, longitudinal dose-aware modeling, and explainable AI to identify candidate medications for ADRD from real-world electronic health record data. The findings should be interpreted as signals for hypothesis generation rather than evidence of causality. This framework may support prioritization of repurposing candidates for expert review, follow-up cohort validation, and future clinical investigation.},
}

@article {pmid42282202,
year = {2026},
author = {Guo, Q and Ping, L and Rathore, S and Duong, DM and Shantaraman, A and Fox, EJ and Johnson, ECB and Lah, JJ and Levey, AI and Seyfried, NT},
title = {Plasma Proteomic Networks Reveal Shared Biology with Brain Linked to Alzheimer's Disease Pathology.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.26.26353866},
pmid = {42282202},
abstract = {Alzheimer's disease (AD) drives widespread molecular changes beyond the brain that are increasingly detectable in plasma. To map plasma proteomic signatures of AD in a broadly unbiased manner with high depth and reproducibility, we profiled plasma from 214 individuals spanning cognitively normal controls, mild cognitive impairment, and AD using microbead-based enrichment and data-independent acquisition mass spectrometry (DIA-MS). We reliably quantified 5,823 proteins across samples, and network analysis identified 29 plasma modules enriched for functions related to lipid metabolism, extracellular matrix remodeling, immune signaling, mitochondrial function, and proteostasis. Several modules were associated with cognition, APOE4, sex, race, and cerebrospinal fluid (CSF) amyloid and tau biomarkers. Among 129 individuals with paired CSF and plasma biomarker measurements, over 1,500 proteins differed between CSF biomarker-positive and -negative groups, including amyloid-linked matrisome proteins such as SMOC1, FRZB, SPON1 and CTHRC1. A 10-protein plasma panel classified CSF biomarker positivity with performance similar to plasma pTau217 (AUC = 0.91), and combining both improved accuracy (AUC = 0.99). Integration with a human brain proteomic network revealed that two-thirds of plasma modules were preserved in brain, with many AD-altered modules changing concordantly across compartments. This study establishes a scalable DIA-MS plasma proteomics platform that captures systemic and brain-linked AD biology and identifies complementary biomarkers beyond phosphorylated tau.},
}

@article {pmid42282205,
year = {2026},
author = {Mansel, CO and Mishra, S and Craver, A and Salathe, SF and Thyfault, JP and Bauer, JA and Mazzotti, DR and Veatch, OJ},
title = {A Favorable Modifiable Risk Factor Profile Mitigates Polygenic Risk for Alzheimer's Disease and Related Dementia.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.01.26354634},
pmid = {42282205},
abstract = {BACKGROUND: A recent Lancet Commission estimated that up to 45% of Alzheimer's Disease and Related Dementias (ADRD) cases could be prevented by addressing modifiable lifestyle risk factors. Meanwhile, genome-wide association studies (GWAS) have shown that common genetic variants also account for substantial ADRD risk. Whether a favorable lifestyle can offset risk in genetically predisposed individuals remains unclear.

METHODS: We conducted a retrospective cohort study of 105,886 participants from the All of Us Research Program enrolled between 2018-2023. Participants were over age 49, assigned male or female at birth, of European ancestry, and without ADRD at baseline. ADRD diagnoses were identified via electronic health records (EHR). Fourteen potentially modifiable risk factors for ADRD were assessed using surveys, EHR records, and wearable data. Genetic risk was quantified as a polygenic risk score (PRS) based on 81 independent GWAS loci and APOE ε4 genotype.

RESULTS: Overall, 967 incident ADRD events occurred over a median follow-up of 3.7 years. Ten out of 13 modifiable risk factors were significantly associated with ADRD. When grouped into risk factor profiles, intermediate and unfavorable modifiable risk factor scores were associated with substantially higher ADRD risk (HR 3.07, 95% CI 2.47-3.83; HR 8.01, 95% CI 6.39- 10.05, respectively) compared to a favorable lifestyle; APOE ε4 dosage and polygenic risk score were also independently associated with ADRD risk. Among individuals in the highest polygenic risk group, a favorable lifestyle reduced ADRD risk from HR 18.63 (95% CI 10.25-33.86) to 1.90 (95% CI 0.94-3.81), whereas APOE ε4 homozygotes remained at elevated risk even with a favorable lifestyle (HR 6.52, 95% CI 2.97-14.33).

CONCLUSIONS: Our data suggest ADRD risk is driven more by modifiable risk factors and APOE genotype than polygenic risk score. Future genomic-informed risk assessments for ADRD should calibrate their findings to accurately identify high-risk individuals.},
}

@article {pmid42282207,
year = {2026},
author = {Gonzales, M and Kang, X and Adamson, MM and Chao, SZ and Yoon, BC and , },
title = {Multimodal neuroimaging approach for cognitive impairment in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.04.26354924},
pmid = {42282207},
abstract = {PURPOSE: Alzheimer's disease (AD) is associated with cognitive impairment, brain atrophy, and elevated amyloid-beta (Aß) and tau. The study aimed to characterize regional atrophy associated with elevated Aß and tau, as measured by [[1] F]florbetapir (FBP) and [[1] F]flortaucipir (FTP) positron emission tomography (PET), respectively, and determine whether combining PET and atrophy data improves the prediction of cognitive impairment.

METHODS: Alzheimer's Disease Neuroimaging Initiative data (n = 381) were retrospectively analyzed. PET results were correlated with cortical thickness, gray matter (GM) volumes, Mini-Mental State Examination, and Montreal Cognitive Assessment. Linear/logistic regression and area under the curve (AUC) were used to evaluate for significant correlations and compare performances in distinguishing cognitive impairment, respectively.

RESULTS: Incremental loss of cortical thickness and GM volume was observed from FBP-/FTP-(n = 205) to single PET-positive (FBP+/FTP-, n = 133; FBP-/FTP+, n = 5) and FBP+/FTP+ (n = 38) groups, particularly in the temporal and parietal lobes. FBP+/FTP+ showed the most severe cortical thickness loss in the entorhinal cortex, temporal lobe GM atrophy, and cognitive impairment. Adding brain atrophy as the third variable resulted in higher odds ratios and improved AUCs for cognitive impairment, with FBP+/FTP+/temporal GM or entorhinal cortical atrophy+ demonstrating the strongest associations with cognitive impairment.

CONCLUSION: A multimodal approach combining PET and MRI may help improve the assessment of cognitive impairment in AD.},
}

@article {pmid42282265,
year = {2026},
author = {Kwa, E and Ogilvie, CE and Kormos, NC and Green, AJE and Smith, TK and Gunn-Moore, FJ},
title = {The inhibitors of 17β-HSD10: are they any good?.},
journal = {RSC chemical biology},
volume = {},
number = {},
pages = {},
pmid = {42282265},
issn = {2633-0679},
abstract = {The advent of the first disease-modifying therapies for Alzheimer's disease (AD) has renewed optimism for effective prevention and treatment strategies. Growing mechanistic insights indicate that AD pathogenesis is multifactorial and non-linear, better conceptualized as a circular vortex in which interconnected pathological processes reinforce one another. This complexity highlights the necessity for multiple druggable targets and combination-based therapeutic approaches. A hallmark of AD is reduced cerebral glucose utilization, revealed by positron emission tomography studies, reflecting profound metabolic disruption and mitochondrial dysfunction. Among mitochondrial candidates, 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), encoded by HSD17B10, has emerged as a protein of interest. Despite debate surrounding its substrate specificity due to conflicting in vitro data, its elevated expression in neurons and astrocytes within AD brains underscores its potential relevance. This review outlines chemical entities targeting both catalytic and non-catalytic functions of 17β-HSD10 and examines whether its inhibition offers biological efficacy and clarifies its metabolic roles in the living brain.},
}

@article {pmid42282268,
year = {2026},
author = {Frame, LA and Warren, A and Al Qalam, A and Corr, PG and Farah, M and Karam, M and Rangoussis, K and Fahim Devin, M and Celikkol, Z and Gordon, L and Villarreal, D and Catto, E and Udam, Y and Thompson, K and Lubinski, O and Samman, A and Badawi, A and Hack, H and Hunter, M and Hines, I and Servetas, S and Jackson, SA and Hasan, NA and Kogan, M},
title = {Brain health and the gut microbiome (bMicrobiome Study): a proof-of-concept, feasibility study integrating shotgun metagenomics, metrology, and multidimensional phenotyping across the cognitive aging spectrum.},
journal = {Gut microbes reports},
volume = {3},
number = {1},
pages = {2679810},
pmid = {42282268},
issn = {2993-3935},
abstract = {BACKGROUND: Associations between the gut microbiome and cognitive decline remain inconsistent, reflecting methodological variability, small cohorts, and limited integration of behavioral and lifestyle factors. The microbiota-gut-brain axis may influence cognition through metabolic, immune, and neuroendocrine pathways affecting mood, decision-making, and health behaviors.

METHODS: This prospective, proof-of-concept study integrated multidimensional phenotyping with metagenomic sequencing (shotgun) in adults (50-90 y) around Washington, DC. Participants were classified as healthy controls (HC) or mild cognitive impairment (MCI) by clinical history; early Alzheimer's disease (eAD) participants were unable to complete study requirements. Longitudinal assessment used Boston Cognitive Assessment (BoCA), patient-reported outcomes (PROMIS-29), dietary intake and quality (DietID™), readiness-for-change (adapted URICA), at-home stool sample collection.

RESULTS: Seventeen participants completed sufficient assessments (HC n = 11; MCI n = 6). Substantial overlap in gut microbiome composition was observed between HC and MCI. Poorly characterized or uncommon taxa drove trends; unassigned taxa were common. Assessment revealed high diet quality and variability in dietary patterns and key components (vegetables, whole grains, fat, fish). Participants demonstrated high readiness to engage in nutritional behavior change, with individuals with MCI reporting greater concern about maintaining changes and a stronger desire for external support.

CONCLUSIONS: Integrating multidimensional phenotyping with metagenomics is feasible in cognitive decline. Findings highlight biological and behavioral heterogeneity, limitations of species-level inference, and diet and behavioral readiness as modifiable contextual factors.},
}

@article {pmid42282537,
year = {2026},
author = {Pang, K and Guo, S and Yang, R and Kumar, A and Morse, WD and Xu, L and Liu, Q and Jiang, D and Zhong, P},
title = {Hypothalamic MCH neurons links tau pathology to sleep disruption.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.31.729026},
pmid = {42282537},
issn = {2692-8205},
abstract = {Sleep disruption is an early and pervasive feature of Alzheimer's disease (AD), yet the circuit mechanisms linking tau pathology to sleep-wake dysfunction remain unresolved. Here, we identify melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) as a critical node disrupted in tauopathy. Longitudinal EEG/EMG recordings in PS19 mice reveal progressive impairments in sleep architecture and homeostasis. Histological analyses revealed significant degeneration of both MCH neurons and the neighboring hypocretin (Hcrt) neuronal population in the LH at late stages of tauopathy. In vivo fiber photometry recordings demonstrated a selective functional impairment of MCH neurons, characterized by reduced activity during REM sleep, whereas Hcrt neuronal activity remained largely preserved. In addition, cell-autonomous expression of mutant tau in MCH neurons recapitulates sleep disruption, establishing a causal role. Despite tauopathy-induced neuronal loss and reduced endogenous activity, optogenetic and chemogenetic activation show that MCH neurons retain functional capacity, and their activation restores sleep in aged PS19 mice. Together, these findings define a circuit mechanism linking tau pathology to sleep and identify MCH neurons as a tractable therapeutic target.},
}

@article {pmid42282546,
year = {2026},
author = {Owusu Kwarteng, D and Jackson, RJ and Nakajima, T and Altig, K and Melloni, A and Oakley, D and Serrano-Pozo, A and Maesako, M and Hyman, BT},
title = {Lipidated ApoE is found in nanoscale proximity to Aβ aggregates in human Alzheimer brains.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.30.729004},
pmid = {42282546},
issn = {2692-8205},
abstract = {Apolipoprotein E (APOE) associates with amyloid plaques (Aβ) in Alzheimer disease (AD). The ε4 allele of apolipoprotein E (APOE ε4) is the strongest genetic risk factor for sporadic AD and exacerbates Aβ plaque burden relative to APOE ε3 and APOE ε2. The majority of ApoE associates with multiple lipid classes to form lipoproteins both in the brain and the periphery. However, the lipidation status of Aβ plaque-associated ApoE is not yet fully defined. Here, we use fluorescence lifetime imaging microscopy coupled with Förster resonance energy transfer (FLIM-FRET) to determine the lipidation status of ApoE in plaques, as well as the nanoscale spatial proximity of ApoE and Aβ to anionic lipids and cholesterol within human AD brain tissue. We demonstrate that lipids are in close nanoscale proximity to ApoE and Aβ within Aβ plaques. Our results reveal that lipidated ApoE complexes enriched in anionic lipids and cholesterol are core constituents of AD plaques in-situ . We propose a pathological mechanism in which the surface presentation of anionic lipids on ApoE lipoproteins facilitates initial interaction with and subsequent aggregation of Aβ.},
}

@article {pmid42282601,
year = {2026},
author = {Boyton, I and Rennie, C and van der Hoven, J and Valle, MD and Diaz, D and Ruan, J and Luque, D and Saunders, B and Collins-Praino, LE and Ittner, L and Care, A},
title = {Engineering a Novel Bacterial Encapsulin for Programmable Surface Functionalization: From Single-Target to Mosaic Nanovaccines.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.01.729406},
pmid = {42282601},
issn = {2692-8205},
abstract = {Encapsulins are prokaryotic self-assembling protein nanocages with promise as nanovaccine scaffolds. Their utility as modular platforms require tolerance to surface engineering, high-yield soluble production, formulation stability, and controlled antigen (co-)display. Herein, a previously uncharacterized encapsulin from Alkaliphilus metalliredigens is engineered into a SpyCatcher-decorated nanoscaffold (Am-S) that enables controlled surface display of SpyTagged antigens. Cryo-EM confirms that the native encapsulin forms a T = 1 icosahedral nanocage, and that C-terminal SpyCatcher fusion yields Am-S without compromising nanocage assembly, symmetry, or structural integrity. Notably, Am-S exhibits high-yield soluble production in Escherichia coli , remains monodisperse after freeze-thaw and extended storage, and supports efficient SpyTagged peptide conjugation for single- and multi-antigen display. As a proof-of-concept, Am-S is functionalized with Alzheimer's disease-associated amyloid-β and/or hyperphosphorylated tau epitopes to generate single-target nanocages displaying either antigen and dual-target mosaic nanocages co-displaying both. In mice, Am-S antigen display enhances antigen-specific IgG responses relative to free antigens and induces predominantly IgG1-biased humoral immunity. Mosaic nanocages elicit antibodies against both targets, with immune sera selectively recognizing amyloid-β- and phosphorylated tau-associated pathology in ex vivo brain sections from Alzheimer's disease mouse models. These findings position Am-S as a manufacturable scaffold for developing multi-targeting nanovaccines against complex diseases.},
}

@article {pmid42282610,
year = {2026},
author = {Tao, Y and Francis, AE and Liu, W and Watkins, C and Bennett, DA and Selkoe, DJ and Flynn, RA and Stern, AM},
title = {Aβ Aggregates Bind the U1 Spliceosomal Ribonucleoprotein in Alzheimer Disease Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.02.729610},
pmid = {42282610},
issn = {2692-8205},
abstract = {Missplicing due to U1 small nuclear ribonucleoprotein (U1 snRNP) insolubilization and dysfunction has been identified in Alzheimer disease (AD) brain. Cytoplasmic aggregation and mislocalization of the U1 snRNP partly co-localizes with tau neurofibrillary tangles, and some evidence for tau-U1 binding has been identified. However, tau-U1 co-localization by immunohistochemistry is only partial, and insoluble U1 small nuclear RNA (snRNA) binding proteins correlate better with Aβ than with tau in unbiased proteomics. While investigating the sedimentation characteristics of Aβ aggregates capable of diffusing out of AD brain tissue, we unexpectedly found that some were bound to small RNA. Aβ immunoprecipitation and deep sequencing revealed the U1 snRNA, with specific binding confirmed through reverse immunoprecipitation and oligonucleotide hybridization. Double immunoelectron microscopy revealed decoration of Aβ fibrils, more than tau fibrils, with the U1-70k protein, a component of the U1 snRNP. Immunofluorescence of unfixed cryostat sections but not formalin fixed paraffin embedded sections of AD brain revealed labeling of a subset of amyloid plaques with anti-U1-70k antibodies, confirmed by RNA in situ hybridization of the U1 snRNA. We conclude that a subset of AD brain Aβ aggregates are bound to the U1 snRNP at the edges of some amyloid plaques, explaining prior proteomics findings. These data provide a potential link between Aβ aggregation and spliceosome dysfunction and unite Aβ with other fibril-forming proteins across the neurodegenerative diseases whose aggregation is affected by RNA binding.},
}

@article {pmid42282664,
year = {2026},
author = {Fang, X and Border, JJ and Zhang, H and Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Yang, J and Hwang, SH and Morisseau, C and Hammock, BD and Fan, F and Roman, RJ},
title = {Inhibition of Soluble Epoxide Hydrolase Rescues Cognitive Deficits by Preserving Neurovascular Integrity and Attenuating Glial- and Neuropathology in Diabetic-Related Dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.01.729327},
pmid = {42282664},
issn = {2692-8205},
abstract = {Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous work also demonstrated that chronic inhibition of sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day for 9 weeks) reduced brain sEH expression, improved cortical-based long-term non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect linked to upregulation of Kir2.1 expression in cerebral capillaries. Furthermore, TPPU restored tight junction proteins (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of key pro-inflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in DM-ADRD. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation, and gliosis while protecting synaptic integrity and neuronal survival, representing a promising therapeutic strategy for DM-ADRD.},
}

@article {pmid42282676,
year = {2026},
author = {Li, C and Leitner, D and Liang, Z and Yakovishina, V and Ibrahim, M and Faustin, A and Wisniewski, T and Wadghiri, YZ and Ge, Y and Zhang, J},
title = {Short T1 Fraction as a Marker of Myelin Content: Evidence from Postmortem MRI and Histology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.31.728778},
pmid = {42282676},
issn = {2692-8205},
abstract = {PURPOSE: To investigate the short-T1 fraction as a potential biomarker of white matter myelin integrity, using myelin histology as ground truth.

METHODS: Multi-inversion-time MRI data were acquired from four postmortem brain hemisphere specimens from donors with Alzheimer's disease on a clinical 3T scanner, and from five dissected tissue blocks containing white matter hyperintensities (WMHs) on a preclinical 3T system. Short-T1 fraction maps were generated using inverse Laplace transform to isolate short-T1 components and were compared with T2-based myelin water imaging metrics through joint T1-T2 correlation analysis. Short-T1 fraction maps from the tissue blocks were further compared with myelin-stained histology. In addition, in vivo short-T1 fraction data were acquired from two elderly volunteers with WMHs to demonstrate translational feasibility.

RESULTS: Postmortem MRI revealed reduced short-T1 fractions in WMHs. T1-T2 correlation analysis showed that the short-T1 fraction was closely associated with the short-T2 (myelin water) component. Strong correlations were observed between short-T1 fractions and optical densities from both Luxol Fast Blue- and myelin basic protein-stained histological sections, supporting the link between the short-T1 signal and myelin content. Consistent findings were also observed in vivo, where significant reductions in short-T1 fractions were detected within WMHs.

CONCLUSION: The short-T1 fraction correlated with myelin content in postmortem brain white matter, supporting its potential as a clinically translatable biomarker of myelin integrity.},
}

@article {pmid42282685,
year = {2026},
author = {Emenheiser, AM and Gentry, E and Xue, H and Alvarez, P and O'Neill, KM and Cao, K and Losert, W},
title = {Network-Level Characterization of Spontaneous Calcium Activity in an In-Vitro Alzheimer's Disease Model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.28.728474},
pmid = {42282685},
issn = {2692-8205},
abstract = {The neurodegenerative disorder Alzheimer's disease (AD) is widely known for biomarkers such as amyloid beta plaques and tauopathy, as well as functional differences in memory and cognitive ability. Despite this devastating functional impact, a large body of work only focuses on molecular biomarkers of AD. In this study, we investigate collective neural dynamics in vitro and assess how network-level properties differ between a well-established model of familial AD (FAD) and a newly developed in vitro accelerated model (acAD). The new model system reliably develops the key structural characteristics of AD in three weeks, but its calcium dynamics had not been characterized previously. Spontaneous network dynamics influences information processing as part of the internal network state. Here we measure this spontaneous activity of a network of hundreds of cells in each field of view. We find that the FAD model has a larger fraction of hyperactive cells, while the acAD model displays similar characteristics to healthy cells. Additionally, the FAD model has altered cooperation between cells, losing a proportion of highly correlated cellular activities, both for fast and slow coupling among cells. The acAD model is again consistent with healthy networks. Since the acAD model does not show the same spontaneous network dysfunction seen in FAD, it can enable measurements of changes in learning and memory associated with the plasticity, rather than the structure of the internal network state.},
}

@article {pmid42282713,
year = {2026},
author = {Yassa, C and Zolfaghari, E and Neel, MJ and Scanlon, R and Johnson, BA and Monuki, ES},
title = {Age-associated oncocytic transformation correlates with an increased prevalence of small multiple Biondi body inclusions in human choroid plexus epithelial cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.27.728253},
pmid = {42282713},
issn = {2692-8205},
abstract = {The choroid plexus epithelial cells (CPECs) at the blood-cerebrospinal fluid (CSF) interface possess an exceptionally high mitochondrial content to support CNS homeostasis. Oncocytic CPECs (O-CPECs), characterized by enlarged and granular eosinophilic cytoplasm composed of excessive abnormal mitochondria, likely contribute to an energetic failure of this energy-demanding tissue. The relationship between O-CPECs and other CPEC pathologies in humans, such as Biondi body (BB) amyloid inclusions, remains poorly defined. In the present study, using H&E-stained sections from 68 postmortem cases, we classified O-CPECs by quantitative size criteria and cytological features, and found an increase in the prevalence of O-CPECs with age after adjusting for sex and tissue source. After excluding two influential control cases, there was evidence for a further increase associated with Alzheimer's disease. Using antibodies to ATP synthase beta chain to classify O-CPECs, and thioflavin-S to identify BBs, we revealed an increased prevalence of BBs in O-CPECs compared to neighboring non-oncocytic cells. Small multiple BB inclusions were responsible for the increase in O-CPECs, while the prevalence of larger inclusions was decreased in O-CPECs. Together, our data support a clear age-associated oncocytic transformation of CPECs and implicate mitochondrial dysfunction-amyloid interactions.},
}

@article {pmid42282834,
year = {2026},
author = {Pachicano, M and Hurtado, A and Mehta, S and Breningstall, B and Zhou, Y and Bienkowski, MS},
title = {Differential vulnerability of CA1 pyramidal neuron cell types in the 5xFAD Alzheimer's disease mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.29.728864},
pmid = {42282834},
issn = {2692-8205},
abstract = {Selective neuronal vulnerability is a defining feature of Alzheimer's disease, yet how neurodegeneration unfolds across defined hippocampal CA1 pyramidal neuron populations remains unresolved. Previously, we showed that CA1 pyramidal neurons are organized into molecularly defined laminar cell types that form stable spatial signatures along the longitudinal axis (Pachicano et al., 2025). Here, we investigated how vulnerability manifests across CA1 pyramidal cell types in the 5xFAD mouse model of amyloid pathology. HiPlex single-molecule fluorescence in situ hybridization was used to quantify gene expression at single-cell resolution across hippocampal CA1 subregions across disease progression. Cells were classified into molecularly defined CA1 pyramidal cell types based on marker gene expression, and changes in density, proportion, and molecular state were assessed. Amyloid-associated pathology differentially affected CA1 pyramidal cell types, revealing distinct trajectories of vulnerability and resilience. Specific populations exhibited early and progressive susceptibility, while other populations demonstrated relative preservation across disease timepoints. These effects were consistent across CA1 subregions, indicating that vulnerability follows cell type identity rather than regional anatomy alone. Together, these findings demonstrate that neurodegeneration in Alzheimer's disease is structured by intrinsic cell type identity and provide a cellular framework for understanding selective vulnerability.},
}

@article {pmid42283184,
year = {2026},
author = {Rong, C and Wei, Z and Xie, D and Wang, Q and Ren, H and Wang, X and Zhao, D},
title = {Environmental Pollutant Tetrachloro-1,4-benzoquinone Exerts Neurotoxicity and Potential Protective Effects of Curcumin: A Network and Mendelian Randomization Analysis.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266461615260518205032},
pmid = {42283184},
issn = {1873-4294},
abstract = {INTRODUCTION: The neurotoxicity mechanisms of tetrachloro-1,4-benzoquinone(TCBQ) remain poorly understood. This study integrated computational simulations validation to elucidate TCBQ-induced neurotoxicity.

METHODS: In our investigation of the neurotoxic effects of TCBQ, we employed a diverse range of analytical techniques, including protein-protein interaction (PPI) networks, screening for target genes and protective drugs, as well as performing KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analyses. Additionally, we utilized advanced methodologies such as molecular docking and molecular dynamics simulations to gain deeper insights into the mechanisms underlying TCBQ's neurotoxicity. These comprehensive approaches enabled us to construct a detailed understanding of how TCBQ may contribute to neurotoxic outcomes. To further assess the potential connections between key target proteins and Alzheimer's disease, we utilized Mendelian randomization as a robust analytical strategy. This statistical method allowed us to explore the causal relationships that may exist between the identified proteins and the incidence of Alzheimer's disease, providing a clearer understanding of the biological pathways involved. For our analysis, we extracted summary-level data regarding the circulating levels of 4,907 proteins from a significant protein quantitative trait loci study conducted by the deCODE Genetics Consortium, which comprised a total of 35,559 individuals. Moreover, the outcome data for Alzheimer's disease were obtained from genome-wide association studies organized by the International Genomics of Alzheimer's Project (IGAP). This extensive research analyzed data from 17,008 participants who were diagnosed with Alzheimer's disease, alongside 37,154 control subjects, all of whom shared a European ancestry.

RESULTS: The results of integrated network analysis indicate that TCBQ may promote neurotoxicity through alzheimer 's disease. The main targets involved TNF, NOS2, IL6, and others. TCBQ and protective drug curcumin have a low binding score and compact complex with TNF, NOS2, IL6. 5 TNF subtype TNFSF13B, TNFRSF1B, TNFRSF13C, TNFSF12, NFRSF11B has a causal relationship with Alzheimer's disease.

DISCUSSION: TCBQ can promote neurotoxicity by increasing inflammation and alzheimer 's disease.

CONCLUSION: Our study provides a theoretical basis for the subsequent experimental study of TCBQ in neurotoxicity. TNF plays an important role in alzheimer 's disease.},
}

@article {pmid42283223,
year = {2026},
author = {Ruthirakuhan, M and Taha, AY and Swardfager, W},
title = {Targeting Brain Cholesterol Homeostasis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.},
journal = {Journal of neurochemistry},
volume = {170},
number = {6},
pages = {e70492},
doi = {10.1111/jnc.70492},
pmid = {42283223},
issn = {1471-4159},
support = {ECA-508989/CAPMC/CIHR/Canada ; CRC-2020-00353/CAPMC/CIHR/Canada ; PJT-159711/CAPMC/CIHR/Canada ; RGPIN-2017-06962//Natural Sciences and Engineering Research Council of Canada/ ; ER21-16-141//Early Researcher Awards/ ; 2018-AARGD-591676/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Cholesterol/metabolism ; *Homeostasis/physiology/drug effects ; *Brain/metabolism/drug effects ; Animals ; Oxidative Stress/physiology/drug effects ; },
abstract = {Cholesterol is a fundamental component of the central nervous system, supporting myelin integrity, synaptic structure, membrane organization, and neuronal signaling. Because the brain is largely isolated from peripheral cholesterol pools, tight regulation of brain cholesterol homeostasis is required to sustain neuronal and glial function across the lifespan. Growing evidence indicates that disruption of this balance is not merely a downstream consequence of neurodegeneration, but an upstream contributor to Alzheimer's disease (AD) pathogenesis. Altered brain cholesterol homeostasis has been linked to amyloidogenic processing, tau pathology, neuroinflammation, synaptic dysfunction, and cerebrovascular injury. This review synthesizes current evidence showing how multiple converging stressors, including peripheral hypercholesterolemia, neurodegeneration, oxidative stress, and inflammatory signaling, perturb brain cholesterol regulation. These drivers disrupt the coordinated processes of cholesterol synthesis, metabolism, and transport, shifting the system from tightly regulated sterol flux toward impaired clearance, abnormal lipid distribution, and membrane instability. Such disturbances remodel membrane lipid composition, alter lipid raft organization, and impair glial-neuronal lipid coupling, thereby accelerating amyloid-β production, tau-related vulnerability, innate immune activation, and neurovascular dysfunction. Finally, we provide an overview of therapeutic strategies aimed at restoring cholesterol balance, and highlight the potential of integrated, multi-target strategies to complement amyloid- and tau-directed therapies. By clarifying how disruptions in brain cholesterol homeostasis link systemic and central stressors to AD pathology, this review identifies cholesterol regulation as a critical, upstream axis for therapeutic intervention and disease prevention.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Cholesterol/metabolism
*Homeostasis/physiology/drug effects
*Brain/metabolism/drug effects
Animals
Oxidative Stress/physiology/drug effects

@article {pmid42283246,
year = {2026},
author = {Fikry, H and Saleh, LA and Sadek, DR},
title = {Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.},
journal = {Clinical anatomy (New York, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/ca.70147},
pmid = {42283246},
issn = {1098-2353},
abstract = {Neurodegenerative diseases, which afflict millions worldwide and threaten public health, have no cure. Neurodegenerative diseases lack effective therapies, burdening society and the economy. Over the past 20 years, regenerative cell therapy (stem cell therapy) has advanced, opening novel neurodegenerative disease treatments. Thus, the current review aimed to systematically highlight experimental and clinical studies of potentially effective therapeutic strategies for stem cells and report histological, cellular, or ultrastructural outcomes following stem cell interventions in neurodegenerative diseases. PRISMA-compliant computerized literature searches of PubMed, Scopus, and Web of Science identified studies on embryonic, induced pluripotent, mesenchymal, or neural stem cells (NSCs) in neurodegenerative disease models and histological and tissue-level outcomes. Search terms included nervous system diseases, histology, neuron regeneration, stem cells, stem cell treatment, and transplantation. Peer-reviewed articles published between 2000 and 2025 were selected. Experimental animal and clinical studies that reported histological or tissue-level results after stem cell treatments were included. Eighty-six studies met the eligibility criteria, covering models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Across these studies, stem cell therapies were linked to improved neuron survival, better synaptic structure, diminished gliosis, and some restoration of tissue structure. These effects depended on the type of stem cell used, the disease model, and how the treatment was given. Overall, the evidence suggests that stem cell therapies can lead to significant histological and tissue-level improvements in neurodegenerative diseases, supporting their potential for regeneration. Further standardized and translational studies are needed to clarify the underlying mechanisms and improve treatment strategies.},
}

@article {pmid42283567,
year = {2026},
author = {},
title = {Editor's Note: Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.},
journal = {Human molecular genetics},
volume = {35},
number = {12},
pages = {},
doi = {10.1093/hmg/ddag051},
pmid = {42283567},
issn = {1460-2083},
}

@article {pmid41998020,
year = {2026},
author = {Bisht, M and Gomes, MC and Bordon Sosa, FH and Mano, JF and Pandey, S and Ventura, SPM and Coutinho, JAP},
title = {Superbase ionic liquid mediated solubilization of curcumin for improved bioavailability and anticancer efficacy.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41998020},
issn = {2045-2322},
support = {REDE/1517/RMN/2005//Fundação para a Ciência e a Tecnologia/ ; PDF/2019/001024//Government of India/ ; },
abstract = {UNLABELLED: Curcumin is a promising natural drug for the treatment of various diseases ranging from cancer to Alzheimer’s. However, a major hindrance in its use as a drug is its low aqueous solubility, rapid degradation, and poor cellular uptake. In recent years, the use of ionic liquids (ILs) in biomedical applications has gained significant attention due to their unique properties and tunability. In this study, we demonstrate the capacity of the superbase ionic liquid (SBIL) 5-Methyl-1,5,7-triaza-bicyclo[4.3.0]non-6-enium acetate [mTBNH][OAc] to dissolve highly hydrophobic and water-insoluble curcumin. An optimized concentration of 4 mol.kg[-1] of SBIL was used to dissolve 3.5 mg.g[-1] of curcumin, resulting in a formulation (curcumin/SBIL) that could be easily dispersed in an aqueous medium. Compared to the aqueous solubility of curcumin alone, the curcumin/SBIL formulation exhibited almost an 8,000-fold increase in solubility, also demonstrating a reduction of ~ 60% of human triple-negative breast cancer epithelial cells (MDA-MB-231) viability with only 10 µg.mL[-1] of curcumin (the active compound), without any cytotoxic effects on non-tumorogenic mouse fibroblasts (L929). Our study presents a straightforward methodology for improving the solubility and bioavailability of curcumin, which holds promise for its clinical application as an effective anti-cancer drug.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-44082-7.},
}

@article {pmid42015307,
year = {2026},
author = {Terao, CM and Erani, F and Urias, U and Lopez, F and Chang, F and Banks, SJ and Gilbert, PE and Coughlin, DG and Bangen, KJ and Thomas, KR},
title = {Global and domain-specific cognitive intraindividual variability associations with neurodegenerative diagnoses and postmortem pathologies.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42015307},
issn = {1758-9193},
support = {1RF1AG082726-01/NH/NIH HHS/United States ; 1RF1AG082726-01/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Cognitive intraindividual variability (IIV) or within-person variation in neuropsychological test performance relates to in vivo biomarkers of neurodegeneration and progression to mild cognitive impairment (MCI) and dementia. The current study aimed to explore longitudinal associations between global and domain-specific IIV with cognitive status and neuropathological findings at autopsy, and whether these associations differed by sex.

METHODS: The sample included 20,715 older adults from the National Alzheimer’s Coordinating Center (NACC) who completed cognitive testing as part of the Uniform Data Set. Participants were cognitively unimpaired at Visit 1. Baseline neuropsychological data was used to calculate coefficient of variation IIV (intraindividual standard deviation/mean performance) for global, executive, language, and memory domains. Global and domain-specific IIV associations with final visit cognitive status, etiological diagnosis, and progression to MCI/dementia were examined. Associations between each IIV score and neuropathological data were examined for participants with available autopsy data (ns = 1184–1717). Secondary models explored sex by IIV interactions.

RESULTS: Greater IIV (i.e., more variability) in global and specific domains related to worse cognitive status at final visit and final etiological diagnosis. Across all IIV domains, higher IIV related to greater risk of progressing to MCI/dementia. Higher global IIV related to greater postmortem burden of amyloid-β plaques, neurofibrillary tangles (NFT), AD neuropathologic change (ADNC) scores, hippocampal atrophy, substantia nigra neuron loss, hypopigmentation in the locus coeruleus, and cerebral amyloid angiopathy (CAA). Domain-specific effects included: higher executive IIV related to greater NFT, neuritic plaques, ADNC scores, and CAA; and higher memory IIV related to greater neuritic plaques and NFT. There were no significant interactions of sex and IIV.

CONCLUSIONS: Among cognitively unimpaired older adults, global IIV was a sensitive but non-specific marker associated with cognitive decline and neuropathology at autopsy. Domain-specific IIVs were also associated with cognitive progression but offered more specificity in neuropathologic outcomes. Associations were largely consistent across sexes, indicating IIV is robust to sex-specific effects. Findings highlight IIV as sensitive to long-term cognitive health and neuropathological burden and may improve early risk stratification for dementia.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02041-4.},
}

@article {pmid42267694,
year = {2026},
author = {Verma, M and Mohd Siddique, MU and Singh, NK},
title = {Corrigendum to: Neuroactive Phytoconstituents of Glycyrrhiza glabra for the Treatment of Alzheimer's Disease.},
journal = {Current topics in medicinal chemistry},
volume = {26},
number = {4},
pages = {422},
doi = {10.2174/156802662604260406111327},
pmid = {42267694},
issn = {1873-4294},
abstract = {It has come to our notice that in the published version of this article [1], the reference [96] was cited erroneously. The author has now corrected the reference sequence, and it is now cited as [95]. The revised section is provided below. The original article can be found online at https://www.eurekaselect.com/article/145138.},
}

@article {pmid42267709,
year = {2026},
author = {Toyli, A and Zhao, C and Su, KJ and Shen, H and Deng, HW and Chen, QH and Sha, Q and Zhou, W},
title = {Cardiovascular Disease Subtypes and Alzheimer's Disease: Phenotypic and Genetic Associations in the UK Biobank and All of Us Research Program.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e046172},
doi = {10.1161/JAHA.125.046172},
pmid = {42267709},
issn = {2047-9980},
abstract = {BACKGROUND: Cardiovascular disease (CVD) and Alzheimer's disease (AD) are major public health concerns that share overlapping risk factors and potential mechanistic pathways. Although vascular contributions to cognitive decline are well documented, the specific relationships between AD and different CVD subtypes remain poorly understood.

METHODS: In this cross-sectional study, we examined associations between AD and 11 CVD subtypes using logistic regression models in 2 large biobanks: the UK Biobank (n=502 133) and the All of Us Research Program (n=287 011). Models were adjusted for demographic, lifestyle, and clinical covariates. We also explored genetic overlap between AD and CVD traits through proximity-based analysis of significant single nucleotide variants (P<5 × 10[-8]) using genome-wide association study data.

RESULTS: Most CVD subtypes were significantly associated with AD in both cohorts. Hypotension had the strongest and most consistent association, although it has been comparatively understudied in AD research. Strong associations were also consistently observed between AD and hypertension and cerebral infarction. Notably, acute myocardial infarction was not significantly linked to AD. Genetic analyses revealed shared loci between AD- and CVD-related traits, particularly in regions near APOE, MAPT, and genes influencing myocardial structure and vascular function.

CONCLUSIONS: This study identifies subtype-specific CVD associations with AD across 2 diverse cohorts and highlights shared genetic architecture underlying heart-brain interactions. These findings underscore the importance of vascular health in AD risk and suggest that certain CVD subtypes, especially hypotension, may play underrecognized roles in cognitive decline.},
}

@article {pmid42267754,
year = {2026},
author = {Katti, VB and Kolusu, AS and Madhana, RM and Pindiprolu, SKSS and Tummala, UK and Samudrala, PK},
title = {Therapeutic Potential of Stearylamine-Conjugated Phenylboronic Acid-Modified Nanocarriers of 4-Allyl Pyrocatechol in Modulating Sialylation and Neuroinflammation in Scopolamine-Induced Cognitive Impairment in the Rat Model.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c01768},
pmid = {42267754},
issn = {1543-8392},
abstract = {Alzheimer's disease is a progressive neurodegenerative condition and is regarded as the most prevalent type of dementia among older adults. It is characterized by the accumulation of beta-amyloid, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, neuroinflammation, and neuronal loss, all of which contribute to the gradual decline in cognitive function. Recent research has highlighted the role of sialylation in the pathogenesis of Alzheimer's disease. Sialylation plays a critical role in the pathophysiology of Alzheimer's disease, influencing amyloid plaque formation, neuroinflammation, and synaptic function. CD33 plays a significant role in regulating immune responses, particularly in the central nervous system, and has been implicated in the progression of Alzheimer's disease. In this study, we explore the neuroprotective effect of stearylamine-conjugated phenyl boronic acid-modified 4-allyl pyrocatechol (PAPS) nanoparticles in modulating sialylation and neuroinflammation against scopolamine-induced Alzheimer's disease in rats. 4-Allyl pyrocatechol is known to possess antioxidant and anti-inflammatory activities. On the other hand, stearylamine-conjugated phenyl boronic acid (PBSA) not only is a potential vehicle for delivering drugs or therapeutic agents to the brain but also has a propensity to inhibit the interaction of sialic acid-conjugated ligands with CD33 receptors, which facilitates clearance of amyloid beta through microglia-mediated phagocytosis. A total of 36 animals were divided into 6 groups (n = 6) as control group, disease group, standard group, PBSA carrier group, 4-allyl pyrocatechol group, and PAPS group, which were treated with 5% carboxy methyl cellulose (p.o.), scopolamine 3 mg/kg (i.p.), donepezil 3 mg/kg (i.p.), stearylamine-conjugated phenyl boronic acid 2 mL/kg (p.o.), 4-allyl pyrocatechol 10 mg/kg (p.o.), and PAPS 10 mg/kg (p.o.) respectively. The study was designed for 16 days. From day 8, all the groups except the control group were administered scopolamine 3 mg/kg (i.p.) 45 min before they were given their respective treatments. Behavioral tests (open field test, novel object recognition test, Y-maze, and Morris' water maze) were conducted from day 8 to day 15. On day 16, animals were euthanized by cervical dislocation, brains were isolated, and the hippocampus and prefrontal cortex were separated and homogenized, followed by centrifugation at 4 °C, 10,000 rpm for 15 min. The biochemical estimations like acetylcholinesterase activity were used; oxidative and antioxidant parameters like nitric oxide, malondialdehyde, and reduced glutathione were determined; enzyme-linked immunosorbent assays for amyloid beta, inflammatory cytokines, brain-derived neurotrophic factor, and CD33 were performed. The results from behavioral and biochemical tests suggested that the PAPS formulation had a more significant impact on slowing the progression of scopolamine-induced cognitive impairment compared to the stearylamine-conjugated phenyl boronic acid carrier and 4-allyl pyrocatechol alone treatments. The histopathological studies revealed a decline in neural degeneration and showed improved neuronal morphology in the PAPS-treated group compared with the disease group. From the data obtained, the PAPS nanoparticle formulation would be an effective strategy for reducing the progression of cognitive impairment.},
}

@article {pmid42268233,
year = {2026},
author = {Shakoor, A and Elhenawy, AA and Alam, A and Ahmad, I and Rahman, MU and Khan, A and Zouidi, F and Almutairi, TM and Al-Harrasi, A and Khan, M},
title = {Benzimidazole derived hydrazone Schiff bases as potent cholinesterase inhibitors: synthesis, in vitro and in silico approaches.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17568919.2026.2684691},
pmid = {42268233},
issn = {1756-8927},
abstract = {AIMS: The current study aimed to synthesize and evaluate benzimidazole Schiff bases as dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).

METHODS: Ten benzimidazole Schiff bases were synthesized and characterized by spectroscopic techniques. These compounds were assessed for in vitro AChE and BuChE inhibitory activities. Density functional theory (DFT) analysis was carried out to know the electronic properties, while molecular docking studies were performed to expose protein ligand interactions.

RESULTS: In the series, compounds (2c, 2f, 2h, 2a, and 2b) displayed potent inhibition against AChE and BuChE comparable to the standard galantamine. DFT study showed that compounds having higher electrophilicity (ω), lower hardness (η), higher softness (σ), and lower energy gap (ε) increase the inhibitory activity. In addition, electron donating groups at meta position of the benzene improved the potency, while docking studies confirmed favorable binding interactions with the active site of the enzymes.

DISCUSSION: These consequences show that both geometric and electronic properties have a vital role in determining the cholinesterase inhibition. These derivatives facilitate multiple interactions within the enzyme active site, supporting its potential as biologically relevant nucleus.

CONCLUSION: The experimental and computational findings provide valuable insights for the optimization and rational design of new therapeutic agents for Alzheimer's disease.},
}

@article {pmid42268276,
year = {2026},
author = {Zakharov, AV and Komarova, YS and Moskvitina, PM and Pavlova, ON and Romanchuk, NP and Sergeeva, MS and Shirolapov, IV},
title = {[Bidirectional links between sleep deprivation and neurodegenerative diseases].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {5. Vyp. 2},
pages = {74-80},
doi = {10.17116/jnevro202612605274},
pmid = {42268276},
issn = {1997-7298},
mesh = {Humans ; *Sleep Deprivation/complications/metabolism/physiopathology ; *Neurodegenerative Diseases/etiology/metabolism ; Risk Factors ; Alzheimer Disease ; },
abstract = {Sleep is essential for maintaining homeostatic functions, supporting optimal brain activity, and facilitating recovery processes. The clinical consequences of sleep deprivation and sleep disorders require an integrated approach to diagnosis and therapy, as these conditions affect the progression and development of various diseases and systemic pathological processes. Sleep disturbances are a significant global health concern. This article reviews the potential impact and bidirectional associations between sleep deprivation and the risk of neurodegenerative diseases.The mechanisms underlying the imbalance between the formation and clearance of abnormal proteins, which are central to the pathogenesis of proteinopathies associated with sleep disorders or deprivation, are examined. Although treating Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions remains challenging, recent research may enable prevention and targeted interventions at early stages, including extensive screening and modification of risk factors such as sleep deprivation and disturbance.},
}

Humans
*Sleep Deprivation/complications/metabolism/physiopathology
*Neurodegenerative Diseases/etiology/metabolism
Risk Factors
Alzheimer Disease

@article {pmid42268277,
year = {2026},
author = {Agaltsov, MV},
title = {[Sleep-disordered breathing in older adults: clinical features and effects on the nervous system and mental health].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {5. Vyp. 2},
pages = {81-86},
doi = {10.17116/jnevro202612605281},
pmid = {42268277},
issn = {1997-7298},
abstract = {Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder characterized by upper airway collapse, intermittent hypoxemia, intrathoracic pressure fluctuations, and sleep fragmentation. In older adults, the clinical presentation and consequences of OSA differ from those observed in middle-aged individuals, necessitating age-specific management strategies. This review discusses age-related aspects of OSA epidemiology and pathophysiology, as well as associations with neurological and psychiatric outcomes in later life. Evidence demonstrates that OSA prevalence increases with age in both sexes, with postmenopausal hormonal and metabolic changes further elevating risk in women. Aging is associated with reduced slow-wave sleep, increased sleep fragmentation, and upper airway structural alterations, all of which may affect respiratory event patterns and arousals. Notably, excessive daytime sleepiness may be less prominent in older adults despite clinically significant OSA. Emerging data link OSA in older adults to cognitive decline, Alzheimer's disease biomarkers, and heightened risk of cerebrovascular disorders, although research specifically targeting elderly populations remains limited. Positive airway pressure (PAP) therapy may enhance mood, daytime functioning, and certain cognitive outcomes; however, current evidence is constrained by small sample sizes, short follow-up, and adherence challenges. Diagnosis and management of OSA in older adults require age-appropriate clinical interpretation and further longitudinal and interventional studies to elucidate causal relationships and the effects of treatment on neurodegenerative and cerebrovascular outcomes.},
}

@article {pmid42268317,
year = {2026},
author = {Choi, SA and Hong, SH},
title = {MiR-125a C > T, MiR-152 C > T, MiR-938 G > A, and MiR-491 G > A single nucleotide polymorphisms and their influence on genetic susceptibility to type 2 diabetes.},
journal = {Genes & genomics},
volume = {},
number = {},
pages = {},
pmid = {42268317},
issn = {2092-9293},
support = {NRF 2017R1D1A3B03027985//Ministry of Education, Science and Technology/ ; },
abstract = {BACKGROUND: Diabetes mellitus (DM) is a chronic metabolic disorder that carries the risk of severe complications, such as cardiovascular disease, renal impairment, and an increased susceptibility to Alzheimer's disease. Considering these significant health implications, it is crucial to deepen our understanding of this condition. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, play a critical role in various biological processes and, when dysregulated, can contribute to the development of diseases such as diabetes mellitus.

OBJECTIVE: This study aimed to investigate the association between type 2 diabetes mellitus (T2DM) and specific miRNA polymorphisms (miR-125a C > T, miR-152 C > T, miR-938 G > A, and miR-491 G > A) in a Korean population.

METHODS: We examined the distribution of miRNA polymorphisms through genotyping in 238 T2DM patients and 343 healthy controls using polymerase chain reaction-restriction fragment length polymorphism technique.

RESULTS: Our findings indicate that the miR-938 GA genotype and its dominant model were significantly associated with an elevated risk of T2DM. Moreover, specific combinations of genetic variations were linked to either an increased or decreased risk of developing T2DM.

CONCLUSIONS: These results suggest that miRNA polymorphisms may influence an individual's genetic susceptibility to T2DM and offer potential therapeutic targets and diagnostic tools.},
}

@article {pmid42268366,
year = {2026},
author = {Shirvani, H and Pescatello, LS and Eftekhari Moghadam, AR and Arabzadeh, E},
title = {Unlocking Neuroprotection: Exercise-Induced Muscle Secretome (Myokines) as a Therapeutic Avenue Against Alzheimer's Disease Pathogenesis.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42268366},
issn = {1559-1166},
mesh = {Humans ; *Myokines/metabolism ; *Alzheimer Disease/metabolism/therapy ; Animals ; *Exercise ; *Neuroprotection ; Neuroprotective Agents/therapeutic use ; },
abstract = {This review critically evaluates exercise-induced myokines as neuroprotective agents against Alzheimer's disease (AD) and is structured around three thematic sections: (1) mechanistic foundations of myokine neuroprotection, (2) translational barriers to therapeutic development, and (3) a strategic framework for future research. Epidemiological studies associate physical exercise with reduced AD risk (30-45%), yet mechanisms remain incompletely resolved. Preclinical studies demonstrate that exercise-induced myokines (Irisin, BDNF, Cathepsin B) modulate AD pathology by: (1) attenuating amyloid-beta (Aβ)/tau accumulation, (2) suppressing neuroinflammation, and (3) enhancing synaptic plasticity. However, human exercise interventions show conflicting results influenced by APOE genotype, age, and exercise modality. Associative human data suggest that Interleukin-6 (IL-6) exemplifies pleiotropy-affording neuroprotective effects in acute contexts but potentially detrimental effects in states of chronic inflammation. Therapeutic hurdles include blood-brain barrier (BBB) penetration, pleiotropic risks, and patient heterogeneity. Emerging concepts such as combinatorial approaches (nanocarriers, exercise mimetics) and biomarker-driven trials are proposed as hypothetical future strategies; however, these remain unvalidated and require substantial preclinical development before implemented in clinical care. This narrative review is structured around three thematic sections: mechanistic foundations of myokine neuroprotection, translational barriers to therapeutic development, and a strategic framework for future research. The muscle-brain axis represents a compelling but complex therapeutic target. Based on current preclinical and correlational human evidence, future research should prioritize mechanistic rigor, standardized biomarker validation, and clinically viable delivery strategies. Notably, several approaches discussed herein-including nanocarrier delivery systems, exercise mimetics, and combinatorial myokine cocktails-remain speculative and are presented as future research directions rather than established therapeutic interventions.},
}

Humans
*Myokines/metabolism
*Alzheimer Disease/metabolism/therapy
Animals
*Exercise
*Neuroprotection
Neuroprotective Agents/therapeutic use

@article {pmid42268445,
year = {2026},
author = {Mohasel-Roodi, M and Nozari, M and Baghalishahi, M and Shamsara, A},
title = {The protective effects of dexmedetomidine via AMPK/SIRT1 pathway activation in a rat model of alzheimer's disease: evidence from preliminary findings.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42268445},
issn = {1573-4978},
mesh = {Animals ; *Dexmedetomidine/pharmacology/metabolism ; *Sirtuin 1/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Male ; Rats ; Rats, Wistar ; Disease Models, Animal ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; Streptozocin ; *Neuroprotective Agents/pharmacology ; Neurons/drug effects/metabolism ; Hippocampus/metabolism/drug effects ; },
abstract = {BACKGROUND: Metabolic dysfunction and impaired energy signaling play critical roles in Alzheimer's disease (AD). The AMP-activated protein kinase (AMPK) / sirtuin-1 (SIRT1) pathway is a key regulator of neuronal energy homeostasis and survival. Dexmedetomidine (Dex), a selective α -2 adrenergic receptor agonist, has shown neuroprotective effects in acute neurological injury and energy homeostasis; however, its efficacy in metabolically driven AD models remains unclear.

METHODS: Forty-two adult male Wistar rats were randomly assigned to seven groups: control, sham, STZ, sham + Dex 25, STZ + Dex 25, STZ + Dex 50, and STZ + Dex 100 (n = 6/group). Sporadic AD was induced by bilateral intracerebroventricular injections of streptozotocin (STZ, 3 mg/kg) on days 1 and 3. Dex was administered intraperitoneally at doses of 25, 50, or 100 µg/kg following STZ injection. Hippocampal neuronal injury was assessed by Nissl staining, and AMPK and SIRT1 protein levels were evaluated using Western blot analysis 30 days after STZ administration.

RESULTS: STZ administration significantly increased neuronal injury in the hippocampal CA1 region and markedly reduced AMPK and SIRT1 expression compared with control and sham groups (p < 0.05-0.001). Dex treatment at all doses significantly attenuated CA1 neuronal damage, with the most pronounced histological protection observed at 25 µg/kg (p < 0.001). In parallel, Dex reversed STZ-induced downregulation of AMPK and SIRT1, with maximal molecular upregulation observed at 100 µg/kg (p < 0.05).

CONCLUSIONS: Dex mitigates STZ-induced hippocampal neurodegeneration, at least in part, through modulation of the AMPK/SIRT1 signaling pathway. These findings support the therapeutic potential of Dex in metabolically driven models of sporadic AD.},
}

Animals
*Dexmedetomidine/pharmacology/metabolism
*Sirtuin 1/metabolism
*Alzheimer Disease/drug therapy/metabolism
Male
Rats
Rats, Wistar
Disease Models, Animal
*AMP-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
Streptozocin
*Neuroprotective Agents/pharmacology
Neurons/drug effects/metabolism
Hippocampus/metabolism/drug effects

@article {pmid42268464,
year = {2026},
author = {Mishra, H and Mishra, MK},
title = {Advances in anti-tau therapeutics for alzheimer's disease: immunotherapy, gene modulation, and combination approaches.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42268464},
issn = {1573-4978},
abstract = {Tau protein abnormalities are more detrimental to neurocognitive function and behaviour than amyloid plaque formation in patients affected by Alzheimer's Disease (AD) - the most common cause of dementia worldwide. Pathologically, tau misfolding, neurofibrillary tangle formation, hyper phosphorylation, and dissociation from microtubules lead to synaptic dysfunction and neuron death. With this understanding, tau is now a major therapeutic target; there is a growing research effort to assess immunotherapy, kinase inhibitors, and tau aggregation inhibitors, and evidence suggests that combination therapies may have synergistic effects. Although there are many challenges remaining, including poor late-stage trial efficacy and limited therapeutic access through the blood-brain barrier, the preliminary results from early preclinical and clinical studies suggest that tau pathology can be reduced and neuronal function improved. Additionally, RNA interference, antisense oligonucleotides, and other gene-based therapies are under investigation. Overall, tau-directed treatments show promise for the treatment of AD, with particular optimism about improvements in delivery systems and combination therapies that will lead to substantial therapeutic benefits and improved quality of life for patients with AD.},
}

@article {pmid42268478,
year = {2026},
author = {Khajouei, F and Ghaemi, A and Abnous, K and Taghdisi, SM and Ramezani, M and Alibolandi, M},
title = {CRISPR-Based Gene Therapy for Brain Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42268478},
issn = {1559-1182},
abstract = {Neurological disorders are complex and often very challenging for patients. Many of these conditions result from mutations in genes that are essential for normal function. Most existing treatments only alleviate symptoms, highlighting the urgent need for more effective therapeutic strategies. In the current drug development landscape, gene therapy offers hope as a promising approach. Specifically, CRISPR-Cas9 technology enables precise gene editing across diverse cell types and organisms. An increasing number of research groups are investigating innovative therapies and the molecular mechanisms behind neurological diseases. This review highlights the use of CRISPR-based gene therapies for various brain diseases, including multiple sclerosis, Alzheimer's, Parkinson's disease, epilepsy, stroke, and brain tumors. It consistently recognizes significant challenges in clinical applications, including overcoming the blood-brain barrier (BBB), managing off-target effects, ensuring efficient delivery, and addressing immunogenicity and ethical concerns.},
}

@article {pmid42268484,
year = {2026},
author = {Asadi Anar, M and Fathollahi, MA and Zare, F and Farrokhi, Z and Habibzadeh, E and Hasany, S and Mirmazloumi, M and Arab Bafrani, M and Abedian Kenari, F and Falahati, M and Khorsand, K and Zakavi, A and Asadollah Salmanpour, Y and Yadegarifard, E and Khosravi, F and Goudarzi, P},
title = {Mitochondrial enzyme dysfunction in Alzheimer's disease: a systematic review of human metabolic evidence.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42268484},
issn = {1573-7365},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline accompanied by profound disturbances in cerebral energy metabolism. Mitochondrial dysfunction has long been implicated in AD pathophysiology; however, the specific contribution of mitochondrial enzymes in human disease remains fragmented across heterogeneous studies. Enzymes regulating carbon entry into the tricarboxylic acid cycle, oxidative phosphorylation, and redox balance represent key metabolic control points whose dysfunction may contribute to neuronal vulnerability. To systematically synthesize human evidence on mitochondrial enzyme alterations in Alzheimer's disease and to evaluate the feasibility of quantitative meta-analysis based on current reporting practices. A systematic literature search was conducted in PubMed, Scopus, and Web of Science from database inception through January 2026 in accordance with PRISMA 2020 guidelines. Studies were included if they investigated mitochondrial enzymes in human postmortem brain tissue, human-derived cellular models, or peripheral biospecimens. Risk of bias was assessed using the ROBINS-I tool. The feasibility of meta-analysis was evaluated based on the availability and comparability of group-level summary statistics. Fifteen studies met the eligibility criteria and were included in the final synthesis. Mitochondrial enzymes involved in carbon entry into the tricarboxylic acid cycle, oxidative phosphorylation, redox regulation, and neurotransmitter-linked mitochondrial metabolism were the most frequently investigated targets. Direct enzyme-activity evidence most consistently implicated selected metabolic control points, particularly PDHC and αKGDHC, whereas additional studies supported mitochondrial impairment through protein or post-translational modification changes, respiratory dysfunction, redox alterations, or RNA-regulatory mechanisms. Quantitative meta-analysis was not feasible due to heterogeneous assay methodologies, variable normalization strategies, and inconsistent reporting of group-level summary statistics. Human evidence consistently implicates mitochondrial enzyme dysfunction as a central metabolic feature of Alzheimer's disease. However, progress toward cumulative quantitative synthesis remains limited by methodological heterogeneity and incomplete reporting of enzyme activity outcomes. Standardized measurement and reporting of mitochondrial enzyme alterations will be essential to advance mechanistic understanding and enable future meta-analytic integration.},
}

@article {pmid42268486,
year = {2026},
author = {Hashem, S and Yamashiro, S and Joe, E and Chui, H and Marmarelis, V},
title = {PRBS Gas Challenges Reveal Impaired Chemoreflex and Cholinergic Dynamics in MCI.},
journal = {Annals of biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {42268486},
issn = {1573-9686},
support = {R01-AG058162/AG/NIA NIH HHS/United States ; },
abstract = {PURPOSE: This study investigates the dynamic regulation of cerebral oxygenation in individuals with mild cognitive impairment (MCI) compared to healthy controls, using a novel pseudorandom binary sequence (PRBS) gas challenge. Traditional assessments often overlook frequency-dependent features of cerebrovascular control; this work aims to uncover latent deficits through broadband perturbations and nonparametric dynamic modeling.

METHODS: Seventeen ApoE4-negative participants (9 controls, 8 MCI) underwent a three-session supine protocol involving PRBS-modulated inhalation of hypoxic and hypercapnic gas mixtures. Physiological signals-including near-infrared spectroscopy (TOI), arterial pressure (ABP), and end-tidal CO2 (PETCO2)-were recorded. Laguerre-based Volterra modeling and Principal Dynamic Mode (PDM) decomposition were used to analyze the dynamic response of cerebral oxygenation to ABP and CO2 stimuli. Group differences were statistically assessed using Welch's t-tests and repeated measures ANOVA.

RESULTS: Controls showed significant increases in ventilation and TOI from baseline to stimulation (p < 0.01), while MCI did not. Gain of the first CO2 PDM increased in controls during PRBS (p = 0.016) but decreased in MCI. A low-frequency ABP-derived PDM (∼  0.014 Hz), consistent with endothelial-dependent vasodilation, was elevated only in controls during stimulation. Persistent differences in spectral recovery, kernel profiles, and PDM Gains suggested impaired baroreflex and chemoreflex regulation, and possible disruption of cholinergic-linked neurovascular coupling in MCI.

CONCLUSION: PRBS gas modulation combined with dynamic modeling revealed subtle but significant cerebrovascular control impairments in MCI. This methodology enables mechanistic insights into early pathophysiology and may aid future physiomarker development.},
}