@article {pmid42680483,
year = {2026},
author = {Kim, SH and Lee, SK},
title = {Lithium: the protective cation singled out by Alzheimer's disease.},
journal = {BMB reports},
volume = {59},
number = {10},
pages = {456-465},
pmid = {42680483},
issn = {1976-670X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Lithium/pharmacology/therapeutic use/metabolism ; Animals ; Glycogen Synthase Kinase 3 beta/metabolism ; Lithium Compounds/pharmacology/therapeutic use ; Phosphoric Monoester Hydrolases/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Lithium is a mood stabilizer that is most prescribed in psychiatry for managing mental disorders. Many findings indicate that lithium is also neuroprotective in various neurodegenerative diseases. In particular, lithium has been of great interest as an affordable but still effective treatment for Alzheimer's disease (AD), due to its diverse neuroprotective actions and mechanistic overlap with key AD pathways, such as A(?) production and tau modification. While the multifaceted activities may result from lithium's inhibitory action on two key enzymes, glycogen synthase kinase-3 beta (GSK-3(?)) and inositol monophosphatase (IMPase), recent findings suggest that selective lithium depletion in neurons mediated by amyloid deposits may be a key pathological trigger in AD and supplementation with lithium orotate, a lithium salt with reduced amyloid binding, may even reverse brain damage and prevent cognitive decline. In this study, we review the neuroprotective properties of lithium, its known mechanisms of action, and discuss its therapeutic potential in AD, a topic that has been debated for decades. [BMB Reports 2026; 59(10): 456-465].},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
*Lithium/pharmacology/therapeutic use/metabolism
Animals
Glycogen Synthase Kinase 3 beta/metabolism
Lithium Compounds/pharmacology/therapeutic use
Phosphoric Monoester Hydrolases/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42935028,
year = {2026},
author = {Khuman, YM and Kapadiya, YM and Maru, JJ},
title = {Synthetic Insights on Donepezil: An Anti-Alzheimer Drug.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {10},
pages = {},
doi = {10.1002/ardp.70364},
pmid = {42935028},
issn = {1521-4184},
mesh = {*Donepezil/chemical synthesis/pharmacology/chemistry/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Nootropic Agents/chemical synthesis/pharmacology ; Animals ; Molecular Structure ; },
abstract = {Alzheimer's disease is a severe condition that poses significant global health concerns to international health agencies and remains a major threat to public health. As there is no cure for Alzheimer's disease, various anti-Alzheimer's medications are used to manage its symptoms. Donepezil is one of the most highly marketed drugs, known for its positive effects on cognition, function, behaviour and overall patient condition, making it a standout treatment option. Various synthetic methods have been developed to produce more efficient pathways that minimise by-products and maximise yield. This review summarises the reported literature on various synthetic routes for producing Donepezil. We have also made an effort to highlight the advantages and limitations of prior literature, which may lead to potential improvements for future research. This work will serve as a foundation for upcoming researchers, ultimately benefiting the well-being of Alzheimer's patients and human society as a whole.},
}

*Donepezil/chemical synthesis/pharmacology/chemistry/therapeutic use
Humans
*Alzheimer Disease/drug therapy
*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry
*Nootropic Agents/chemical synthesis/pharmacology
Animals
Molecular Structure

@article {pmid42935657,
year = {2026},
author = {Hussain, A and Bokhari, SAI},
title = {Mechanistic insights of Artemisia-derived therapeutics in Alzheimer's disease (AD): from crude botanical extracts to artemisinin and derivatives.},
journal = {3 Biotech},
volume = {16},
number = {11},
pages = {479},
pmid = {42935657},
issn = {2190-572X},
abstract = {Alzheimer's disease (AD) is characterized by several pathological processes including amyloid-β (Aβ) accumulation, Tau hyperphosphorylation, oxidative stress, synaptic dysfunction, neuroinflammation, mitochondrial impairment and loss in neuronal stability. This review assessed the reported neuroprotective potential of crude extracts of different Artemisia species and artemisinin with its derivatives in AD. It focuses on targets, mechanisms, observational markers and functional effects validated by Artemisia extracts and compounds like artemisinin, artemisinin B, artemether, artesunate and dihydroartemisinin in experimental AD models. A comprehensive review of studies was conducted including in vitro, in vivo and in silico research on Artemisia extracts and derivatives focusing on their effects on various pathological processes related to brain. Results showed crude extracts from 17 Artemisia species, which have been reported with considerable neuroprotective effects. Artemisinin and derivatives deliver neuroprotection via targeted mechanisms and effecting observational markers with varying functional outcomes. However, differences in AD models, administration routes, doses, extract composition and outcomes limit direct efficacy comparisons. Hence, direct comparisons of efficacy among Artemisia extracts, artemisinin and its derivatives should be interpreted cautiously. Future inquiries should highlight standardized preparations, brain exposure and pharmacokinetics, mechanistic validation, long-term safety and well-designed comparative and clinical trials to evaluate their potential for AD treatment.},
}

@article {pmid42936906,
year = {2026},
author = {Valentim, C and Denecke, J and Frerich, S and Betthauser, TJ and Li, Y and Ahmadi, R and Franzmeier, N and , and Malik, R and Ewers, M},
title = {Pathway-specific polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42936906},
issn = {1552-5279},
support = {//European Union's Horizon/ ; 01KU2203//Bundesministerium für Bildung und Forschung/ ; 2525FSB005//Bundesministerium für Gesundheit/ ; 570971002//Deutsche Forschungsgesellschaft/ ; /ALZ/Alzheimer's Association/United States ; //Joachim Herz Foundation/ ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism/diagnostic imaging ; Cross-Sectional Studies ; Genetic Predisposition to Disease ; *Genetic Risk Score ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Positron-Emission Tomography ; *tau Proteins/metabolism ; },
abstract = {BACKGROUND: Genome-wide association studies (GWASs) identified multiple genetic variants associated with Alzheimer's disease (AD) risk, yet the biological pathways linking these to amyloid and tau pathology remain unclear.

METHODS: We conducted a meta-analysis of recent GWASs to identify independent genome-wide significant single nucleotide polymorphisms which were mapped via gene-set enrichment to derive pathway-specific polygenic risk scores (pPRSs). Analyses included 441 amyloid-positive participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 224 with longitudinal tau positron emission tomography [PET]) and 250 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study (113 with longitudinal tau PET). Robust linear regressions tested cross-sectional and longitudinal pPRS-by-amyloid chronicity interactions on tau PET.

RESULTS: Four pPRSs were identified including adaptive immune response, leukocyte activation, transport, and intracellular signaling. Only the transport pPRS strengthened amyloid-tau coupling cross-sectionally across all Braak stages in ADNI (p < 0.05) and at Braak I in A4 (p < 0.05), with stronger effects observed in females; in ADNI, these associations persisted longitudinally only at the higher Braak stages.

DISCUSSION: Genetic variation in transport pathways modulates amyloid-driven tau accumulation, revealing mechanisms shaping AD progression, beyond apolipoprotein E.},
}

Aged
Aged, 80 and over
Female
Humans
Male
*Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Brain/metabolism/diagnostic imaging
Cross-Sectional Studies
Genetic Predisposition to Disease
*Genetic Risk Score
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Positron-Emission Tomography
*tau Proteins/metabolism

@article {pmid42937271,
year = {2026},
author = {Wang, D and Zhao, Z and Ding, Y},
title = {Relaxin-2 protects synaptic integrity via hippocampal NLRP3-mTOR-autophagy pathways in an age-dependent Alzheimer-like model.},
journal = {Acta pharmaceutica (Zagreb, Croatia)},
volume = {},
number = {},
pages = {},
doi = {10.2478/acph-2026-0023},
pmid = {42937271},
issn = {1846-9558},
abstract = {Alzheimer disease (AD) is associated with age-related synaptic degeneration, neuroinflammation, and impaired autophagy. The present study aimed to investigate the age-dependent neuroprotective effects of relaxin-2 (RLN2) in amyloid-beta 1-42 (Aβ1 - 42)-induced AD-like pathology and hypothesised that RLN2 would provide greater therapeutic benefit in young than aged mice. Young (3-4 months) and aged (12-14 months) mice were intracerebrally (i.c.) injected with amyloid-β (Aβ1 - 42) to develop an AD-like phenotype and treated with RLN2 or a control. Western blot analysis of hippocampal tissues was performed to assess the expression levels of ionised calcium-binding adaptor molecule 1 (Iba1) (microglial activation marker), NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components, and mechanistic target of rapamycin (mTOR) pathway activity. Neuroinflammation was determined by interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α), while synaptic integrity was assessed by synaptophysin and PSD-95. The Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests were used to measure cognitive and memory performance. Neuroinflammation markers IL-1β and TNF-α were significantly elevated in Aβ1 - 42-injected mice, with aged mice showing a greater increase than young mice. RLN2 treatment markedly reduced IL-1β and TNF-α levels in young mice, whereas the reduction was limited in aged mice. RLN2 treatment had a significant inhibitory effect on hippocampal NLRP3 signalling, reduced mTOR signalling, modulated autophagy-related protein expression, preserved synaptic proteins, and improved cognitive and memory performance (decrease in the MWM escape latency and increase in the NOR discrimination index). RLN2 was not effective in the aged mice, and there was persistent inflammatory activation, impaired autophagy, minimal improvement in synaptic recovery, and a moderate improvement in cognition. These findings suggest that RLN2 could be a potential therapeutic candidate for early-stage AD by targeting neuroinflammation, mTOR-mediated autophagy-related dysregulation, and synaptic loss, while also potentially providing a basis for age-based stratification of treatment responsiveness; however, further studies are required to determine its utility as a biomarker of treatment response or disease progression. Overall, RLN2 exerted neuro-protective effects in i.c. Aβ1 - 42-induced AD-like pathology in an age-dependent manner.},
}

@article {pmid42939269,
year = {2026},
author = {Dong, H and Wang, W and Zeng, W and Zou, Q and Lu, W and Chen, C and Yao, J and Li, Y},
title = {Acupuncture in Aging-Related Brain Diseases: From Mitochondrial Homeostasis to Clinical Signals.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939269},
issn = {2076-3425},
support = {82405582//National Natural Science Foundation of China/ ; GZB20240087 and 2024M750285//China Postdoctoral Science Foundation/ ; },
abstract = {Mitochondria play a key role in maintaining cellular homeostasis through energy metabolism, ROS regulation, calcium handling, and apoptosis control. Mitochondrial dysfunction contributes to neurological vulnerability in the aging brain, where neuronal energy demand, axonal transport, synaptic activity, and neurovascular repair depend on mitochondrial integrity. Animal studies in chronic brain disease and acute brain-injury models have examined acupuncture-related changes in phenotypic outcomes and mitochondrial measures, including behavioral, physiological, and molecular readouts. Their findings span mitochondrial ultrastructure, biogenesis, dynamics, mitophagy, and downstream signaling. Clinical studies have examined acupuncture in Parkinson's disease, stroke, and Alzheimer's disease. Animal studies report acupuncture-related changes in mitochondrial structure and indices of quality control alongside improvements in neurological, behavioral, or injury-related outcomes. These mitochondrial changes may influence oxidative stress, calcium regulation, apoptosis, mitochondrial transport, and intercellular mitochondrial support. Clinical studies mainly report symptom and functional outcomes, while a small number of imaging studies also describe changes in cerebral glucose metabolism or neural activity. These preliminary clinical and metabolic signals may inform further investigation into whether mitochondrial processes are associated with clinical responses to acupuncture. Current experimental work also has important limitations: most studies focus on a limited set of mitochondrial quality-control markers, while the mitochondrial unfolded protein response, axonal mitochondrial trafficking, and dynamic mitochondrial transfer are rarely assessed. Future clinical studies should pair neurological outcomes with feasible measures of mitochondrial function and energy metabolism. Tracking these measures over time may help clarify how changes in mitochondrial function and energy metabolism during acupuncture treatment relate to functional recovery.},
}

@article {pmid42939322,
year = {2026},
author = {Bodria, M and Daini, E and Pioli, S and Piemontese, M and Vandini, E and Ottani, A and Zoli, M and Giuliani, D and Vilella, A},
title = {Chronic Inhalation of Sulphureous Water Mitigates Early Amyloid Pathology and Associated Microglial Changes in 5XFAD Mice.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939322},
issn = {2076-3425},
support = {//Fondazione per la Ricerca Scientifica Termale/ ; //MIUR Dipartimenti di Eccellenza 2018-2022/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Hydrogen sulfide (H2S) is an endogenous gasotransmitter that exerts pleiotropic neuromodulatory, anti-inflammatory, cytoprotective, and trophic effects within the central nervous system. Objectuves: This study investigated whether chronic inhalation of naturally H2S-rich sulphureous water, a non-invasive and clinically applicable intervention, exerts neuroprotective effects in 5XFAD mice, a transgenic model of severe AD pathology.

METHODS: Two-month-old male and female wild-type and 5XFAD mice underwent daily inhalation of saline or sulphureous water for eight weeks. Sulphureous water exposure was well tolerated and did not impair baseline learning or memory in either genotype. A detailed analysis of swim trajectories revealed selective enhancement of spatially accurate navigation strategies in sulphureous water-exposed 5XFAD female mice, with nearly a threefold increase in effective search behaviors, whereas male mice showed no treatment-specific effects. In addition, sulphureous water inhalation significantly reduced the number and area of 6E10[+] and 11A1[+] amyloid-β plaques in corticohippocampal regions and decreased cortical microglia number. Transcriptional profiling of cortical tissue revealed strong genotype-dependent upregulation of microglial, inflammatory, and stress-response genes. Sulphureous water exposure selectively modulated inflammatory and stress-response genes, including Cd11b, Cst, Sod1, Tgfb1, and Hsp90a, with distinct genotype-dependent interactions.

RESULTS: Overall, chronic inhalation of naturally H2S-rich sulphureous water during the prodromal phase of AD-like pathology mitigated early amyloid burden, reduced cortical microgliosis, and improved qualitative aspects of spatial navigation, particularly in female mice.

CONCLUSIONS: These findings warrant further translational investigation of sulphureous water inhalation as a potential preventive or disease-modifying strategy for AD in humans.},
}

@article {pmid42939431,
year = {2026},
author = {Wang, J and Rong, M and Cui, J and Guo, H and Xu, J and Guo, Y},
title = {A Docking-Guided Strategy Prioritizes Parishin B as a Potential Anti-Alzheimer's Constituent of Gastrodia elata Blume.},
journal = {Biology},
volume = {15},
number = {20},
pages = {},
pmid = {42939431},
issn = {2079-7737},
support = {22177054//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Phosphodiesterase 4B (PDE4B) is a key regulator of neuroinflammation and has been implicated in AD pathology. Using molecular docking against PDE4B as a screening anchor, we analyzed constituents from G. elata water extract and identified Parishin B as a top-ranked candidate. Parishin B directly inhibited recombinant PDE4B, reducing activity to 22.1% of control at 100 μM. In an Al[3+]-induced zebrafish AD model, both the crude extract and purified Parishin B significantly rescued behavioral deficits; Parishin B at 100 μM showed no statistical difference from the donepezil group, while the crude extract was effective at 30 μg/mL. Mechanistically, Parishin B protected SH-SY5Y neurons against H2O2-induced oxidative stress by reducing ROS and apoptosis and suppressed LPS-induced neuroinflammation in BV-2 microglia via downregulation of iNOS and COX-2. These results suggest that Parishin B is a chemically traceable constituent with dual neuroprotective actions, validating the docking-guided screening strategy and supporting further investigation of G. elata as a source of AD-relevant bioactive compounds.},
}

@article {pmid42940016,
year = {2026},
author = {Uhl, GR and Choi, J and Kannan, B and Henderson, I and Hess, E and Rogers, H and McFarland, D and Dowell, H and Nolan, S and Schultz, K},
title = {Alzheimer's Disease Neurofibrillary Pathophysiology: PTPRD- and Flavonol-Modified Mechanisms, Prevention and Therapeutics.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940016},
issn = {2227-9059},
support = {Supplements to U)1DA047713 and UG3DA056039/AG/NIA NIH HHS/United States ; },
abstract = {A variety of evidence now supports two interrelated hypotheses concerning Alzheimer's disease (AD) neurofibrillary pathology (NFT), its prevention and treatment. The first hypothesis: the receptor type protein tyrosine phosphatase D (PTPRD) plays a key role in AD NFT pathogenesis by modulating activities of neuronal glycogen synthase kinase 3s (GSK3s) in hyperphosphorylating tau. The second hypothesis: positive allosteric modulation of PTPRD's downregulation of GSK3s by flavonols and improved flavonol analogs provides a novel path to prevention and treatment of AD. We review the convergence of evidence from human, mouse, in vitro and in silico studies that enhances the likely translational relevance of these hypotheses.},
}

@article {pmid42940037,
year = {2026},
author = {Sahuquillo, J and Al-Nusaif, M and Torrecilla-Vall-Llossera, M and Durduran, T and Poca, MA},
title = {Five Decades of Infusion Testing in Idiopathic Normal-Pressure Hydrocephalus: Resistance to CSF Outflow as a Biomarker in Search of a Gold Standard.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940037},
issn = {2227-9059},
support = {PI25/01408//Institute of Health Carlos III/ ; 2021SGR/00810//Agency for Administration of University and Research/ ; 10108144//European Union/ ; SCOSWEAR PID2023-147553OB-I00//Spanish State Research Agency/ ; SAFEICP PLEC2022-009290//Spanish State Research Agency/ ; LitMuscle DTS22/00023//Institute of Health Carlos III/ ; },
abstract = {Idiopathic normal-pressure hydrocephalus (iNPH) is a potentially reversible cause of gait impairment, cognitive decline, and urinary dysfunction in older adults, yet identifying patients most likely to benefit from cerebrospinal fluid (CSF) diversion remains a major diagnostic challenge. For more than five decades, the lumbar infusion test, introduced by Katzman and Hussey in 1970, has served as the principal method for assessing CSF absorptive capacity through measurement of resistance to CSF outflow (Rout). This narrative review examines the historical development, physiological basis, and contemporary clinical application of infusion testing in iNPH, with particular emphasis on the diagnostic and prognostic value of Rout. We critically review the evidence supporting the Rout thresholds recommended by current international, Japanese, and American Academy of Neurology guidelines and reassess their performance using a Bayesian framework. Recalculation of likelihood ratios from published meta-analyses demonstrates that none of the commonly proposed Rout thresholds (10-18 mmHg·min/mL) achieves the prognostic performance typically associated with a strong rule-in or rule-out test. We argue that this limited performance reflects not only methodological heterogeneity in infusion-testing protocols but also a more fundamental problem: the absence of a universally accepted reference standard for iNPH. We further examine the limitations of using postoperative clinical improvement as a surrogate reference standard, including variability in outcome definitions, delayed treatment effects, and the potential for circular reasoning. Finally, we review emerging CSF proteomic biomarkers of neuroinflammation, axonal injury, and concomitant Alzheimer-type pathology that may complement hydrodynamic assessment by capturing the balance between reversible hydrocephalus-related dysfunction and irreversible neurodegenerative burden. We conclude that Rout should be regarded as a valuable but incomplete biomarker and that future progress will likely depend on multimodal, probabilistically interpreted models integrating CSF hydrodynamics, neuroimaging, and molecular biomarkers to improve prognostic stratification and establish more robust diagnostic frameworks for iNPH.},
}

@article {pmid42922412,
year = {2026},
author = {Keler Soares, L and Srivastava, G and Dwelle, C and Waggoner, B and Tedone, V and Hickman, JJ and Guo, X},
title = {Deanna Protocol Ameliorates the Deficits in Human iPSC-Cortical Neurons Carrying Familial Alzheimer's Mutation.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {10},
pages = {},
pmid = {42922412},
issn = {1755-5949},
support = {R03 AG070514/AG/NIA NIH HHS/United States ; R43 AG060886/AG/NIA NIH HHS/United States ; R44AG071386-01A1//National Institutes of Health, National Institute on Aging/ ; R01 AG077651/AG/NIA NIH HHS/United States ; 1R03AG070514-01//National Institutes of Health, National Institute on Aging/ ; 1R43 AG060886-01//National Institutes of Health, National Institute on Aging/ ; 1R01AG077651//National Institutes of Health, National Institute on Aging/ ; R44 AG071386/AG/NIA NIH HHS/United States ; AWD4941//Winning the Fight Against Neurodegenerative Diseases (WFND)/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/physiology ; *Alzheimer Disease/genetics/pathology/therapy ; *Presenilin-1/genetics ; *Neurons/drug effects/pathology/physiology ; *Mutation/genetics ; *Cerebral Cortex/pathology/cytology ; Cells, Cultured ; Long-Term Potentiation/drug effects/physiology ; Patch-Clamp Techniques ; Mitochondria/drug effects/metabolism ; },
abstract = {AIMS: Deanna Protocol (DP) is an anaplerotic, mechanism-based therapy designed to address impaired cellular energy flux. The present study aims to investigate the effects of DP in treating Alzheimer's disease (AD) by using cortical neurons derived from AD patient iPSCs carrying a PSEN1 mutation, while cortical neurons differentiated from iPSCs of a healthy subject serve as control.

METHODS: PSEN1 cortical neurons were treated with DP acutely (24 h) and chronically (1-3 weeks). The effect of DP was assessed by utilizing TMRE assay for mitochondrial function, immunofluorescent staining for AD neuron morphological pathology, whole cell patch clamp for neuron electrophysiological property, and microelectrode array (MEA) analysis of long-term potentiation (LTP) for neurocircuit function.

RESULTS: PSEN1 cortical neurons demonstrated impaired mitochondrial function, elevated pathological biomarkers, reduced neurite complexity, altered electrophysiology, and decreased LTP. DP treatment significantly ameliorated all these phenotypes.

CONCLUSION: This study, while confirming iPSC-PSEN1 cortical neurons as a valid AD model, demonstrated the efficacy of DP on ameliorating structural and functional pathologies in AD neurons. It highlights that targeting energy production could be an effective approach in treating neurodegeneration in AD and suggests its potential efficacy in other neurodegenerative diseases.},
}

Humans
*Induced Pluripotent Stem Cells/physiology
*Alzheimer Disease/genetics/pathology/therapy
*Presenilin-1/genetics
*Neurons/drug effects/pathology/physiology
*Mutation/genetics
*Cerebral Cortex/pathology/cytology
Cells, Cultured
Long-Term Potentiation/drug effects/physiology
Patch-Clamp Techniques
Mitochondria/drug effects/metabolism

@article {pmid42922684,
year = {2026},
author = {Soto, C and Gorski, D and Evans, H and Pinho, M and Rehan, Z and Perkins, M and Pinarbasi, E and Reader, J and Barmada, S and Paulson, H and Pritzkow, S},
title = {Tandem Tau and α-Synuclein Seed Amplification Assays Reveal α-Synuclein Copathology Potentiates Tau Seeding in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10845149/v1},
pmid = {42922684},
issn = {2693-5015},
abstract = {Accumulating evidence highlights the frequent co-occurrence of tau and α-synuclein (αSyn) pathology across neurodegenerative diseases, including Alzheimer's disease (AD) and synucleinopathies. Whether the co-deposition of these proteinopathic aggregates influences their respective seeding capacities remains unknown. Seed amplification assays (SAAs) enable sensitive and specific detection of pathological seeding activity in brain tissue and cerebrospinal fluid (CSF) and have been widely used to assess tau or αSyn seeding independently; however, their tandem application in the same individuals has not been thoroughly investigated. Here we apply Tau- and αSyn-SAA in parallel on a well-characterized postmortem cohort of matched brain tissue and CSF spanning AD, synucleinopathies, other neurological diseases, and neuropathologically defined controls. We demonstrate that tau seeding activity in both brain and CSF closely reflects underlying neuropathological burden, increasing stepwise with the grade of AD neuropathological change (ADNC) and neurofibrillary tangle (NFT) stage, with strong within-donor concordance between matrices (r = 0.79, p < 0.001). Tau-SAA measured in postmortem CSF robustly discriminated AD-related neuropathology from other groups, supporting its potential as a neuropathologically informed biomarker. αSyn-SAA identified all synucleinopathy donors as positive and revealed that 44% of AD donors harbor concomitant αSyn seeding activity. Leveraging this tandem dataset, we find that αSyn-SAA positive AD donors exhibit significantly enhanced tau seeding activity in both brain and CSF, independent of NFT stage, age, and sex (p = 0.014). In synucleinopathy donors, tau seeding did not alter αSyn seeding capacity (p = 0.606). Together, these results suggest a potentially unidirectional relationship between tau and αSyn seeding in human disease, wherein αSyn copathology acts as a catalyst of tau seeding in AD. Our findings carry implications for understanding how mixed proteinopathies shape disease burden and trajectory and may represent the beginning of a new direction in the field moving towards precision medicine to identify all types of pathology concomitantly affecting the brain, which will have a profound impact on patient prognosis and treatment.},
}

@article {pmid42923225,
year = {2026},
author = {Zhao, J and Nie, C and Gao, R and Hu, Z and Lin, Y},
title = {Noninvasive diagnosis of Alzheimer's disease: a review of emerging biomarkers and multimodal approaches.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1964029},
pmid = {42923225},
issn = {2296-634X},
abstract = {Noninvasive biomarkers are expanding access to biological assessment of Alzheimer's disease (AD). This review evaluates blood-based, neuroimaging, retinal, electrophysiological, digital, and behavioral measures alongside structured cognitive and functional assessment, and examines multimodal and machine-learning approaches for detection, differential diagnosis, prognosis, and treatment monitoring. Plasma phosphorylated tau, particularly p-tau217, currently offers the strongest scalable evidence for identifying amyloid and advanced tau pathology, whereas PET and MRI retain complementary roles in pathological confirmation, regional staging, exclusion of alternative causes, and characterization of atypical phenotypes. Retinal, electrophysiological, speech, sleep, and eye-tracking measures remain promising but require greater standardization and external validation. Across modalities, biomarker trajectories are temporally staggered, assay and platform differences affect interpretation, and pathology-phenotype mapping is modified by disease stage, cognitive reserve, copathology, vascular factors, and population characteristics. We therefore propose a phenotype-anchored, stepped pathway that begins with patient and informant history, objective cognitive and functional assessment, structural imaging, and routine laboratory evaluation; adds validated blood biomarkers when they resolve a defined uncertainty; and reserves CSF or PET for unresolved, atypical, or treatment-relevant cases. Discordant findings should prompt reassessment rather than automatic reclassification. We describe the literature-search and descriptive evidence-categorization approach used to select and categorize the evidence reviewed, and we place the findings within the emerging regulatory context of blood-based testing. Clinical translation will depend on harmonized thresholds, representative prospective cohorts, calibration, independent validation, and evidence that multimodal systems improve decisions and patient outcomes rather than benchmark accuracy alone.},
}

@article {pmid42923644,
year = {2026},
author = {Wang, R and Zhu, B and Guo, Q and Huang, JS and Zhang, W},
title = {Neuromodulatory interventions for Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1925914},
pmid = {42923644},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) and mild cognitive impairment (MCI) represent an escalating global public health challenge with major socioeconomic consequences. Although anti-amyloid monoclonal antibodies have introduced disease-modifying treatment options for early symptomatic AD, their benefits remain modest and must be balanced against cost, monitoring burden, and safety risks. Neuromodulatory interventions have therefore emerged as promising investigational strategies that may complement existing therapeutic approaches. This narrative review evaluates current clinical and neurophysiological evidence for seven major neuromodulation approaches: 40 Hz gamma rhythm sensory stimulation, also known as gamma entrainment using sensory stimulation (GENUS), transcranial alternating current stimulation (tACS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), focused ultrasound (FUS), deep brain stimulation (DBS), and transcranial photobiomodulation (tPBM). Integrating clinical findings with mechanistic evidence, we examine synaptic plasticity, neuroinflammation, glymphatic clearance, oscillatory entrainment, and cholinergic signaling as candidate therapeutic mechanisms. A comparative matrix summarizes target specificity, invasiveness, stimulation parameters, and translational status. Finally, we discuss key barriers, including biological heterogeneity, protocol standardization, durability of benefit, caregiver burden, and the uncertain implications of continuous network stimulation for future personalized and closed-loop interventions.},
}

@article {pmid42925434,
year = {2026},
author = {Shah, A and Godad, A and Bagwe Parab, S},
title = {Unlocking therapeutic potential of Wnt signaling pathway in neurodegenerative diseases.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42925434},
issn = {1573-7365},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Wnt Signaling Pathway/drug effects/physiology ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The Wnt Signaling pathway is a regulatory network that is highly conserved in the central nervous system and is essential for the survival of neurons, synaptic plasticity, and the blood-brain barrier's integrity. The pathophysiology of major neurodegenerative and neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), is highly influenced by canonical and non-canonical Wnt Signaling dysregulation, according to increasingly compelling evidence. In addition to emphasising common molecular events such as GSK-3β overactivation, β-catenin destabilisation, neuroinflammation, synaptic dysfunction, and BBB disruption, this study offers a comparative and mechanistic overview of Wnt pathway changes across various illnesses. This article identifies overlapping treatment targets, such as GSK-3β, DKK1, LRP5/6, and Wnt ligands, by integrating common and disease-specific Wnt-associated pathways, in contrast to traditional disease-specific reviews. Furthermore, new translational approaches involving natural substances, Wnt modulators, and pathway-targeted treatments are critically examined. All things considered, this study presents Wnt Signaling as a potential neuroprotective and regenerative target for upcoming precision-based treatments in neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Wnt Signaling Pathway/drug effects/physiology
Animals
Blood-Brain Barrier/metabolism/drug effects

@article {pmid42925515,
year = {2026},
author = {Zhang, T and Xu, L and Huang, W and Chen, Z and Miao, J and Zhang, Y and Zhu, Y and Yuan, Y and Gu, X},
title = {Amelioration of early pathological changes in the 3xTg-AD mouse model: Mechanism of action of the Chinese herbal formula Tianqi Granules.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRRONLINE-D-26-00875},
pmid = {42925515},
issn = {1673-5374},
abstract = {Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline. This study investigated the effects of the Chinese herbal formula Tianqi Granules on early pathological progression in the 3xTg-AD mouse models and investigated the underlying mechanisms. After 31 days of Tianqi Granule treatment initiated at 5 months of age, Tianqi Granules-treated mice showed improved performance in the open-field test, novel object recognition test, and Morris water maze test. Amyloid deposition and glial activation were attenuated, and immunoreactivity for interleukin-1β and LC3 was reduced. Hippocampal transcriptome sequencing at multiple time points showed that, in untreated mice, early pathological progression occurred in three successive phases, with the dominant processes shifting from compensatory programs to failing homeostasis and subsequently to degenerative changes. Tianqi Granule treatment was associated with a three-phase response centered on the restoration of homeostasis and involving proteostasis, nuclear processes, lipid and carbohydrate metabolism, and redox-related pathways. Multiple biological domains were engaged rather than a single target. In males, an interferon-related program associated with Irf7 was induced early and shifted in the opposite direction under Tianqi Granule treatment during the same time window. Network pharmacology identified OPRK1 as the only candidate target shared by both sexes, making it a potential target for future investigation. These findings suggest that Tianqi Granule modulates the pathology of Alzheimer's disease through coordinated actions on multiple targets and may influence systemic metabolic homeostasis, providing experimental support for early therapeutic intervention in Alzheimer's disease.},
}

@article {pmid42926064,
year = {2026},
author = {Marick, A and Reddy, PH and Manna, PR},
title = {Restoration of StAR-governed neurosteroids with all-trans retinoic acid in alleviating cognitive deficits in a humanized amyloid-β knock-in mouse model of late-onset Alzheimer's disease: New insights into therapeutics.},
journal = {Neurochemistry international},
volume = {201},
number = {},
pages = {106280},
doi = {10.1016/j.neuint.2026.106280},
pmid = {42926064},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder of the elderly characterized by cognitive decline that involves diverse pathological processes. Aging, modulating neuronal instability, is the primary risk factor AD, resulting in dementia, for which a crucial neuropathological feature is the accumulation of amyloid-β (Aβ) plaques wherein suppression of neurosteroids plays important roles. Neurosteroidogenesis gradually decreases during aging, and the regulation of neurosteroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. We demonstrate that treatment with all-trans retinoic acid (atRA, 20 mg/kg, 12-weeks) in humanized Aβ knock-in (hAbKI) mice (11-month old) resulted in increases in hippocampal StAR and sex neurosteroid (estradiol-17β/(E2) in females and testosterone in males) levels, when compared with controls. Elevated StAR and sex neurosteroid levels were associated with reductions in not only Aβ accumulation but also toxic soluble Aβ1-40 and Aβ1-42 peptides in both sexes, emphasizing an inverse correlation between neurosteroidogenesis and AD pathogenesis. Notably, atRA was capable of ameliorating cognitive impairments in both female and male hAbKI mice, as evaluated by Morris Water Maze analyses. These findings provide insights into the mechanistic events by which atRA restores neurosteroid instability, reduces neurotoxicity, and alleviates cognitive impairments in sex-specific hAbKI mice, demonstrating that retinoid therapy could serve as a novel target for the management of AD-related dementia for healthy aging.},
}

@article {pmid42926678,
year = {2026},
author = {Elia, A and Vazquez-Torres, R and Carey, A and Wolf, M and Gade, VR and Alves, M and Fossati, S},
title = {Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer's mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic-signaling impairment.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.757731},
pmid = {42926678},
issn = {2692-8205},
abstract = {FDA-approved carbonic anhydrase inhibitors (CAIs) have shown robust efficacy in reducing amyloid-β (Aβ) pathology, neurodegeneration, and cerebrovascular dysfunction in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) models, highlighting carbonic anhydrase (CAs) as a promising, previously untapped therapeutic target for AD and vascular contribution to dementia. We have recently shown that Aβ aggregates disrupt neuro-signaling and deplete neurotrophic factors (particularly BDNF) in the heart of AD mouse models and human subjects. In this study, we present the first in-depth examination of CAI therapy (acetazolamide-ATZ) in Tg2576 mice, a well-established model of AD and CAA. We confirm that progressive cardiac fibrosis and Aβ deposition in 13-month-old mice severely impair the cardiac neuro-signaling system, marked by a drastic decrease in BDNF and reductions in adrenergic fibers and regenerating nerve endings (TH and GAP-43 markers), leading to significant declines in ejection fraction and fractional shortening compared to age-matched WT littermates. Critically, this study demonstrates that long-term ATZ treatment in Tg2576 mice significantly reduces cardiac Aβ burden, prevents adverse neuro-signaling remodeling, and restores heart physiological function, as assessed via speckle tracking strain echocardiography. These in vivo findings were corroborated in human cardiomyocytes, in which CA inhibition reduced human Aβ40 oligomer-dependent disruption of CREB signaling, thus preserving BDNF expression. Together, these results reveal a previously unrecognized cardio-neuroprotective role for CAIs in preventing Aβ-induced cardiovascular remodeling and neuro-signaling disruption in the Tg2576-AD model. Given the established benefits of CAIs on cerebrovascular function and cognition, our findings further support advancing repurposing efforts into clinical trials. CAIs such as ATZ could offer a dual-action therapy approach, addressing both the central nervous system and cardiac pathologies associated with AD and, potentially, the systemic effects of amyloidosis.},
}

@article {pmid42927299,
year = {2026},
author = {Gil, N and Naik, P and Koran, ME and Silverman, D and Kako, B and Chen, J},
title = {PET-based molecular imaging in neurodegeneration and dementia: current and emerging radiotracers.},
journal = {Radiology advances},
volume = {3},
number = {5},
pages = {umag046},
pmid = {42927299},
issn = {2976-9337},
abstract = {Positron emission tomography (PET)-based molecular imaging is a clinically important tool for the evaluation of dementia and other neurodegenerative disorders, using radiotracers that target specific molecular and pathophysiological processes. Fluorodeoxyglucose brain PET has historically supported neurodegenerative disorder evaluation through detection of characteristic patterns of regional glucose hypometabolism. In recent years, the molecular imaging of protein aggregates has taken on an increasingly important role. This is evident with the widespread clinical adoption of amyloid PET and early use of tau PET to provide diagnostic and prognostic information for patients with suspected Alzheimer's disease. Additional classes of radiotracers relevant to neurodegenerative diseases are under active investigation, including those targeting neuroinflammation, synaptic density, and α-synuclein aggregates. We review the major classes of PET radiotracers for neurodegenerative diseases, describing their molecular mechanisms, diagnostic performance, and their current and emerging clinical roles in dementia evaluation. Case examples for clinically used tracers illustrate imaging features relevant to diagnosis and characterization of prognosis and treatment effect. Finally, we discuss early developments and current challenges in the development of theranostic approaches and novel radiotracers for neurodegenerative diseases.},
}

@article {pmid42927368,
year = {2026},
author = {Kandilas, A and Samolis, A and Kalamatianos, T and Margaritis, I and Tsakotos, G and Triantafyllou, G and Piagkou, M},
title = {Network Neuroanatomy of Self-Awareness: A Narrative Review of Self-Referential Processing, Metacognition, and Embodiment.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e116848},
pmid = {42927368},
issn = {2168-8184},
abstract = {Self-awareness encompasses the capacity to recognize and evaluate information about oneself, including mental states, actions, autobiographical history, and bodily experience. Although closely related to consciousness, autobiographical memory, metacognition, clinical insight, anosognosia, and bodily self-consciousness, these constructs are not interchangeable. This focused narrative review synthesizes human neuroanatomical and neuroimaging evidence identified through a targeted PubMed/MEDLINE search covering January 1997 to August 15, 2026, supplemented by reference-chain searching. To improve methodological transparency, the revised review specifies eligibility principles, the narrative synthesis strategy, and reproducible domain-specific Boolean search strings; because the article is a narrative rather than a systematic review, no protocol registration, PRISMA screening flow, formal study-level risk-of-bias assessment, or quantitative pooling was undertaken. The evidence is organized into four interacting domains: self-referential representation, autobiographical continuity, metacognitive monitoring, and embodied self-processing. Cortical midline and default mode regions are prominent in self-referential evaluation; medial temporal systems support autobiographical information; anterior and lateral prefrontal and frontoparietal regions contribute to monitoring and updating; and temporoparietal, precuneal, insular, and sensorimotor regions contribute to bodily self-processing. Importantly, these macroscopic territories overlap and contain functionally heterogeneous subregions, so the proposed mappings represent network-weighted tendencies rather than one-to-one anatomical assignments. Clinical findings further show that anosognosia in Alzheimer's disease, impaired insight in schizophrenia, altered self-experience in depersonalization-derealization disorder, and awareness deficits after acquired brain injury (ABI) involve different combinations of these processes. We therefore propose a representation-memory-monitoring-embodiment framework as a heuristic neuroanatomical synthesis, not a diagnostic or treatment model. Its value lies in separating constructs often grouped under the term self-awareness and in generating testable hypotheses for longitudinal multimodal imaging, lesion mapping, causal studies, and construct-matched interventions.},
}

@article {pmid42929812,
year = {2026},
author = {Zhang, N and Freeman, DD and Polster, BM},
title = {BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the "Hole" Story?.},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
pmid = {42929812},
issn = {2073-4409},
support = {R01NS112212/NS/NINDS NIH HHS/United States ; R21NS133527/NS/NINDS NIH HHS/United States ; R21 NS133527 (B.M.P.)./NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *DNA, Mitochondrial/metabolism ; Animals ; *bcl-2-Associated X Protein/metabolism ; *Mitochondrial Permeability Transition Pore/metabolism ; *Voltage-Dependent Anion Channels/metabolism ; Mitochondria/metabolism ; *Inflammation/metabolism ; },
abstract = {Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.},
}

Humans
*DNA, Mitochondrial/metabolism
Animals
*bcl-2-Associated X Protein/metabolism
*Mitochondrial Permeability Transition Pore/metabolism
*Voltage-Dependent Anion Channels/metabolism
Mitochondria/metabolism
*Inflammation/metabolism

@article {pmid42930485,
year = {2026},
author = {Huang, D and Lu, R and Sheng, C and Zheng, J and Wang, Y and Sang, Z},
title = {Therapeutic Potential of Marine Natural Products Against Alzheimer's Disease: Molecular Mechanisms, Druggability Evaluation and Clinical Translation Barriers.},
journal = {Marine drugs},
volume = {24},
number = {10},
pages = {},
pmid = {42930485},
issn = {1660-3397},
support = {22367007//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Biological Products/pharmacology/therapeutic use/chemistry/pharmacokinetics ; Animals ; *Aquatic Organisms/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Blood-Brain Barrier/metabolism ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder with complex multifactorial pathological cascades, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, sustained neuroinflammation, oxidative stress, cholinergic dysfunction and gut-brain axis imbalance. Current marketed anti-AD drugs merely relieve symptomatic cognitive impairment without halting or reversing disease progression, highlighting an urgent demand for novel multi-target therapeutic candidates. Marine ecosystems, covering 71% of the Earth's surface, generate structurally unique, low-toxicity secondary metabolites via adaptive metabolic pathways of marine algae, invertebrates and microorganisms, which represent promising lead compounds for developing marine anti-AD therapeutics with synergistic multitarget neuroprotective activities. This systematic review comprehensively summarizes the anti-AD bioactivities and underlying molecular mechanisms of seven major categories of marine natural products, including marine polysaccharides, terpenoids, macrolides, alkaloids, polyphenols and carotenoids, sterols/lipids, and aminosulfonates. We further perform an integrated ADMET druggability assessment of representative marine bioactive molecules to evaluate their blood-brain barrier penetration, oral absorption, physicochemical properties and toxicological risks, identifying homotaurine as the most balanced candidate with favorable central nervous system delivery and safety profiles. We also elaborate the core bottlenecks restricting clinical translation, including insufficient blood-brain barrier permeability and unsatisfactory in vivo pharmacokinetic behaviors of most marine-derived compounds. Finally, we outline future research directions, covering structural modification, nanocarrier delivery, gut-brain axis-targeted intervention and cross-disciplinary translational research. This work aims to provide a comprehensive theoretical reference for the discovery, optimization and clinical transformation of marine anti-Alzheimer drugs, and facilitate high-value exploitation of marine bioactive resources for neurodegenerative disease treatment.},
}

*Alzheimer Disease/drug therapy
Humans
*Biological Products/pharmacology/therapeutic use/chemistry/pharmacokinetics
Animals
*Aquatic Organisms/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Blood-Brain Barrier/metabolism

@article {pmid42931616,
year = {2026},
author = {Capobianco, M and Zeppieri, M and Nicolosi, SG and Castellino, N and Cappellani, F and Gattazzo, I and Gagliano, C},
title = {Translational Applications of Retinal Biomarkers in Chronic Cardiovascular, Neurological, Metabolic, and Renal Diseases.},
journal = {Vision (Basel, Switzerland)},
volume = {10},
number = {4},
pages = {},
pmid = {42931616},
issn = {2411-5150},
abstract = {Imaging the retina is a powerful non-invasive probe of systemic vascular, neurological, metabolic, and renal disease, making it a cornerstone of the new field of systemic oculomics. Advanced retinal imaging techniques like optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) provide detailed imaging of structural and microvascular changes potentially associated with systemic disease. Derived from fundus photography, structural imaging, vascular imaging, and artificial intelligence-based image analysis, retinal biomarkers have been associated with cardiovascular and cerebrovascular disease, neurodegenerative disorders, diabetes, chronic kidney disease, and related clinical outcomes. However, the translational maturity of these biomarkers is variable depending on imaging modality, target disease, intended clinical use, and level of validation. Longitudinally, retinal vascular characteristics have been associated with cardiovascular as well as cerebrovascular outcomes. In addition, optical coherence tomography has provided reproducible measures of neuroaxonal injury in selected neurological conditions. This is especially true for multiple sclerosis. The majority of retinal biomarkers in Alzheimer disease, Parkinson disease, chronic kidney disease, and systemic risk prediction remain experimental because of heterogeneous methodologies, insufficient external validation, and insufficient evidence for incremental clinical utility. Diabetes is the most developed translational model with established retinal screening pathways and validated ocular applications of imaging and artificial intelligence, although these cannot be directly extrapolated to systemic diagnosis or treatment guidance. This narrative review assesses retinal biomarkers for cardiovascular, neurological, metabolic, and renal disease with a focus on analytical validity, clinical validity, incremental value, clinical utility, and implementation. The retina is increasingly accepted as a site for discovery of systemic biomarkers and adjunctive risk assessment, although most applications to systemic disease remain to be standardized, validated independently, and studied prospectively before being suitable for routine clinical use.},
}

@article {pmid42932621,
year = {2026},
author = {Ketcham, JD},
title = {Artificial Intelligence as a Return on Investment Multiplier in Health Care.},
journal = {NEJM AI},
volume = {3},
number = {6},
pages = {AIpc2600139},
doi = {10.1056/AIpc2600139},
pmid = {42932621},
issn = {2836-9386},
mesh = {Humans ; *Artificial Intelligence ; Alzheimer Disease/therapy/economics ; *Delivery of Health Care/economics ; Value-Based Health Care ; },
abstract = {AbstractIn heterogeneous clinical populations, the clinical and economic value of therapies depends on how they are allocated. Predictive artificial intelligence (AI) models can improve the precision of treatment allocation beyond what earlier clinical decision support tools could achieve by integrating data across clinical, biomarker, imaging, and administrative domains simultaneously. This capacity can increase the realized value of existing and emerging therapies relative to the status quo by improving two types of treatment decisions: risk-based targeting, which concentrates treatment among patients at higher baseline risk, and response-based targeting, which identifies patients with greater expected treatment benefit. Both mechanisms reduce effective numbers needed to treat (NNT) and improve return on investment (ROI), reducing low-value care and strengthening incentives to develop therapies for well-defined patient subgroups. We illustrate this argument using remote physiological monitoring and Alzheimer's disease - two settings where current deployment heuristics produce high effective NNT and limited ROI, and where improved predictive targeting could materially improve the economic conclusion. Realizing this potential depends on data governance, incentives, and regulatory pathways that support the development, continuous refinement, and clinical integration of predictive models. Framing predictive AI as an ROI multiplier on the therapies it guides has broader consequences for how those therapies are developed, regulated, priced, and covered, and for how predictive AI models themselves should be valued and evaluated.},
}

Humans
*Artificial Intelligence
Alzheimer Disease/therapy/economics
*Delivery of Health Care/economics
Value-Based Health Care

@article {pmid42933736,
year = {2026},
author = {Chakraborty, W and Anand, A and Kumar, S and Roy, KK},
title = {Circadian aging and neurodegeneration: the emerging role of the melatonin-cortisol axis in brain homeostasis, disease progression, and precision chronomedicine.},
journal = {Frontiers in neuroendocrinology},
volume = {83},
number = {},
pages = {101292},
doi = {10.1016/j.yfrne.2026.101292},
pmid = {42933736},
issn = {1095-6808},
abstract = {Circadian aging may promote neurodegenerative illnesses by dysregulating the melatonin-cortisol axis. Low nighttime melatonin synthesis, blunted cortisol circadian cycles, abnormal clock-gene oscillation patterns, and sleep-wake architecture undermine central and peripheral circadian equilibrium with age. Neuroendocrine alterations produce oxidative stress, mitochondrial failure, pervasive neuroinflammation (CNS immune function loss), and proteostasis. Increasing Alzheimer's, Parkinson's, ALS, Huntington's, frontotemporal dementia, Lewy body disease, PTSD, and vascular cognitive impairment due to impaired glymphatic axonal clearance/blood-brain barrier dysregulation/synaptic degeneration/pathoproteopathic protein We examine how clock genes, melatonin signaling, hypothalamic-pituitary-adrenal axis administration, microglia reactivity, and immune-mediated metabolic dysregulation affect dementia. New endocrine, transcriptomic, multi-omics, and wearable-derived digital biomarkers, chronopharmacology (including melatonin receptor agonists), bright-light therapy, time-restricted eating with exercise chronotherapy guidance/synchronization, sleep optimization, and gut microbiota modulation This study addressed inter-individual circadian variability, genetic susceptibility to therapy timing, biomarker standardization, and clinical trial design. The melatonin-cortisol axis may identify and treat age-related neurodegenerative diseases with tailored treatment.},
}

@article {pmid42933739,
year = {2026},
author = {Tian, Y and Guo, J and Lin, X and Zhang, F and Xie, J and Hou, X and Deng, J and Hao, E and Du, Z},
title = {Mechanisms of Traditional Chinese Medicine-Derived Active Components in the Treatment of Alzheimer's Disease: A Comprehensive Review.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122574},
doi = {10.1016/j.jep.2026.122574},
pmid = {42933739},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and multifactorial pathology. Because AD involves interacting pathological processes, the limited efficacy of conventional single-target therapies has increased interest in traditional Chinese medicine (TCM) and other natural medicines with multi-target pharmacological actions. TCM-derived active components originate from medicinal materials used in traditional practice and are evaluated using modern pharmacological approaches. Their source medicines have diverse traditional-use backgrounds. Some have historical associations with memory or cognitive symptoms, whereas many others were traditionally used for broader deficiency, phlegm, blood-stasis, heat, or related syndromic patterns. These records provide ethnopharmacological context for the source medicines but should not be taken as historical evidence for the anti-AD activity of their isolated constituents.

AIM OF THE REVIEW: This review synthesizes current evidence on the mechanisms of TCM-derived bioactive components in AD while incorporating relevant traditional-use information on their source medicines. Particular attention is given to their multi-target actions and emerging mechanisms involving ferroptosis, mitophagy, and the gut-brain axis.

MATERIALS AND METHODS: Mechanistic literature published between January 2019 and November 2025 was retrieved from Ovid MEDLINE, PubMed, ScienceDirect, and Web of Science. Ovid MEDLINE and PubMed were searched separately to maximize retrieval across indexed and additional PubMed records, with overlapping records removed during deduplication. Traditional-use information was evaluated separately for the source medicines. A targeted search of PubMed and ClinicalTrials.gov was also conducted to assess human interventional evidence for compounds covered in the review, with trial-registration information updated through August 2026.

RESULTS: Current preclinical findings suggest that TCM active components may produce coordinated preclinical pharmacological effects through multiple pathways, including the inhibition of β-amyloid (Aβ) production and deposition, regulation of tau aggregation and phosphorylation, alleviation of neuroinflammation and oxidative stress, improvement of mitophagy and iron metabolism disorders, and modulation of gut microbiota homeostasis. Among these components, saponins show broad mechanistic coverage. Flavonoids, polysaccharides, and other bioactive substances have likewise shown anti-inflammatory and antioxidant activities, together with protective effects on synaptic function, in preclinical models. These mechanistic findings were derived predominantly from cellular and animal studies, with computational analyses providing mainly hypothesis-generating support. Human evidence was available for only a small subset of compounds and was not uniformly positive. Huperzine A has progressed to controlled clinical testing but has shown mixed efficacy findings; resveratrol demonstrated CNS exposure and biomarker activity without consistent cognitive benefit; curcumin did not show efficacy in a placebo-controlled AD trial; and favorable signals from ginseng studies were limited by open-label designs and the use of whole preparations rather than isolated ginsenosides.

CONCLUSIONS: The available evidence supports broad preclinical activity of TCM-derived components across several interconnected AD-related processes, but the strength of mechanistic support varies markedly among compounds and pathways. Human translation remains limited and inconsistent, and current clinical data do not establish disease-modifying efficacy for the compounds reviewed. Further development should therefore be guided by the main uncertainty surrounding each candidate-whether mechanistic causality, reproducibility, systemic or CNS exposure, preparation standardization, or clinical efficacy-rather than by a fixed sequence of technologies.},
}

@article {pmid42934100,
year = {2026},
author = {Chen, L and Long, Y and Huang, D and Zheng, G and Meng, X},
title = {[Lead exposure aggravates Aβ1-42-induced microglial activation through mitochondrial calcium uniporter-mediated mitochondrial calcium accumulation].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {10},
pages = {2384-2392},
pmid = {42934100},
issn = {1673-4254},
support = {82473665//National NaturalScience Foundation of China/ ; },
mesh = {*Microglia/drug effects/metabolism ; *Amyloid beta-Peptides ; *Calcium Channels/metabolism ; Animals ; Mice ; *Peptide Fragments ; *Calcium/metabolism ; *Mitochondria/metabolism ; *Lead/toxicity ; Cell Line ; Oxidative Stress ; Nitric Oxide Synthase Type II/metabolism ; Alzheimer Disease ; },
abstract = {OBJECTIVES: To investigate the role of mitochondrial calcium uniporter (MCU) in lead (Pb)‑potentiated microglial activation induced by amyloid β‑protein (1-42) (Aβ1-42) and the regulatory mechanism by which Pb exacerbates Alzheimer disease (AD)-like pathology.

METHODS: Cultured BV2 cells treated with 10 μmol/L Aβ1-42 for 12 h (Aβ1-42 group), 10 μmol/L Pb for 12 h (Pb group), or 10 μmol/L Aβ1-42 for 1 h followed by 10 μmol/L Pb for 12 h (Aβ1-42+Pb group) were examined for changes in intracellular calcium levels using ICP-MS. Morphological changes of the treated cells were observed, and iNOS release and oxidative stress were assessed with immunofluorescence staining. The changes in cellular MCU protein expression was determined with Western blotting, and cell viability was evaluated using CCK-8 assay.

RESULTS: Compared with Aβ1-42-treated cells, the cells with the combined treatment showed significantly elevated mitochondrial Ca²⁺ content and increased MCU protein expression. Downregulation of MCU expression obviously alleviated the reduction of viability of HT22 cells treated with the supernatant from BV2 cells co-treated with Pb and Aβ1-42. The combined treatment with lead and Aβ1-42 caused activation of BV2 cells, manifested by increased cell volume and number of protrusions and intensified fluorescence signals of both Iba1 and iNOS. Downregulation of MCU expression significantly suppressed activation of BV2 cells in the siMCU+Aβ1-42+Pb group, and obviously lowered oxidative stress level, mitochondrial calcium overload, and membrane potential level in the cells.

CONCLUSIONS: Pb exposure exacerbates neuronal injury mediated by Aβ1-42-activated microglia through upregulation of MCU expression, which causes mitochondrial calcium accumulation to trigger oxidative stress.},
}

*Microglia/drug effects/metabolism
*Amyloid beta-Peptides
*Calcium Channels/metabolism
Animals
Mice
*Peptide Fragments
*Calcium/metabolism
*Mitochondria/metabolism
*Lead/toxicity
Cell Line
Oxidative Stress
Nitric Oxide Synthase Type II/metabolism
Alzheimer Disease

@article {pmid42934111,
year = {2026},
author = {Ruan, Y and Cui, C and Li, J and Wang, Y and Wang, X},
title = {[Jiaotaiwan improves lipid metabolism abnormalities in a mouse model of Alzheimer disease by regulating the AMPK signaling pathway].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {10},
pages = {2509-2517},
pmid = {42934111},
issn = {1673-4254},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; Male ; *Lipid Metabolism/drug effects ; *Signal Transduction/drug effects ; Mice ; *AMP-Activated Protein Kinases/metabolism ; *Drugs, Chinese Herbal/pharmacology ; Mice, Inbred C57BL ; Mice, Transgenic ; Disease Models, Animal ; Brain/metabolism ; PC12 Cells ; },
abstract = {OBJECTIVES: To explore whether Jiaotaiwan ameliorates Alzheimer disease (AD) by regulating lipid metabolism via the AMPK pathway.

METHODS: Twenty 3-month-old male transgenic APP/PS1 mice were randomized equally into two groups for treatment with Jiaotaiwan or normal saline via gavage for 4 weeks, with 10 saline-treated wild-type C57BL/6J mice as the control group. Brain lipid deposition, plasma and brain TC, TG and NEFA levels, and expressions of BACE1, Aβ, p-Tau, ZO-1, occludin, AMPK/p-AMPK, SREBP1, ACC, ATGL, and APOE in the brain tissues were detected. In the in vitro experiment, PC12 cell co-cultured with mature adipocytes were treated with Jiaotaiwan, AICAR, or both, and the intracellular lipid droplets, TG, NEFA, AMPK activity, and ACC expression were measured.

RESULTS: In the AD mouse models, Jiaotaiwan significantly reduced brain lipid deposits, lowered plasma TC and TG levels, increased plasma NEFA level, and decreased brain TG and NEFA expressions without affecting TC expression. Jiaotaiwan treatment also significantly lowered the expressions of cerebral Aβ and p-Tau, increased cerebral occludin expression and p-AMPK/AMPK ratio, and reduced ACC, SREBP1 and APOE expressions without affecting ATGL expression in the mouse models. In the co-cultured cells, Jiaotaiwan obviously alleviated cellular lipid accumulation, lowered cellular TG and NEFA levels, reduced supernatant TG content, and enhanced NEFA release. In both the AD mouse model and co-cultured cell model, Jiaotaiwan significantly lowered Aβ level, increased AMPK activity and p-AMPK/AMPK expression, and lowered the expressions of ACC. Jiaotaiwan combined with AICAR produced a synergistic effect for enhancing p-AMPK/AMPK expressions in the co-cultured cells.

CONCLUSIONS: In the APP/PS1 mouse model of AD, Jiaotaiwan alleviates AD-related lipid deposition and dysregulation by activating AMPK and modulating the downstream lipogenic effectors, providing also protective effects on the blood-brain barrier and neural cells.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy
Male
*Lipid Metabolism/drug effects
*Signal Transduction/drug effects
Mice
*AMP-Activated Protein Kinases/metabolism
*Drugs, Chinese Herbal/pharmacology
Mice, Inbred C57BL
Mice, Transgenic
Disease Models, Animal
Brain/metabolism
PC12 Cells

@article {pmid42934592,
year = {2026},
author = {Atri, A and Curiale, GG and Aisen, P and Barakos, J and Purcell, D and Bracoud, L and Haeberlein, SB and Grassi, C and Hughes, R and Smirnakis, K},
title = {Spectrum of amyloid-related imaging abnormalities associated with aducanumab treatment: a case series report.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {42934592},
issn = {1471-2377},
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Female ; Magnetic Resonance Imaging ; Male ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; *Brain/diagnostic imaging/drug effects/pathology ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) observed on magnetic resonance imaging (MRI) are known adverse events associated with beta-amyloid plaque-lowering monoclonal antibodies. A spectrum of radiographic and clinical presentations of ARIA have been observed. ARIA-E refer to vasogenic edema in the brain parenchyma and/or leptomeningeal/subpial sulcal effusion; ARIA-H refer to hemosiderin deposits including cerebral microhemorrhage and localized superficial siderosis. With clinical availability of anti-amyloid therapies for treatment of early clinical stage Alzheimer's disease, there is an important need for better awareness of ARIA and education among a diversity of clinicians and practice settings.

METHODS: To illustrate the wide spectrum of ARIA, we present the clinical history, course, and MRI findings as well as summarize learnings and implications of 10 ARIA-E cases from the aducanumab phase 3 clinical trials EMERGE and ENGAGE (ClinicalTrials.gov identifiers NCT02484547 and NCT02477800). Monitoring and management of ARIA, including criteria and timing of MRI, and drug dosing actions were defined per protocol and based upon radiographic severity and clinical symptoms associated with ARIA. ARIA were detected by MRI performed at pre-specified intervals or in response to symptoms or for safety follow-up reasons.

RESULTS: The majority of ARIA-E events were asymptomatic. Most ARIA-E events occurred within the first 8 aducanumab doses and generally resolved within 3-4 months whether dosing was continued (i.e. when ARIA-E was asymptomatic and of mild radiographic severity) or whether dosing was suspended or discontinued. Occasionally, ARIA-E were recurrent. ARIA-H (microhemorrhages and superficial siderosis) most commonly occurred concurrently with ARIA-E. However, ARIA-H without ARIA-E, termed isolated ARIA-H, occurred at a similar frequency in aducanumab- and placebo-treated groups. 10% of participants with ARIA in the 10 mg/kg group had accompanying symptoms. When present, symptoms of ARIA most frequently included headache, nausea, fatigue, dizziness, confusional state, and visual disturbance. Serious symptoms associated with ARIA were uncommon (occurring in 0.3% of the participants treated with the 10 mg/kg dose regimen).

CONCLUSIONS: These illustrative cases provide learnings into the nature and factors associated with ARIA that can increase knowledge for clinicians and trialists regarding the varied radiographic and clinical presentations and evolution of ARIA.

TRIAL REGISTRATION: Clinical Trials NCT02484547, registered June 18, 2015, https://clinicaltrials.gov/study/NCT02484547 . Clinical Trials NCT02477800, registered June 18, 2015, https://clinicaltrials.gov/study/NCT02477800 .},
}

Humans
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use
Female
Magnetic Resonance Imaging
Male
Aged
*Alzheimer Disease/drug therapy/diagnostic imaging
*Brain/diagnostic imaging/drug effects/pathology
Middle Aged
Aged, 80 and over

@article {pmid42934641,
year = {2026},
author = {Li, S and Gu, J and Xu, Z and He, C and Yu, C},
title = {Advances in modified anti-Aβ antibodies for the treatment of Alzheimer's disease.},
journal = {BMC medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42934641},
issn = {1741-7015},
support = {82460264//the National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy/immunology ; Humans ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Animals ; Antibodies, Bispecific/therapeutic use ; *Antibodies, Monoclonal/therapeutic use ; Blood-Brain Barrier/metabolism ; Immunotherapy/methods ; Immunoconjugates/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder, the treatment of which remains a major clinical challenge. In recent years, significant progress has been made in the immunotherapy of AD. Notably, monoclonal antibodies targeting amyloid-β (Aβ) have already been applied in clinical practice. However, as macromolecular therapeutics, antibodies face substantial challenges in crossing the blood-brain barrier (BBB) efficiently. Systemic administration typically requires high dosages to achieve the therapeutic level of brain exposure, which may trigger adverse events such as amyloid-related imaging abnormalities (ARIA) and thus restrict their widespread clinical application. To resolve this problem, various engineering strategies for modifying anti-Aβ antibodies have been developed. This review summarizes four major modification categories: BBB-penetrating bispecific antibodies (BsAbs), glycosylation engineering, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-based cell therapies (including CAR-macrophages, CAR-T cells, and CAR-astrocytes). We provide an in-depth discussion of their delivery efficiency, targeting capability, and safety, aiming to lay a foundation for developing safer and more effective next-generation anti-Aβ antibody therapeutic strategies.},
}

*Alzheimer Disease/therapy/drug therapy/immunology
Humans
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Animals
Antibodies, Bispecific/therapeutic use
*Antibodies, Monoclonal/therapeutic use
Blood-Brain Barrier/metabolism
Immunotherapy/methods
Immunoconjugates/therapeutic use

@article {pmid42921194,
year = {2026},
author = {Li, J and Wang, WJ and Chen, H and Sun, JQ and Zhong, WJ and Guan, CX and Zhou, Y},
title = {B-Cell-Related Neuroinflammation Across Central Nervous System Diseases: A Bibliometric and Science-Mapping Analysis, 2006-2026.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {635719},
pmid = {42921194},
issn = {1178-7031},
abstract = {PURPOSE: Research on B cells in central nervous system (CNS) diseases rests on a mature multiple sclerosis (MS) literature, whereas evidence in CNS injury and neurodegeneration is still emerging. We mapped publications from 2006 to 2026 and separated bibliometric visibility from mechanistic maturity.

METHODS: We searched the Web of Science Core Collection (WoSCC) on August 17, 2026, for English-language records carrying the Article document-type tag and published from January 1, 2006, through August 17, 2026. Two reviewers independently screened all records, with unresolved disagreements adjudicated by a third reviewer. Publication trends, collaboration, co-citation, journal flows, citation bursts, and keyword evolution were analyzed using VOSviewer, CiteSpace, bibliometrix, R, and SCImago Graphica. Search materials, parameters, and source tables were archived.

RESULTS: After database-level limits, 2,701 records were screened; 467 (17.3%) were excluded and 2,234 (82.7%) included. The corpus had accrued 91,218 WoSCC citations. Annual output rose from 91 articles in 2016 to 231 in 2025; 173 articles from 2026 represent a partial year. The United States contributed the most articles, and the University of California, San Francisco ranked first after affiliation normalization. Co-citation and keyword analyses showed an MS/experimental autoimmune encephalomyelitis (EAE)-centered foundation built around B-cell depletion trials, meningeal pathology, diagnostic criteria, and regulatory B-cell biology. Recent bursts included anti-CD20 therapy, single-cell RNA sequencing, autoimmune encephalitis, ischemic stroke, Mendelian randomization, B-cell depletion, and Alzheimer disease.

CONCLUSION: B-cell-related CNS research has expanded, but evidence maturity remains disease-specific. MS/EAE provides the clearest foundation. Findings in CNS injury, neurodegeneration, and candidate peripheral-CNS routes remain context-dependent and require validation by disease, anatomical compartment, B-cell state, and stage. Bibliometric prominence reveals attention, not shared causality or therapeutic efficacy.},
}

@article {pmid42921272,
year = {2026},
author = {He, Z and Zeng, J and Wang, G and Li, Y and Zhang, F},
title = {Neurodegenerative Diseases: Epidemiology, Risk Factors, Classification, Pathophysiology, Clinical Features, Diagnosis, and Therapeutic Strategies.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71090},
pmid = {42921272},
issn = {2688-2663},
abstract = {Neurodegenerative diseases are a growing cause of disability worldwide, particularly as populations age. Although these disorders differ in etiology and clinical presentation, advances in genetics, neuropathology, and biomarker research have identified shared disturbances in protein homeostasis, mitochondrial function, and immune regulation. These processes may contribute to selective neuronal vulnerability and neural circuit dysfunction. These findings are refining disease classification and diagnosis, yet effective disease-modifying therapies remain limited. Disease-specific abnormalities remain essential to clinical interpretation and treatment selection. Existing reviews often focus on individual disorders or isolated mechanisms, leaving the links between shared biology and disease-specific phenotypes insufficiently clear. We synthesize evidence on the epidemiology, risk factors, classification, and pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal dementia, Friedreich's ataxia, and multiple sclerosis. We compare their clinical manifestations and diagnostic approaches, including the evolving role of biomarkers, and critically assess established and emerging therapies. By distinguishing shared mechanisms from disease-specific abnormalities, we identify key translational gaps and explore how common biological disturbances may lead to distinct clinical trajectories. This cross-disease perspective may inform diagnostic reasoning, treatment development, and future comparative research.},
}

@article {pmid42921589,
year = {2025},
author = {Zhang, Y and Bobryk, P and Morrow, SA and Wilken, J and Marrie, RA and Bainbridge, J and Stewart, R and Stacom, R and Bostick, MD and Choman, MT and Foley, FW and Corboy, JR and Newsome, SD and Hua, LH and Graves, JS},
title = {Age-Related Changes in Multiple Sclerosis Pathophysiology and Clinical Function.},
journal = {International journal of MS care},
volume = {27},
number = {Suppl 2},
pages = {T53-T58},
pmid = {42921589},
issn = {1537-2073},
abstract = {Older adults with multiple sclerosis (MS) face unique issues related to the combined effects of MS and age-related changes, which often present with overlapping symptoms that complicate assessment and treatment decisions. In this review, based on the Consortium of MS Centers' Aging and MS Consensus Statement committee meeting in 2024, we address the contributions of aging in MS by focusing on direct, biological aging effects on MS pathology and comorbid age-related changes in physical and cognitive function. Features of biological aging include cellular senescence and immune dysregulation, which may drive disease progression in MS through a variety of proinflammatory mediators that may maintain low levels of chronic inflammation in the immune and central nervous system compartments and offset regulatory processes, ultimately impairing remyelination and increasing neurodegeneration. Measuring biological aging in MS may help identify individuals at risk of worse MS outcomes and support gerotherapeutic treatments that target aging mechanisms. Compounding any direct effects of aging on MS pathology, aging-related impairments in neuromuscular function and cognition can worsen functional outcomes in people with MS. Characteristics of cognitive impairments in MS affecting attention and processing speed occur early in the disease course and are distinct from other age-associated neurodegenerative disorders, such as Alzheimer disease, that commonly affect language and executive function domains. As MS clinicians care for growing numbers of older adults with MS, a more comprehensive understanding of the interplay between aging and MS-related changes can improve the timing and modality of treatments to optimize MS neurogeriatric care.},
}

@article {pmid42921714,
year = {2026},
author = {Renwick, R and Rossmann, C and Patterson, S and Gabbert, J},
title = {Pharmacist role in transforming Alzheimer's care: Anti-amyloid therapy experience at Vanderbilt University Medical Center.},
journal = {American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists},
volume = {},
number = {},
pages = {},
doi = {10.1093/ajhp/zxag359},
pmid = {42921714},
issn = {1535-2900},
abstract = {PURPOSE: Anti-amyloid infusion therapies are a new and complex treatment option for patients with Alzheimer's disease. Use of lecanemab or donanemab requires specific diagnostic criteria and frequent ongoing monitoring that requires in-depth coordination of care. We describe how neurology clinical pharmacists were an integral part of adoption of anti-amyloid therapy at our institution. With implementation of this service by pharmacists, we describe the impact on patient outcomes for those receiving anti-amyloid infusions and several aspects of impact on the health system as a whole that pharmacists should anticipate with these complex infusions.

SUMMARY: Neurology clinical pharmacists dedicated to infusions therapies are responsible for many aspects of use of anti-amyloid therapies, including order entry, patient counseling, Centers for Medicare and Medicaid Services (CMS) registry submission, infusion scheduling, and coordination of magnetic resonance imaging. At our institution, the first year of anti-amyloid infusions included 58 patients starting infusions. Safety and adverse effects, including amyloid-related imaging abnormalities, were similar to those previously reported in the primary literature. The majority of patients utilized Medicare as their primary coverage for infusions, and we describe successful navigation of the unique CMS registry requirement for billing.

CONCLUSION: Adoption of anti-amyloid therapies by a health system requires unique aspects of coordination not previously encountered. Clinical pharmacists are positioned to successfully coordinate care for patients receiving anti-amyloid infusions.},
}

@article {pmid42921942,
year = {2026},
author = {Zi, M and Ye, Q and Yao, M and Feng, J and Meng, S and Wu, X and Jiang, H and Yang, F and Huang, Y and Hu, X and Ma, C and Zheng, J and Zeng, S and Li, H},
title = {Pathogenesis and therapeutic targets of neuroinflammation in Alzheimer's disease mediated by microglia lysosomal dysfunction.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500025},
doi = {10.1177/13872877261500025},
pmid = {42921942},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by two core pathological features: senile plaques formed by amyloid-β protein (Aβ) deposits and neurofibrillary tangles formed by hyperphosphorylated tau protein. In recent years, neuroinflammation has been recognized as a key driver in the pathogenesis of AD, and microglia, as innate immune cells of the central nervous system, play a central role in regulating the onset and progression of neuroinflammation. Lysosomes are key organelles within microglia responsible for degrading pathological proteins and regulating inflammatory signaling; dysfunction of lysosomes in microglia severely impairs their ability to clear Aβ, damaged proteins, and cellular debris, thereby promoting inflammatory responses. This manuscript summarizes upstream mechanisms that may influence microglial lysosomal dysfunction from four perspectives: pathological proteins, genetic factors, lipid metabolism disorders, and proinflammatory cytokines. Pathological proteins can impair lysosomal acidification and biogenesis by interfering with key pathways such as the TFEB-v-ATPase axis; various genetic factors exacerbate functional dysregulation by influencing the expression of lysosome-related genes and lipid metabolism; lipid metabolism disorders promote lysosomal membrane permeabilization, block the autophagy cascade and activate the inflammasome; proinflammatory cytokines can exert varying effects on the clearance of pathological substrates and by regulating lysosomal function. The aforementioned factors can influence microglial lysosomal function through various mechanisms, thereby contributing to impaired clearance of pathological substrates and the onset and progression of neuroinflammation. Intervention strategies targeting microglial lysosomal dysfunction, including enhancing lysosomal degradation capacity, regulating autophagy related pathways, correcting cellular metabolic dysregulation and suppressing excessive neuroinflammation, may offer new avenues for AD treatment.},
}

@article {pmid42922329,
year = {2026},
author = {Izhytska, NV and Sobczyk, KA and Ogrodnik, KW and Mazurkiewicz, M and Malentowicz, D and Szafraniec, NJ},
title = {Effects of hyperbaric oxygen therapy in the treatment of selected diseases of the nervous system.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {8},
pages = {1982-1988},
doi = {10.36740/WLek/226613},
pmid = {42922329},
issn = {0043-5147},
mesh = {Humans ; *Hyperbaric Oxygenation ; *Nervous System Diseases/therapy ; Parkinson Disease/therapy ; Animals ; Diving and Hyperbaric Medicine ; Alzheimer Disease/therapy ; },
abstract = {Hyperbaric Oxygen Therapy (HBOT) has attracted increasing interest as a potential supportive intervention in neurological disorders. By increasing the amount of oxygen dissolved in blood plasma, HBOT enhances oxygen delivery to hypoxic tissues and may influence mechanisms involved in neuroplasticity, inflammation, and tissue repair. Experimental and clinical studies suggest that HBOT may support neurological recovery in selected conditions, particularly following ischemic or traumatic brain injury. However, the effectiveness of HBOT varies depending on the underlying disease, and further high-quality clinical studies are needed to establish its role in neurological rehabilitation.The article was based on an analysis of data from Google Scholar and PubMed regarding the effects of hyperbaric therapy.},
}

Humans
*Hyperbaric Oxygenation
*Nervous System Diseases/therapy
Parkinson Disease/therapy
Animals
Diving and Hyperbaric Medicine
Alzheimer Disease/therapy

@article {pmid42919002,
year = {2026},
author = {Singh, B and Rajapaksha, W and Koppisetti, H and Nakmode, D and Song, Y and Garg, S},
title = {PLGA-Phospholipid Hybrid Oleogel In Situ Forming Implant for Sustained 30-Day Co-Delivery of Dosnepezil and Memantine.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {8},
pages = {},
pmid = {42919002},
issn = {1530-9932},
mesh = {*Memantine/administration & dosage/chemistry ; Donepezil/administration & dosage/chemistry ; Animals ; Delayed-Action Preparations/chemistry/administration & dosage ; *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Mice ; Drug Liberation ; *Phospholipids/chemistry ; Gels/chemistry ; Sesame Oil/chemistry ; *Polyglycolic Acid/chemistry ; Viscosity ; Drug Carriers/chemistry ; Drug Implants/chemistry ; Chemistry, Pharmaceutical/methods ; Drug Delivery Systems/methods ; Cholinesterase Inhibitors/administration & dosage/chemistry ; Indans/administration & dosage/chemistry ; },
abstract = {The management of Alzheimer's disease requires continuous therapeutic intervention due to its progressive nature. Currently, the FDA has approved acetylcholinesterase inhibitors, NMDA receptor antagonists, and disease-modifying monoclonal antibodies for the treatment of Alzheimer's disease. This study aimed to develop a long-acting injectable formulation for symptomatic therapy. An in-situ gel formulation, DM00PG-M13, comprising Lipoid, PLGA (50:50), and sesame oil, was developed and loaded with memantine and donepezil for combination therapy. The optimized gel formulation demonstrated good uniformity with a pH of 7.80 ± 0.015. Rheological and syringeability studies showed a consistent viscosity in the range of 0.20-0.22 Pa·s and an injection force of 9.97 ± 0.29 N using a 22-G needle. In vitro drug release studies performed in phosphate-buffered saline (pH 7.4) demonstrated sustained drug release over one month, with cumulative releases of 82.58% for donepezil and 87.61% for memantine after 30 days. Furthermore, the release kinetics were best described by the Peppas-Sahlin model for donepezil and the Weibull-lag model for memantine. Ex vivo studies evaluating the optimized formulation injected into pig muscle tissue showed release profiles comparable to the in vitro release pattern, with approximately 20% release of donepezil and 26% release of memantine over 7 days, indicating sustained release behavior. Cytotoxicity studies using NIH/3T3 fibroblast cells confirmed the formulation's safety profile. Overall, these results suggest that the drug-loaded DM00PG-M13 formulation can be administered intramuscularly as a depot system for sustained drug release, potentially improving patient compliance.},
}

*Memantine/administration & dosage/chemistry
Donepezil/administration & dosage/chemistry
Animals
Delayed-Action Preparations/chemistry/administration & dosage
*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
Mice
Drug Liberation
*Phospholipids/chemistry
Gels/chemistry
Sesame Oil/chemistry
*Polyglycolic Acid/chemistry
Viscosity
Drug Carriers/chemistry
Drug Implants/chemistry
Chemistry, Pharmaceutical/methods
Drug Delivery Systems/methods
Cholinesterase Inhibitors/administration & dosage/chemistry
Indans/administration & dosage/chemistry

@article {pmid42919432,
year = {2026},
author = {Gaffke, L and Szulc, A and Podlacha, M and Myślińska, D and Pierzynowska, K and Węgrzyn, G},
title = {The use of three murine genetic models of Alzheimer's disease reveals efficacy of 4',5,7-trihydroxyisoflavone in alleviating cognitive deficits and reducing levels of amyloid-beta and hyperphosphorylated tau protein.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {42919432},
issn = {1738-6055},
support = {2024/53/B/NZ2/00225//Narodowe Centrum Nauki/ ; },
abstract = {BACKGROUND: Despite intensive studies on developing therapies for Alzheimer's disease (AD), there is still a need to improve the treatment efficacy. Results of recent studies indicated that genistein (4',5,7-trihydroxyisoflavone) was effective in an autophagy stimulation-dependent improving of cognitive deficits and reducing levels of amyloid-beta and hyperphosphorylated tau protein in brains, when employing a streptozotocin-induced rat model of the sporadic form of AD. Despite those encouraging results, the above-mentioned model has its limitations, mainly related to the rapid and inducible character of the symptoms caused by streptozotocin, induction of other effects (like diabetes) by this toxin, and the requirement for invasive administration of this compound to the brain, in contrast to naturally occurring AD. Thus, in this study, we hypothesized that genistein might be effective in reducing symptoms of AD in well-defined genetic models of this disease and tested the efficacy of this compound.

RESULTS: Three genetic models of AD were employed, including mouse lines 5xFAD, THY-Tau22, and 3xTg-AD. Orally administered genistein (at the dose of 150 mg/kg/day) considerably alleviated cognitive deficits (in spatial memory, learning, and long-term memory) of AD animals as estimated using the Morris water maze and the novel object recognition tests. Moreover, significantly reduced levels of amyloid-beta and hyperphosphorylated tau protein in plasma and brains were detected in genistein-treated AD animals relative to those treated with water.

CONCLUSIONS: We conclude that genistein revealed significant efficacy in ameliorating symptoms occurring in murine genetic models of AD. Thus, further studies towards the development of a genistein-based treatment for this disease are substantiated.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid42917927,
year = {2026},
author = {Mastnak-Sokolov, P and Košak, U and Meden, A and Knez, D and Žakelj, S and Horvat, S and Pišlar, A and Kljun, J and Igert, A and Dias, J and Nachon, F and Brazzolotto, X and Novak, M and Rydlova, V and Karasova, JZ and Soukup, O and Manik, A and Detka, J and Sałat, K and Gobec, S},
title = {Structure-Guided Design of a Brain-Penetrant Covalent Inhibitor of Human Butyrylcholinesterase with In Vivo Procognitive Efficacy.},
journal = {Journal of medicinal chemistry},
volume = {69},
number = {19},
pages = {22506-22538},
doi = {10.1021/acs.jmedchem.6c01737},
pmid = {42917927},
issn = {1520-4804},
support = {DZRO-FVZ22-ZHN II//Ministerstvo Obrany České Republiky/ ; P1-0175//Javna Agencija za Raziskovalno Dejavnost RS/ ; P1-0208//Javna Agencija za Raziskovalno Dejavnost RS/ ; //Fakultní nemocnice Hradec Králové/ ; DGA/SSA NBC-5-C-2316//Service de Santé des Armées/ ; DEC-2021/43/I/NZ7/00342//Narodowe Centrum Nauki/ ; DGA/SSA NBC-5-C-2316//Direction Générale de l'Armement/ ; SN-ZRD/22-27/0510//Univerza v Ljubljani/ ; },
mesh = {Humans ; *Butyrylcholinesterase/metabolism/chemistry ; Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry/metabolism/chemical synthesis/pharmacokinetics/therapeutic use ; *Brain/metabolism/drug effects ; *Drug Design ; Mice ; Crystallography, X-Ray ; Structure-Activity Relationship ; *Pyrrolidines/pharmacology/chemistry ; Models, Molecular ; Male ; *Carbamates/pharmacology/chemistry ; *Nootropic Agents/pharmacology/chemistry/chemical synthesis/pharmacokinetics ; Scopolamine ; },
abstract = {Butyrylcholinesterase (BChE) has emerged as a validated therapeutic target for the management of Alzheimer's disease symptoms, particularly in advanced stages when acetylcholinesterase activity declines. Despite the numerous BChE inhibitors reported, only the cymserine derivative bisnorcymserine has progressed to clinical evaluation. Here, we report the design and characterization of a novel selective human BChE (hBChE) inhibitor, N-benzylpyrrolidine carbamate (S)-(+)-14. Kinetic analyses and X-ray crystallography of the hBChE-inhibitor complex confirm a covalent mechanism of inhibition. Compound (S)-(+)-14 demonstrates favorable metabolic stability and achieves brain exposure following intraperitoneal administration in mice. In a scopolamine-induced cognitive impairment model, (S)-(+)-14 improves cognitive performance without causing cholinergic adverse effects or motor deficits. Collectively, these findings identify (S)-(+)-14 as a structurally validated, brain-penetrant covalent hBChE inhibitor and highlight its promise as a lead compound for the treatment of Alzheimer's disease.},
}

Humans
*Butyrylcholinesterase/metabolism/chemistry
Animals
*Cholinesterase Inhibitors/pharmacology/chemistry/metabolism/chemical synthesis/pharmacokinetics/therapeutic use
*Brain/metabolism/drug effects
*Drug Design
Mice
Crystallography, X-Ray
Structure-Activity Relationship
*Pyrrolidines/pharmacology/chemistry
Models, Molecular
Male
*Carbamates/pharmacology/chemistry
*Nootropic Agents/pharmacology/chemistry/chemical synthesis/pharmacokinetics
Scopolamine

@article {pmid42918387,
year = {2026},
author = {Verma, A and Goyal, A and Agrawal, N and Yadav, HN},
title = {Cellular senescence in ageing and neurodegenerative disorders: Molecular mechanisms, biomarkers, and therapeutic strategies.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111985},
doi = {10.1016/j.pnpbp.2026.111985},
pmid = {42918387},
issn = {1878-4216},
abstract = {Cellular senescence has been increasingly associated with neurodegenerative disorders, potentially linking ageing-related cellular impairment with mitochondrial dysfunction, chronic inflammation, and disrupted intercellular signalling. The present study aims to explore the increasing relevance of cellular senescence among key cell types, including neurons, astrocytes, neural progenitor cells, microglia and oligodendrocyte-lineage cells across neurodegenerative ailments such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. This review discusses the findings of pre-clinical and clinical studies which suggest that senescence-associated features may contribute to neurodegeneration. Further, it provides an overview of the biomarkers used in the identification of senescence in the CNS. Also, the review examines senotherapeutic treatment approaches, highlighting their actions on different CNS cell types and the growing clinical evidence. It also points out the challenges in translating these approaches to clinical application, such as targeting specific cell types and the lack of suitable biomarkers. Collectively, present findings suggest that senescence-associated alterations may contribute to neurodegeneration, although their effects appear to vary across cell types and diseases.},
}

@article {pmid42911381,
year = {2026},
author = {Chen, Y and Tong, Z and Wang, H and Xu, X and Chen, Q and Lu, J and Hu, Y and Zhang, X and Zhao, H and Chen, J and Zhang, B},
title = {Dynamic long-term modulation of cognition, brain structure and covariance networks in mild cognitive impairment due to AD by donepezil: A 36-month longitudinal study.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42911381},
issn = {1432-1459},
support = {82330059//Innovative Research Group Project of the National Natural Science Foundation of China/ ; 82271965//Innovative Research Group Project of the National Natural Science Foundation of China/ ; 2023-LCYJ-MS11//Nanjing Drum Tower Hospital/ ; XJSFZLX202333//Nanjing Drum Tower Hospital/ ; RC2022-023//Nanjing Drum Tower Hospital/ ; BE2022679//Jiangsu Provincial Key Research and Development Program/ ; },
mesh = {Humans ; *Donepezil/pharmacology/therapeutic use ; Female ; Male ; Longitudinal Studies ; *Cognitive Dysfunction/drug therapy/etiology/pathology/diagnostic imaging ; *Alzheimer Disease/drug therapy/complications/pathology/diagnostic imaging ; Aged ; Cross-Sectional Studies ; Magnetic Resonance Imaging ; *Brain/drug effects/pathology/diagnostic imaging ; *Nootropic Agents/pharmacology/therapeutic use ; Retrospective Studies ; Disease Progression ; *Nerve Net/drug effects/diagnostic imaging/pathology ; Cognition/drug effects ; Cognitive Enhancement ; Middle Aged ; },
abstract = {BACKGROUND: Whether donepezil exerts long-term efficacy in mitigating cognitive decline, preserving brain structure, and restoring impaired structural covariance networks in patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) remains controversial.

OBJECTIVE: This study aimed to characterize the longitudinal dynamic alterations in cognition, brain morphology, and structural covariance network topology in AD-MCI patients receiving continuous 36-month donepezil treatment, thereby elucidating the long-term modulatory effects of donepezil on AD progression.

METHODS: Cross-sectional analysis included 92 normal controls (NC) and 107 AD-MCI patients to identify baseline abnormalitiesin cognitive performance, brain morphological parameters, global topological features, and nodal metrics of individual gray matter covariance networks. Subsequently, 35 AD-MCI patients who completed 36-month continuous donepezil treatment were retrospectively enrolled to explore the therapeutic modulation of donepezil on the aforementioned abnormal indicators. Linear and piecewise linear mixed-effects models were employed to quantify longitudinal changes.

RESULTS: AD-MCI patients showed left hippocampus (including subfields) atrophy and widespread structural covariance network impairment at baseline. During treatment, significant time main effects were observed in MMSE scores and the volume of the left hippocampus and multiple subfields, both of which continued to show progressive decline, with accelerated deterioration between 12 and 18 months. Global topological metrics stabilized after initial short-term improvement, while right hippocampus nodal metrics were significantly enhanced.

CONCLUSIONS: Donepezil treatment in AD-MCI patients represents a dynamic therapeutic process: it elicits transient short-term improvement of global brain network topology but confers only modest long-term benefits, with insufficient evidence supporting sustained, impactful neuroprotective effects. This study provides novel multi-level longitudinal evidence describing the neuroimaging changes underlying donepezil's modulation of AD progression.},
}

Humans
*Donepezil/pharmacology/therapeutic use
Female
Male
Longitudinal Studies
*Cognitive Dysfunction/drug therapy/etiology/pathology/diagnostic imaging
*Alzheimer Disease/drug therapy/complications/pathology/diagnostic imaging
Aged
Cross-Sectional Studies
Magnetic Resonance Imaging
*Brain/drug effects/pathology/diagnostic imaging
*Nootropic Agents/pharmacology/therapeutic use
Retrospective Studies
Disease Progression
*Nerve Net/drug effects/diagnostic imaging/pathology
Cognition/drug effects
Cognitive Enhancement
Middle Aged

@article {pmid42911727,
year = {2026},
author = {Tojo, T and Itoh, Y and Kurohara, T and Li, Y and Singh, R and Narozny, R and van der Wiel, AMA and Furutani, R and Miyake, Y and Yamashita, Y and Kusuhara, H and Kanamitsu, K and Horiguchi, N and Ono, H and Kusakabe, KI and Uchida, S and Suzuki, T},
title = {Discovery of an HDAC2-Selective Inhibitor via Enzyme-Inhibitor-Binding Thermodynamics/Kinetics as a Prospective Neurological Disorder Drug.},
journal = {Journal of medicinal chemistry},
volume = {69},
number = {20},
pages = {23368-23386},
doi = {10.1021/acs.jmedchem.5c03068},
pmid = {42911727},
issn = {1520-4804},
support = {//Takeda Science Foundation/ ; 22ama121041j0001//Japan Agency for Medical Research and Development/ ; JP24ak0101197h0002//Japan Agency for Medical Research and Development/ ; JP24ama121051//Japan Agency for Medical Research and Development/ ; JP24ama121053//Japan Agency for Medical Research and Development/ ; JP24zf0127010//Japan Agency for Medical Research and Development/ ; JP25zf0127010//Japan Agency for Medical Research and Development/ ; //Uehara Memorial Foundation/ ; 22H02220//Japan Society for the Promotion of Science/ ; 24H00595//Japan Society for the Promotion of Science/ ; 25K03035//Japan Society for the Promotion of Science/ ; 2025-//Nanken/ ; kokunai//Nanken/ ; 47//Nanken/ ; JPMJCR14L2//Core Research for Evolutional Science and Technology/ ; //Ministry of Education, Culture, Sports, Science and Technology/ ; JPMXP1323015483//Institute of Science Tokyo/ ; //Mochida Memorial Foundation for Medical and Pharmaceutical Research/ ; },
mesh = {Animals ; Thermodynamics ; Humans ; *Histone Deacetylase Inhibitors/pharmacology/chemistry/therapeutic use/metabolism ; *Histone Deacetylase 2/antagonists & inhibitors/metabolism/chemistry ; Mice ; Kinetics ; Drug Discovery ; Crystallography, X-Ray ; Structure-Activity Relationship ; Models, Molecular ; Protein Binding ; },
abstract = {In this study, we identified KTT-1 (12) as an HDAC2-selective inhibitor through in vitro evaluations based on both thermodynamics and kinetics of the enzyme-inhibitor binding. This approach stands in sharp contrast to conventional drug discovery research, which usually focuses only on thermodynamics. An X-ray crystallography study on HDAC2 complexed with 12 in combination with quantum chemical calculations on model compounds suggested that the 2-furanyl group of 12 contributes to the selective HDAC2 inhibition. In our cellular assays, 12 preferentially inhibited HDAC2 over its highly homologous HDAC1 and promoted neurite outgrowth of neuro-2a cells. Furthermore, treatment of mice with 12 improved the memory and depression-like behavior of stress-vulnerable mice. The results indicate that 12 is a promising lead compound for neurological disorders such as Alzheimer's disease and depression and demonstrate that inhibitor evaluations that combine enzyme-inhibitor-binding thermodynamics and kinetics are useful tools for drug discovery research.},
}

Animals
Thermodynamics
Humans
*Histone Deacetylase Inhibitors/pharmacology/chemistry/therapeutic use/metabolism
*Histone Deacetylase 2/antagonists & inhibitors/metabolism/chemistry
Mice
Kinetics
Drug Discovery
Crystallography, X-Ray
Structure-Activity Relationship
Models, Molecular
Protein Binding

@article {pmid42911957,
year = {2026},
author = {Dahle, S and Einevoll, GT and Ness, TV},
title = {Cell-type dependence of effects from transcranial electric brain stimulation.},
journal = {PLoS computational biology},
volume = {22},
number = {10},
pages = {e1014895},
doi = {10.1371/journal.pcbi.1014895},
pmid = {42911957},
issn = {1553-7358},
abstract = {There is an urgent need for better treatment options for many neurological conditions, including Alzheimer's disease, Parkinson's disease, depression, and epilepsy. Transcranial electrical stimulation (tES) is a non-invasive, safe, inexpensive, and promising method that could address some of this unmet need. The therapeutic value of tES has been well demonstrated, but the effect is highly variable. To enable tES to reach its full potential requires a better understanding of how tES modulates neural activity so that tES treatments can be tailored to specific neurological conditions and individual patients. The neural response to tES is, however, highly complex, and the parameter space involved in optimizing tES treatments is daunting. This has made it difficult to obtain general insights into how tES modulates neural activity, and a central challenge lies in the cell-type-specific and frequency-dependent nature of these responses. In this study, we investigated cell-type-specific neuronal responses to tES over a broad frequency range, using a large database of biophysically detailed neuron models. We found that pyramidal cells respond strongly to low-frequency tES, but their responses drop sharply with frequency. In contrast, inhibitory neurons show a smaller reduction and, on average, become more responsive than pyramidal cells above ~60 Hz. By leveraging a reciprocity theorem we demonstrated that the effect of tES on a given cell-type is proportional to the frequency-dependent current-dipole moment that determines the EEG-signal contribution of this cell-type. We further identified the dendritic asymmetry as key in determining tES responses across the frequency spectrum. Counterintuitively, we also found that while total cell length increases tES sensitivity at low frequencies, it can have the opposite effect at high frequencies. Furthermore, we derived an analytical formula for idealized neuron models which can approximately predict the tES sensitivity of different cell types at any given frequency. By characterizing the role of morphology and stimulation frequency in determining tES responses of single cells, this is an important step towards a better understanding of tES at the fundamental level. These results also provide an efficient and accurate method for characterizing and comparing the tES responses of different neural populations across the frequency spectrum, which facilitates optimizing tES for cell-type specific targeting.},
}

@article {pmid42912549,
year = {2026},
author = {Guo, Y and Ji, Q and Yang, Y and Liang, M and Wu, Z},
title = {Amyloid PET Changes During Lecanemab Treatment in Patients With and Without Amyloid-related Imaging Abnormalities.},
journal = {Clinical nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/RLU.0000000000006726},
pmid = {42912549},
issn = {1536-0229},
abstract = {Lecanemab reduces cerebral amyloid-β burden in Alzheimer disease, but whether amyloid-related imaging abnormalities (ARIA) are associated with greater amyloid clearance remains unclear. We report 3 patients with comparable clinical backgrounds and similar baseline cognitive performance who underwent amyloid-β PET before and after lecanemab treatment. Quantitative analysis using Centiloid showed a greater reduction in amyloid burden in the patient who developed ARIA than in the 2 patients without ARIA. These observations suggest ARIA may be associated with more pronounced treatment-related amyloid clearance, warranting further investigation in larger cohorts.},
}

@article {pmid42913299,
year = {2026},
author = {Nakamae, MYT and Rivero-Jerez, PS and Butera, AP and Macedo, F},
title = {NMR characterization of Tacrine in aqueous solution and insights into its interaction with amyloid-β1-40 aggregates revealed by STD.},
journal = {Biophysical chemistry},
volume = {340},
number = {},
pages = {107722},
doi = {10.1016/j.bpc.2026.107722},
pmid = {42913299},
issn = {1873-4200},
abstract = {The deposition of β-amyloid peptide (Aβ) aggregates in the brain is widely accepted as one of the major factors driving the development of Alzheimer's disease (AD). Tacrine (9-amino-1,2,3,4-tetrahydroacridine) is one of the most potent acetylcholinesterase inhibitors approved for the symptomatic treatment of AD, but its clinical use was discontinued due to hepatotoxicity. Recent studies have reported that tacrine can interact with Aβ and inhibit its aggregation, although the underlying mechanism is not yet fully elucidated, highlighting the need for detailed spectroscopic characterization under physiologically relevant conditions. Here, we report, to the best of our knowledge, the first complete and unambiguous assignment of the [1]H and [13]C NMR resonances of tacrine in aqueous solution at near-physiological pH using a combination of ROESY, HSQC, and HMBC experiments. pH-dependent [1]HNMR studies revealed that aromatic proton resonances are highly sensitive to protonation state, displaying pronounced but fully reversible chemical-shift variations. The resulting spectral map provides a reliable basis for ligand-observed NMR investigations of tacrine and related compounds in aqueous media. Moreover, saturation transfer difference (STD)-NMR experiments were optimized to investigate the interaction of tacrine with soluble Aβ1-40 aggregates. Under the optimized conditions, clear STD effects were observed exclusively in the presence of Aβ1-40, confirming direct ligand-aggregate interaction. Differential saturation transfer among aromatic protons, particularly for H-7, suggests distinct proximity relationships within the tacrine- Aβ1-40 complex. Together, these results establish a robust spectroscopic and methodological framework for future NMR studies of tacrine-based ligands and their interactions with amyloid assemblies.},
}

@article {pmid42913321,
year = {2026},
author = {Xu, W and Liu, M and Yu, X and Hao, Y and Fu, Z and Jin, L and Liang, H and Liao, K and Wang, X and Xu, J},
title = {Multi-omics analysis of potential therapeutic targets for Alzheimer's disease and associated differences in immune cell infiltration.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {24},
number = {1},
pages = {e01092},
doi = {10.1016/j.neurot.2026.e01092},
pmid = {42913321},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD) represents a progressive neurodegenerative disorder that predominantly impairs the central nervous system. This study integrated single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) analysis to explore AD therapeutic targets and characterize alterations in immune cell infiltration and function. We analyzed the subtypes, developmental trajectories and intercellular communication of peripheral blood T cells from AD scRNA-seq data. Cell clustering identified CD8[+] T cells as the key immune subpopulation in AD, with two vital intercellular communication pathways (MIF-(CD74[+]CD44) and MIF-(CD74[+]CXCR4)) identified by trajectory analysis. The expression quantitative trait loci (eQTL) data retrieved from the IEU OpenGWAS database were utilized to perform MR and colocalization analysis to evaluate the association between target genes and AD. Six multiple-SNP and one single-SNP potential target genes were screened via differential expression and MR analysis. Among these, dual-specificity phosphatase 2 (DUSP2) showed a suggestive but weak association with AD, with a mild positive correlation observed in sensitivity analyses. No statistically significant shared genetic signals were detected via colocalization analysis. Additionally, significant differences in intercellular communication were observed between DUSP2+IM and DUSP2-IM cells, with distinct activity across various communication pathways. Gene expression levels in the AD group were significantly higher than in healthy individuals (P = 0.01). In conclusion, this study identified CD8[+] T cells as crucial factors in AD pathogenesis, while DUSP2 emerged as a suggestive candidate gene requiring further validation, providing novel mechanistic insights and potential therapeutic targets for AD treatment.},
}

@article {pmid42913372,
year = {2026},
author = {Tian, W and He, S and Wang, T and Zhong, S and Sun, J and Chen, J and Wang, X and Du, C and You, Y and Lin, Y and Wang, Y and Wang, G and Li, X and Chen, H},
title = {Spiro-Polycyclic Polyprenylated Acylphloroglucinols from Hypericum monogynum and Their anti-Alzheimer's Disease Effects.},
journal = {Journal of natural products},
volume = {89},
number = {9},
pages = {2486-2501},
doi = {10.1021/acs.jnatprod.6c00583},
pmid = {42913372},
issn = {1520-6025},
support = {2025XKJC0107//Qilu University of Technology/ ; 32270415//National Natural Science Foundation of China/ ; 2024J01042//Natural Science Foundation of Fujian Province/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Animals ; Zebrafish ; *Phloroglucinol/pharmacology/chemistry/isolation & purification/analogs & derivatives ; *Hypericum/chemistry ; Molecular Structure ; Cholinesterase Inhibitors/pharmacology/chemistry ; *Spiro Compounds/chemistry/pharmacology/isolation & purification ; Humans ; Crystallography, X-Ray ; },
abstract = {Eight undescribed spiro-polycyclic polyprenylated acylphloroglucinols (PPAPs) with a 6/6/5 tricyclic architecture (1-8), together with eight known analogues (9-16), were isolated from Hypericum monogynum L. Their structures including absolute configurations were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Biological evaluation revealed that compounds 4 and 16 showed potential as dual-target anti-Alzheimer's disease (AD) lead compounds, as they not only exhibited potent acetylcholinesterase (AChE) inhibitory activities but also induced peroxisome proliferator-activated receptor-γ transactivation and upregulated ATP-binding cassette transporter A1 expression. The in vivo anti-AD effects of 4 and 16 were evaluated by the zebrafish behavioral experiments. Compound 16 exhibited anti-AD effects with no detectable toxicity or teratogenicity, whereas 4 exhibited toxicity to zebrafish at 10 μM. These findings not only expand the chemical diversity of spiro-PPAPs but also underscore their potential as dual-target agents for AD treatment.},
}

*Alzheimer Disease/drug therapy
Animals
Zebrafish
*Phloroglucinol/pharmacology/chemistry/isolation & purification/analogs & derivatives
*Hypericum/chemistry
Molecular Structure
Cholinesterase Inhibitors/pharmacology/chemistry
*Spiro Compounds/chemistry/pharmacology/isolation & purification
Humans
Crystallography, X-Ray

@article {pmid42913958,
year = {2026},
author = {Luo, H and Qi, X and Liu, R and Xu, Z and Liu, Y and Wu, B},
title = {Utilization of Dental Preventive and Treatment Services Among Older Adults with and without ADRD.},
journal = {American journal of preventive medicine},
volume = {},
number = {},
pages = {108612},
doi = {10.1016/j.amepre.2026.108612},
pmid = {42913958},
issn = {1873-2607},
abstract = {INTRODUCTION: Individuals with Alzheimer's disease and related dementias (ADRD) face substantial challenges in accessing dental care, yet the types of services received and how they compare with peers without ADRD remain understudied. This study compared dental service utilization and procedure types between older adults with and without ADRD.

METHODS: A cross-sectional analysis was conducted in 2026 using 2017-2023 Medical Expenditure Panel Survey (MEPS) data for community-dwelling adults aged 65 years and older (N=35,538). Outcomes were any dental visit in the past year and receipt of preventive or treatment-based procedures among those with at least one visit. Survey-weighted logistic regression models estimated associations between ADRD status and each outcome. Blinder-Oaxaca decomposition partitioned the disparity in dental visits into an endowments component (the share explained by group differences in measured characteristics) and a coefficients component (the share reflecting differences in how those characteristics relate to care use).

RESULTS: Older adults with ADRD were less likely to have a dental visit (AOR=0.75, 95% CI: 0.64-0.88), and among those with a visit, less likely to receive preventive care (AOR=0.69, 95% CI: 0.50-0.95). No significant differences were observed in treatment-based procedures after adjustment. The disparity in dental visits (13 percentage points, p <0.001) was explained by both differences in characteristics (43.2%) and differences in coefficients (43.5%). Health status and education were the largest contributors to the explained component, while family income primarily drove the unexplained component. Disparities in preventive care were smaller (approximately 9 percentage points) and largely driven by the unexplained component.

CONCLUSIONS: Disparities in dental care for older adults with ADRD are associated with differences in individual characteristics as well as unexplained factors that may represent barriers to accessing dental care. Closing these gaps requires moving beyond financial coverage toward integrated, community-based delivery models. Such strategies are vital to shifting care from episodic treatment to sustainable prevention.},
}

@article {pmid42915464,
year = {2026},
author = {Huang, X and Ma, S and Li, X and Pan, J},
title = {Rationally Designed Peptides and Peptoids as Inhibitors of Amyloid-β (Aβ) Aggregation.},
journal = {Bioconjugate chemistry},
volume = {37},
number = {9},
pages = {1739-1770},
doi = {10.1021/acs.bioconjchem.6c00145},
pmid = {42915464},
issn = {1520-4812},
support = {22507040//National Natural Science Foundation of China/ ; 2024AFB782//Natural Science Foundation of Hubei Province/ ; B2024278//Scientific Research Program of the Hubei Provincial Department of Education/ ; },
mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism/chemistry ; *Peptoids/chemistry/pharmacology/therapeutic use ; Humans ; *Drug Design ; *Peptides/chemistry/pharmacology/therapeutic use ; Alzheimer Disease/drug therapy/metabolism ; Animals ; *Protein Aggregates/drug effects ; },
abstract = {Peptide and peptoid are two types of peptidomimetics can be used as drugs for diseases. One of the main hallmarks in Alzheimer's Disease (AD) is Aβ aggregation. Due to the natural affinity between peptide and Aβ proteins, peptide therapeutics are found out to be suitable for the disease, as they are almost nontoxic, possess good biocompatibility and are structurally changeable. This review mainly focuses on peptide and peptoid as inhibitors targeting Aβ protein, elaborating on their design strategies and some of their inhibitory effects, providing diverse potential compounds for the treatment of AD. The involved peptide inhibitors are classified into three major categories based on their structural features: inhibitors based on the natural Aβ sequence, inhibitors based on non-natural Aβ sequences, and inhibitors conjugated with small molecule compounds. To facilitate understanding of the development process of each type of inhibitor, we have expounded on each major category in terms of chronological order, specialty and importance. It also summarized the challenges and design strategies faced by peptide inhibitors in targeting Aβ aggregation. This review provides a valuable resource for researchers in the field of synthetic peptide and their biomedical applications, offering structural insights into the design of new peptide for better diagnosis and therapeutic applications.},
}

*Amyloid beta-Peptides/antagonists & inhibitors/metabolism/chemistry
*Peptoids/chemistry/pharmacology/therapeutic use
Humans
*Drug Design
*Peptides/chemistry/pharmacology/therapeutic use
Alzheimer Disease/drug therapy/metabolism
Animals
*Protein Aggregates/drug effects

@article {pmid42915573,
year = {2026},
author = {Singh, S and Singh, SK},
title = {The "Glyco-Remodeling" Hypothesis in Alzheimer's Disease: Linking Protein N-Glycosylation to Pathogenesis and Translation.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {18},
pages = {3252-3271},
doi = {10.1021/acschemneuro.6c00166},
pmid = {42915573},
issn = {1948-7193},
support = {1102015//Ministry of Education, India/ ; 21011503//Indian Institute of Technology (BHU) Varanasi/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; Glycosylation ; Animals ; Amyloid beta-Protein Precursor/metabolism ; Protein Processing, Post-Translational/physiology ; *Brain/metabolism/pathology ; tau Proteins/metabolism ; Membrane Glycoproteins/metabolism ; Receptors, Immunologic/metabolism ; Apolipoproteins E/metabolism ; },
abstract = {Alzheimer's disease (AD), an age-associated neurodegenerative disorder characterized by cognitive decline and accumulation of amyloid-β (Aβ) plaques and tau tangles, has long been studied through the lens of protein aggregation and phosphorylation. However, emerging evidence suggests that aberrant protein N-glycosylation, a key post-translational modification governing protein folding, trafficking, and signaling, plays an equally pivotal role in AD pathogenesis. This review consolidates current knowledge on N-glycosylation, and very briefly about the prominent O-Glycosylation dynamics in the healthy and diseased brain, with a focus on six key proteins amyloid precursor protein, immunoglobulin G (IgG), triggering receptor expressed on myeloid cells-2 (TREM2), tau (τ), apolipoprotein E, and transferrin whose altered glycosylation patterns perturb amyloidogenic processing, tau aggregation, microglial activity, lipid transport, and systemic immune balance. We introduce the glyco-remodeling hypothesis, proposing that stage-specific glycosylation changes act as molecular "remodeling" driving the progression from normal aging, to mild cognitive impairment, and ultimately AD. Framing AD through this lens positions glycans as both markers and modulators of disease progression, with direct implications for biomarker discovery, therapeutic targeting, and systems-level integration across aging and neurodegeneration.},
}

*Alzheimer Disease/metabolism/pathology
Humans
Glycosylation
Animals
Amyloid beta-Protein Precursor/metabolism
Protein Processing, Post-Translational/physiology
*Brain/metabolism/pathology
tau Proteins/metabolism
Membrane Glycoproteins/metabolism
Receptors, Immunologic/metabolism
Apolipoproteins E/metabolism

@article {pmid42916114,
year = {2026},
author = {Milardi, D and Han, J and Lee, HJ and Ding, F and Miller, Y and Faller, P and Bush, AI and Crouch, PJ and Finkelstein, DI and Double, KL and Jeremic, A and Lim, MH and Ramamoorthy, A},
title = {Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies.},
journal = {Chemical reviews},
volume = {126},
number = {18},
pages = {10249-10333},
doi = {10.1021/acs.chemrev.5c00420},
pmid = {42916114},
issn = {1520-6890},
support = {R01AG048934/AG/NIA NIH HHS/United States ; R35GM13973/GM/NIGMS NIH HHS/United States ; R35GM145409/GM/NIGMS NIH HHS/United States ; R01DK132214/DK/NIDDK NIH HHS/United States ; NA//Florida State University/ ; NA//National High Magnetic Field Laboratory/ ; 2022PAAYZE//NextGenerationEU/ ; CUP: B53D23016440006//NextGenerationEU/ ; DP230101031//Australian Research Council/ ; GNT1194028//National Health and Medical Research Council/ ; GNT2019931//National Health and Medical Research Council/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2022-NR073879//National Research Foundation of Korea/ ; RS-2024-00353015//National Research Foundation of Korea/ ; RS-2024-00411134//National Research Foundation of Korea/ ; MRF2007656//Medical Research Future Fund/ ; },
mesh = {Humans ; *Protein Aggregation, Pathological/metabolism/drug therapy ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Metals/chemistry/metabolism ; Animals ; Protein Aggregates ; },
abstract = {Protein aggregation is a pathological process associated with several human diseases termed proteinopathies, including neurodegenerative and metabolic disorders such as Alzheimer's disease, Parkinson's disease, type II diabetes, amyotrophic lateral sclerosis, and Huntington's disease. In these conditions, specific proteins misfold and accumulate into insoluble aggregates, disrupting normal cellular function and contributing to disease progression. Many studies have investigated the molecular mechanisms that underlie the aggregation pathways, the structure of aggregates, such as oligomeric intermediates and fibrils, and their cellular toxicity. Studies have also investigated the effects of cofactors like metals, lipids, other amyloid proteins, and small molecules. Recent research has increasingly emphasized the critical roles of metal ions such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) in amyloid aggregation and toxicity. Alterations in metal ion transport, binding, or redox activity have been linked to the onset and progression of several amyloid-associated diseases. These metal ions can interact directly with amyloidogenic proteins, influencing their structural conformation, aggregation kinetics, and propensity to form toxic oligomers. This review aims to advance our understanding of how the regulation of metal ions within cells and their dysfunction contribute to the accumulation of harmful proteins, which is a key factor in proteinopathies. By examining the interactions between metal ions and key amyloidogenic proteins─including amyloid-β (Aβ), α-synuclein, tau, superoxide dismutase 1 (SOD1), human islet amyloid polypeptide (hIAPP), and insulin─we highlight both common and unique pathways through which metal ions influence protein aggregation. Additionally, this review explores the impact of metal ions on protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, as well as emerging theranostic strategies. These include metal chelation therapies, metal-based imaging agents, and multifunctional compounds designed to restore metal balance while preventing aggregation and toxicity. By integrating biochemical, cellular, and therapeutic insights, this review contributes to a deeper understanding of the metallobiology of proteinopathies and supports the development of novel diagnostic and treatment approaches targeting metal-protein interactions.},
}

Humans
*Protein Aggregation, Pathological/metabolism/drug therapy
*Neurodegenerative Diseases/metabolism/drug therapy
*Metals/chemistry/metabolism
Animals
Protein Aggregates

@article {pmid42917882,
year = {2026},
author = {Gross, S and Koch, P and Strasser, A},
title = {Synthesis and Pharmacological Characterization of Novel Tetrahydropyridine-Based Muscarinic M5 Receptor Antagonists to Investigate the Difference in the SARs of Muscarinic Receptor Subtypes Utilizing Induced Fit Docking Studies.},
journal = {Journal of medicinal chemistry},
volume = {69},
number = {19},
pages = {21789-21811},
doi = {10.1021/acs.jmedchem.6c00587},
pmid = {42917882},
issn = {1520-4804},
mesh = {Molecular Docking Simulation ; Structure-Activity Relationship ; Animals ; Humans ; *Receptor, Muscarinic M5/antagonists & inhibitors/metabolism ; *Pyridines/pharmacology/chemistry/chemical synthesis ; *Muscarinic Antagonists/pharmacology/chemical synthesis/chemistry ; CHO Cells ; Cricetulus ; Radioligand Assay ; },
abstract = {Many studies and experiments suggest the muscarinic M5 receptor (M5R) as a potential target for the clinical treatment of drug abuse, schizophrenia, or Alzheimer's disease. In the present study, a library containing 39 novel hM5R antagonists based on an arecaidine (tetrahydropyridine) core was synthesized, pharmacologically characterized in radioligand competition binding or mini-G protein assays and analyzed in molecular docking studies to elucidate their binding modes and in vitro characteristics. Compound 56m showed low single-digit nanomolar affinity on hM5R combined with a 17-fold selectivity over hM2R, while compound 81d displayed good affinity on hM5R with a 3- to 12-fold selectivity over the other subtypes. Induced fit docking studies suggest the conserved Y2.60 and hM5R-unique Q45.51 as the responsible amino acids regarding affinity and selectivity.},
}

Molecular Docking Simulation
Structure-Activity Relationship
Animals
Humans
*Receptor, Muscarinic M5/antagonists & inhibitors/metabolism
*Pyridines/pharmacology/chemistry/chemical synthesis
*Muscarinic Antagonists/pharmacology/chemical synthesis/chemistry
CHO Cells
Cricetulus
Radioligand Assay

@article {pmid42903279,
year = {2026},
author = {Addo, A and Li, B and Murikinati, S and Gardner, R and Zhao, LR},
title = {Transcriptomic analysis identifies candidate molecular mechanisms underlying SCF+G-CSF-reduced neuropathology in aged APP/PS1 mice.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1705436},
pmid = {42903279},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disease characterized by amyloid plaque deposition, tau hyperphosphorylation, neuroinflammation, and cognitive decline. Our previous studies demonstrated that combined treatment with stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) reduces AD pathology in APP/PS1 mice. The present study aimed to explore the molecular mechanisms underlying the effects of SCF+G-CSF using transcriptomic analysis.

METHODS: Aged APP/PS1 mice received daily subcutaneous injections of SCF+G-CSF or vehicle for 12 days. RNA was extracted from brain tissue on day 13 for gene-chip analysis. Age-matched wild-type (WT) mice served as controls. Data were analyzed using TAC, STRING v12.0, Reactome, and ShinyGO 0.77. A total of 45,037 genes were analyzed. Twenty-seven differentially expressed genes (DEGs) met a ≥ 2-fold threshold in SCF+G-CSF-treated versus vehicle-treated APP/PS1 mice, whereas 89 DEGs met this threshold in APP/PS1 versus WT mice.

RESULTS: SCF+G-CSF treatment upregulated immune-related genes, including S100a8, S100a9, Ngp, Lcn2, Ltf, and Camp, which are associated with immune regulation and amyloid-related processes. Pathway analysis identified downregulation of IL-2, IL-4, IL-7, and EGFR1 signaling and enrichment of IL-17 signaling, suggesting modulation of both innate and adaptive immune responses. SCF+G-CSF also downregulated several genes with known oncogenic functions, including Cbl, Akap9, Kcnq1ot1, and Snhg11, suggesting a potential molecular overlap between cancer- and AD-related pathways. In addition, pathway enrichment analysis identified NADPH oxidase activation through Rho GTPase signaling and greater than 400-fold enrichment of metal ion sequestration pathways following SCF+G-CSF treatment.

CONCLUSION: SCF+G-CSF treatment was associated with broad transcriptional changes involving immune regulation, metal ion homeostasis, and genes with known oncogenic functions. These findings provide new insights into the molecular pathways influenced by SCF+G-CSF in aged APP/PS1 mice and identify candidate mechanisms and therapeutic targets for future investigation.},
}

@article {pmid42903366,
year = {2026},
author = {Bashirzade, AA and Tikhonova, MA and Belichenko, VM and Fedoseeva, LA and Belyaev, MD and Renn, TY and Chang, HM and Kolosova, NG and Belyaev, ND and Amstislavskaya, TG},
title = {Epigenetic regulation of the transcriptional activity of genes mediating the neuroprotective activity of ceftriaxone in the brain in a rat model of sporadic Alzheimer disease: the involvement of histone deacetylase 1.},
journal = {Vavilovskii zhurnal genetiki i selektsii},
volume = {30},
number = {6},
pages = {899-907},
doi = {10.18699/vjgb-26-91},
pmid = {42903366},
issn = {2500-0462},
abstract = {Histone deacetylases (HDACs) are enzymes that provide transcriptional repression, while HDAC inhibitors are considered to be potential drugs in the treatment of Alzheimer disease (AD). Earlier we found that ceftriaxone (CEF), an antibiotic with neuroprotective activity, augmented mRNA levels of Ide and Mme, encoding enzymes involved in the catabolism of amyloid beta in the amygdala of OXYS rats, a model of sporadic AD. On the other hand, disturbances of neurotrophic factors (BDNF in particular) play an important role in AD pathogenesis. Moreover, HDACs of class I (HDAC1) are involved in the regulation of Bdnf transcriptional activity. The study was aimed to assess the effects of CEF on HDAC1 enrichment at Mme, Ide, and Bdnf gene promoters in the amygdala of OXYS rats and on Bdnf mRNA levels in the amygdala of OXYS and Wistar rats. Chromatin immunoprecipitation and qPCR were utilized for epigenetic analysis and assay of Bdnf mRNA levels, respectively. Neither significant HDAC1 enrichment, nor its alteration under CEF treatment at the Mme or Ide promoters were found, whereas CEF attenuated HDAC1 binding at Bdnf promoter IV. This is a novel mechanism of transcription regulation by CEF in the brain, which may be involved in its neuroprotective activity. In 5-month-old OXYS rats, it seems to play a minor role, as CEF did not change Bdnf transcript 5 (containing exons IV and IX) levels. We were first to demonstrate the transcript-specific regulation of Bdnf transcription by CEF. CEF significantly increased the levels of Bdnf transcript 6 (containing exons VII, VIII, and IX). The results of our study can be taken into account in AD treatment.},
}

@article {pmid42903416,
year = {2026},
author = {Park, JJ and Chung, SY and Kim, SM and Yoo, HD},
title = {Post-traumatic cognitive decline and neurodegenerative disease: a narrative review and proposed framework for etiologic assessment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1844523},
pmid = {42903416},
issn = {1664-2295},
mesh = {Humans ; *Neurodegenerative Diseases/etiology/diagnosis/diagnostic imaging ; *Brain Injuries, Traumatic/complications ; *Cognitive Dysfunction/etiology/diagnosis/diagnostic imaging ; Biomarkers ; Neuroimaging ; },
abstract = {BACKGROUND: When a patient with a history of traumatic brain injury (TBI) develops progressive cognitive decline months to years after injury, clinicians must consider injury sequelae, an independent neurodegenerative disease, or both. Existing diagnostic frameworks each address a different aspect of this question, and none was constructed to apportion contribution between them. The distinction matters for management because AD-directed therapy should be considered only after biological Alzheimer's disease (AD) has been established, followed by separate assessment of treatment eligibility and safety.

OBJECTIVE: To synthesise evidence on cognitive change after TBI and the clinical, biomarker, and neuroimaging information available when delayed decline is evaluated, and to propose a structure for that evaluation.

METHODS: Structured narrative review. A documented de novo PubMed search was conducted on 27 July 2026, covering January 2015 to the search date, using two complementary strategies: one addressing cognitive, functional and neurodegenerative outcomes after TBI, and one addressing biomarker and neuroimaging evidence with longitudinal and prognostic terms. Diagnostic and research criteria, neuropathological and mechanistic references, comparator biomarker studies, and treatment trials were identified through targeted retrieval and reference checking. Exhaustive title and abstract screening, dual-reviewer study selection, formal risk-of-bias assessment, and quantitative synthesis were not undertaken.

RESULTS: Four patterns of cognitive change after TBI are proposed as unvalidated longitudinal clinical heuristics rather than validated diagnostic categories, and no prevalence is estimated for any of them. Delayed progressive deterioration following an initial plateau presents the greatest diagnostic difficulty. Blood biomarkers can support evaluation for coexisting biological AD, but neurofilament light and glial fibrillary acidic protein kinetics vary with injury severity and sampling window, and no validated biomarker profile identifies injury-driven neurodegeneration in an individual patient. Tau-related pathology, impaired protein clearance, and chronic neuroinflammatory activity are plausible contributors not shown to form a unified causal cascade.

CONCLUSION: Current evidence supports structured longitudinal reassessment and evaluation of competing explanations rather than etiological classification by biomarker pattern. A proposed assessment pathway, and a framework for stating what can and cannot be concluded in an individual patient, are offered as testable structures, including for medicolegal settings in which causal attribution is requested.},
}

Humans
*Neurodegenerative Diseases/etiology/diagnosis/diagnostic imaging
*Brain Injuries, Traumatic/complications
*Cognitive Dysfunction/etiology/diagnosis/diagnostic imaging
Biomarkers
Neuroimaging

@article {pmid42903448,
year = {2026},
author = {Song, J and He, A and Li, S and Wu, Q},
title = {TPPU, a soluble epoxide hydrolase inhibitor, mitigates Aβ-induced neurotoxicity via dual modulation of mitochondrial stabilization and JNK suppression.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102806},
pmid = {42903448},
issn = {2405-5808},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, primarily driven by β-amyloid (Aβ) aggregation and neuronal apoptosis. This study aims to investigate the neuroprotective effects of soluble epoxide hydrolase (sEH) inhibition against Aβ-induced cytotoxicity in PC-12 cells, focusing on cell viability, apoptosis, and the c-Jun N-terminal kinase (JNK) signaling pathway. Western blotting and fluorometric assays revealed elevated sEH expression and activity in Aβ1-42-treated PC-12 cells compared to untreated controls. Treatment with N-[1-(1-Oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]urea (TPPU), a potent sEH inhibitor, significantly attenuated Aβ-induced apoptosis in PC-12 cells and enhanced cell viability. These findings were corroborated by CCK-8 assays and flow cytometry analyses. Furthermore, TPPU reversed Aβ-induced cleaved Caspase-3 dysregulation and restored mitochondrial membrane potential. Notably, exogenous administration of epoxyeicosatrienoic acids partially mimicked the protective effects of TPPU, primarily by preserving mitochondrial function. Western blot analysis confirmed that TPPU pretreatment suppressed the phosphorylation of JNK, thereby contributing to its anti-apoptotic effects. Collectively, these findings demonstrate that TPPU attenuates Aβ-induced neurotoxicity via dual mechanisms-restoring mitochondrial function and suppressing JNK activation-highlighting its potential as a therapeutic agent for AD.},
}

@article {pmid42904391,
year = {2026},
author = {Hassanzadeh Dostkoh, R and Dastyafteh, N and Iraji, A and Karimian, S and Mohammadi-Khanaposhtani, M and Safapoor, S and Noori, M and Tahmasebi, E and Saeedi, S and Larijani, B and Mahdavi, M and Javanshir, S},
title = {New hybrid molecules with 2,3,4,9-tetrahydro-1H-carbazol-1,3,4-oxadiazole-N-phenylacetamide framework as potent cholinesterase inhibitors.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17568919.2026.2748649},
pmid = {42904391},
issn = {1756-8927},
abstract = {AIMS: In this study, new 2,3,4,9-tetrahydro-1H-carbazol-1,3,4-oxadiazole-N-phenylacetamide hybrids 8a-n as potential dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the treatment of Alzheimer's disease (AD) were introduced.

METHODS: The target compounds were designed using a molecular hybridization strategy and synthesized via straightforward chemical reactions. They were evaluated in vitro for their inhibitory activity against AChE and BChE. The mechanism of inhibition was investigated through kinetic studies. Computational methods, including molecular docking and molecular dynamics simulations, were employed to analyze binding interactions and complex stability. Finally, the drug-likeness and oral bioavailability of the compounds were assessed.

RESULTS: All synthesized compounds showed significant inhibitory effects against BChE and moderate inhibition against AChE. Compound 8m was identified as the most potent dual inhibitor, being approximately 18-fold more potent against BChE than the standard drug donepezil. Kinetic studies on compound 8m revealed a competitive mode of inhibition against AChE and BChE. Computational analyses confirmed that compound 8m forms more stable interactions and a more stable, compact complex with BChE compared with donepezil, characterized by reduced structural fluctuations and more persistent hydrogen bonding.

CONCLUSIONS: Compound 8m is a potent, competitive inhibitor of both AChE and BChE with a favorable drug-like profile and oral bioavailability.},
}

@article {pmid42904474,
year = {2026},
author = {Lakshmi, SM and Singh, V and Vanangamudi, M and Taj, T and Shahin Dh, H and Nath, R and Dutta, G and Avvari, SK and Sridhar, SB and Panigrahy, UP and Noushida, N and Chaudhary, P},
title = {Modulating Microglial Activation Through GLP-1 Pathways: A New Frontier in Neuroinflammation Research.},
journal = {The European journal of neuroscience},
volume = {64},
number = {8},
pages = {e70718},
doi = {10.1111/ejn.70718},
pmid = {42904474},
issn = {1460-9568},
mesh = {*Microglia/metabolism/drug effects/immunology ; Animals ; Humans ; *Neuroinflammatory Diseases/metabolism/drug therapy/immunology ; *Glucagon-Like Peptide 1/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Neurodegenerative Diseases/metabolism/drug therapy/immunology ; Glucagon-Like Peptide-1 Receptor/metabolism ; Signal Transduction ; },
abstract = {Microglia are the immune cells resident in the central nervous system (CNS) and are involved in CNS homeostasis and in responses to injury and disease. Microglia, upon activation, become pro-inflammatory (M1) or anti-inflammatory (M2), with M1 being neurotoxic and M2 participating in tissue repair. The activation of microglia in neuroinflammation and pain hypersensitivity is important in the neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's disease (AD). Recent investigations have identified GLP-1 receptor agonists (GLP-1 RAs) as potent pharmacological agents that can regulate the activity of the microglia. GLP-1RA attaches to the GLP-1 receptor found on the microglia to cause a phenotypic shift to the anti-inflammatory M2 form, which, in turn, reduces neuroinflammation and increases neuronal protection. Experimental evidence shows that GLP-1 RAs are effective at reducing hypersensitivity to pain, improving cognitive performance, and attenuating inflammatory effects in preclinical models of AD, PD, and multiple sclerosis (MS). All these facts suggest that GLP-1 RAs are a significant treatment option in chronic pain and neurodegenerative disease management, as they can change microglial polarization and suppress neuroinflammation.},
}

*Microglia/metabolism/drug effects/immunology
Animals
Humans
*Neuroinflammatory Diseases/metabolism/drug therapy/immunology
*Glucagon-Like Peptide 1/metabolism
*Glucagon-Like Peptide-1 Receptor Agonists
*Neurodegenerative Diseases/metabolism/drug therapy/immunology
Glucagon-Like Peptide-1 Receptor/metabolism
Signal Transduction

@article {pmid42905162,
year = {2026},
author = {Stapf, CD and Uzelac, Z and Iterbeke, L and Guthknecht, A and Barba, L and Strube, D and Kölsch, A and Kleeberg, K and Kendzierski, T and Roos, A and Steinacker, P and Abu-Rumeileh, S and Claeys, KG and Weishaupt, J and Mensch, A and Otto, M},
title = {Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42905162},
issn = {1432-1459},
support = {Clinician Scientist Programme n. CS25/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS22/06//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS26/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; FTLDc 01GI1007A//German Federal Ministry of Education and Research/ ; D.3830//foundation of the state Baden-Württemberg/ ; },
mesh = {Humans ; Female ; *tau Proteins/blood ; Male ; Adolescent ; Biomarkers/blood ; Retrospective Studies ; Adult ; *Muscular Atrophy, Spinal/blood/drug therapy/physiopathology ; Middle Aged ; Phosphorylation ; Young Adult ; Amyotrophic Lateral Sclerosis/blood ; Alzheimer Disease/blood ; *Spinal Muscular Atrophies of Childhood/blood ; Aged ; Longitudinal Studies ; },
abstract = {BACKGROUND: Reliable blood biomarkers for longitudinal monitoring in adolescent and adult 5q spinal muscular atrophy (SMA) are lacking. Phosphorylated tau (p-tau) species are elevated in serum in amyotrophic lateral sclerosis (ALS), where they may reflect peripheral nerve and muscle pathology. We aimed to investigate serum p-tau181 and p-tau217 as longitudinal biomarkers in adolescent and adult SMA and assessed associations with clinical parameters.

METHODS: In this retrospective multi-centre study, we assessed serum p-tau181 and p-tau217 levels in adults with 5q SMA under treatment with nusinersen or risdiplam, comparing levels with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and non-neurodegenerative disease controls. Associations with motor function, respiratory capacity, creatine kinase (CK), and neurofilament light chain (NfL) were assessed using linear mixed-effects models adjusted for age and sex.

RESULTS: Serum p-tau181 was higher in SMA than in disease controls (β = -0.48, 95%-CI -0.81 to -0.15), but lower than in ALS (β = 0.99, 95%-CI 0.58 to 1.39) and AD (β = 0.56, 95%-CI 0.11 to 1.00). P-tau181 declined from baseline to FUP2 (Δ median -1.80 pg/mL, IQR -5.90 to 2.10); p-tau217 showed no longitudinal change. P-tau181 and p-tau217 were positively associated with motor function, functional status, respiratory capacity, and CK, with no association with NfL. In exploratory analyses, higher baseline p-tau181 was associated with greater HFMSE decline (β = 1.79, 95%-CI 0.59 to 2.99).

CONCLUSIONS: Serum p-tau181 and p-tau217 appear to reflect ongoing muscle turnover in adult SMA, declining as muscle mass decreases. Higher baseline p-tau181 was associated with subsequent functional deterioration, suggesting potential utility as a biomarker of active denervation and disease monitoring.},
}

Humans
Female
*tau Proteins/blood
Male
Adolescent
Biomarkers/blood
Retrospective Studies
Adult
*Muscular Atrophy, Spinal/blood/drug therapy/physiopathology
Middle Aged
Phosphorylation
Young Adult
Amyotrophic Lateral Sclerosis/blood
Alzheimer Disease/blood
*Spinal Muscular Atrophies of Childhood/blood
Aged
Longitudinal Studies

@article {pmid42905229,
year = {2026},
author = {Halmos, PM and Dobi, B and Vinnai, P and Ajtay, A and Bereczki, D and Kovács, T},
title = {Memantine in the treatment of dementia: a nationwide real-world analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42905229},
issn = {2509-2723},
support = {FIKP IGSZF/123338-2/2021-ITMFIKP IGSZF/123338-2/2021-ITM//Nemzeti Kutatási, Fejlesztési és Innovaciós Alap/ ; },
abstract = {Despite the growing global burden of dementia, real-world data that adequately reflect the current state of healthcare systems, dementia care pathways, and the actual impact of pharmacological treatment practices remain limited, hindering the evidence-based planning and implementation of novel therapies. This retrospective cohort study evaluated nationwide anti-dementia drug treatment practices, particularly focusing on memantine use, and their effect on survival. Using the nationwide NEUROHUN database, data from 398,584 patients with dementia from 2010 to 2020 in Hungary were analyzed (mean age at diagnosis 75.22 years). Kaplan-Meier analyses and multivariable Cox proportional hazards models were conducted to evaluate survival outcomes, adjusting for age and sex. Annual prescription prevalence, medication adherence, and persistence metrics were also calculated. Only 13% of patients received any anti-dementia drug (donepezil, rivastigmine, or memantine); among those treated, 24% received memantine as monotherapy. Untreated patients had the shortest median survival (3.1 years), followed closely by those on memantine monotherapy alone (3.7 years). This pattern likely reflects the older age, delayed diagnosis, and presumably more advanced disease stage of these patients rather than a direct effect of memantine. Patients receiving memantine and donepezil showed the lowest mortality risk (HR = 0.581) compared to the untreated group. Symptomatic pharmacological treatments are likely to remain important adjuncts to emerging disease-modifying therapies, given their evidence-based benefits in dementia care. This is the first study in the Central-Eastern European region to evaluate memantine under real-world conditions, highlighting the high proportion of late diagnoses and underscoring the need to establish earlier and more efficient diagnostic pathways.},
}

@article {pmid42905846,
year = {2026},
author = {Shee, S and Huang, M and Baghel, MS and Zheng, Y and Lun, S and Yadav, SK and Yadav, NN and Ruiz-Gonzalez, CE and Tyagi, S and Nuermberger, E and Jain, SK and Bhujwalla, ZM and Slusher, BS and Wong, PC and Bishai, W},
title = {BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.},
journal = {Science advances},
volume = {12},
number = {43},
pages = {eaej4603},
pmid = {42905846},
issn = {2375-2548},
mesh = {Animals ; Mice ; *tau Proteins/metabolism ; *BCG Vaccine/pharmacology/immunology/administration & dosage ; *Tauopathies/prevention & control/pathology/metabolism ; Disease Models, Animal ; *Cognition/drug effects ; Vaccination ; Microglia/metabolism ; Hippocampus/metabolism/pathology ; Mice, Transgenic ; Magnetic Resonance Imaging ; },
abstract = {Retrospective studies in patients with nonmuscle invasive bladder cancer have reported a significant reduction in Alzheimer's disease incidence (12 to 78%) among Bacille Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-magnetic resonance Imaging (MRI) demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted chemical exchange saturation transfer-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test, as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature toward that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of trained immunity marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of fluorescein isothiocyanate-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and central nervous system myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.},
}

Animals
Mice
*tau Proteins/metabolism
*BCG Vaccine/pharmacology/immunology/administration & dosage
*Tauopathies/prevention & control/pathology/metabolism
Disease Models, Animal
*Cognition/drug effects
Vaccination
Microglia/metabolism
Hippocampus/metabolism/pathology
Mice, Transgenic
Magnetic Resonance Imaging

@article {pmid42906297,
year = {2026},
author = {Gu, M and Li, J and Liu, B and Yang, N and Lang, M and Han, Y and Kou, B and Yang, P and Ding, W and Lin, W and Zhu, S and Tong, Q and Quan, L},
title = {A synergistic platform integrating iodinated BODIPY photosensitizers and microglial cells for superior photodynamic antibacterial efficacy.},
journal = {Bioorganic chemistry},
volume = {184},
number = {},
pages = {110663},
doi = {10.1016/j.bioorg.2026.110663},
pmid = {42906297},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is closely linked to gut dysbiosis and microbial translocation, highlighting an urgent need for antimicrobial strategies that combine high efficiency with host immune compatibility. Photodynamic therapy using photosensitizers offers a promising approach, yet conventional agents often lack the ability to engage host defense mechanisms for sustained bacterial clearance. Here, we report a synergistic platform that integrates iodinated BODIPY-based photosensitizers with BV-2 microglial cells to achieve enhanced antibacterial efficacy through the cooperative action of photodynamic killing and microglial phagocytosis. A series of BODIPY derivatives bearing iodine atoms at the 2,6-positions and functionalized with isocyano or aldehyde groups at the meso-position were synthesized. Among them, NC-PhBDP-I exhibits both stable and rapid reactive oxygen species (ROS) generation capacity and negligible cytotoxicity, positioning it as an ideal candidate for synergistic application. Mechanistically, photodynamic treatment with NC-PhBDP-I not only induces rapid bacterial membrane disruption but also potently activates BV-2 microglial phagocytic activity, leading to accelerated clearance of residual bacteria that survive the initial photodynamic insult. This dual-modal action results in a pronounced synergistic effect, with the combination markedly surpassing the sum of individual effects from photodynamic treatment or microglial engagement alone. Our findings establish an integrated chemical-biological platform that leverages both photodynamic and innate immune functions, offering a promising strategy for combating bacterial infections in the context of AD and beyond.},
}

@article {pmid42906579,
year = {2026},
author = {Yuwadee, A and Boonprasert, K and Na-Bangchang, K},
title = {Pharmacological Activities of Centella asiatica: A Systematic Review of Preclinical and Clinical Evidence on Cardiovascular, Neurological, Antioxidant, and Anti-inflammatory Effects.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2969-6239},
pmid = {42906579},
issn = {1439-0221},
support = {N42A671041//National Research Council of Thailand (NRCT)/ ; 2025,TUFT-FF49/2569//Thailand Science Research and Innovation Fundamental Fund Fiscal Year/ ; },
abstract = {Centella asiatica (L.) (Gotu Kola) is a medicinal herb traditionally used in Asia for cognitive enhancement, wound healing, and systemic disorders. This systematic review appraises preclinical and clinical evidence on its cardiovascular and neurological effects. Following PRISMA 2020, we searched PubMed, ScienceDirect, Scopus, Embase, and ClinicalTrials.gov (to June 2026) for studies of whole-plant extracts or bioactive compounds (asiatic acid, asiaticoside, madecassoside, madecassic acid, caffeoylquinic acids) in vitro, in animals, or in humans, excluding dermatological studies, reviews, and articles lacking methods. Sixty-two studies met criteria: 54 preclinical and eight clinical trials, assessed using SYRCLE, an in vitro checklist, and Cochrane RoB 2. Preclinically, C. asiatica modulated ischemia-reperfusion injury, reduced doxorubicin-induced cardiotoxicity, improved cognitive deficits in Alzheimer's and Parkinson's models, and showed antidepressant-like effects, via Nrf2/HO-1 antioxidant activation and NF-κB/MAPK anti-inflammatory suppression. Clinical evidence was mixed: Gotu Kola matched or exceeded folic acid for poststroke vascular cognitive impairment, and three trials of a standardized triterpenic fraction (TTFCA) improved microcirculation in venous hypertensive and diabetic microangiopathy; however, a type 2 diabetes trial found no significant effect on glycated hemoglobin, glucose, or LDL cholesterol, a mild cognitive impairment trial found no added benefit over exercise alone, and a Phase 1 safety trial is ongoing. C. asiatica shows preclinical promise as a multitarget cardiovascular and neurological agent, but clinical evidence remains limited and inconsistent, compounded by an 800-fold preclinical dosing range, variable treatment durations, and geographic concentration (47% from one country). Larger, standardized, multiregion trials targeting these outcomes are needed before therapeutic claims are warranted.},
}

@article {pmid42906637,
year = {2026},
author = {Hong, EH and Kim, A and Kim, KY and Rhee, HY and Shin, DI and Kim, JY and Cho, SJ and Kim, DY and Jahng, GH and Lee, HB and Park, WY and Kim, BH and Chung, WK},
title = {Cognitive outcomes of low-dose whole-brain radiation therapy in mild Alzheimer's disease: A multicenter, randomized, sham-controlled phase II clinical trial.},
journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology},
volume = {},
number = {},
pages = {111833},
doi = {10.1016/j.radonc.2026.111833},
pmid = {42906637},
issn = {1879-0887},
abstract = {BACKGROUND AND PURPOSE: Low-dose radiotherapy (LDRT) has shown potential in preclinical Alzheimer's disease (AD) models, but controlled clinical evidence is limited. We evaluated two whole-brain LDRT regimens in mild AD.

MATERIALS AND METHODS: In this multicenter, participant-blinded, three-arm phase II trial, amyloid-positive participants were randomized 1:1:1 to sham irradiation, 0.04 Gy per fraction (0.24 Gy total), or 0.5 Gy per fraction (3 Gy total), delivered twice weekly for 3 weeks. The primary endpoint was change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score from baseline to 6 months. Twelve-month analyses were exploratory. Longitudinal outcomes were estimated using mixed-effects models.

RESULTS: Forty-one participants were randomized; 36 were included in the modified intention-to-treat population and 30 completed 12-month follow-up. At 6 months, adjusted between-group differences in ADAS-cog change versus sham were -2.08 points (95% CI, -7.06 to 2.89; p = 0.401) for 0.24 Gy and -2.92 points (95% CI, -6.72 to 0.89; p = 0.129) for 3 Gy. At 12 months, the corresponding exploratory differences were -3.02 points (95% CI, -10.00 to 3.96; p = 0.386) and -5.36 points (95% CI, -10.58 to -0.14; nominal p = 0.044). No treatment-related adverse events or radiologic safety concerns were identified.

CONCLUSIONS: The prespecified 6-month primary endpoint was not met. Exploratory 12-month and secondary analyses showed differences in selected cognitive outcomes, although the findings varied across doses and outcomes. These findings did not establish efficacy or a dose-response relationship and warrant confirmation in a larger trial with longer follow-up.},
}

@article {pmid42906650,
year = {2026},
author = {Zhai, Y and Acuña, MA and Krzyszkowski, A and Al-Haj, S and Nevian, NE and Finn, DP and Nevian, T and Kwakowsky, A},
title = {Caffeine attenuates Aβ-induced hippocampal dysfunction alongside changes in adenosine receptor-linked GABA handling and neuronal excitability.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109697},
doi = {10.1016/j.phrs.2026.109697},
pmid = {42906650},
issn = {1096-1186},
abstract = {Synaptic and circuit dysfunction in the hippocampus is an early feature of Alzheimer's disease, involving disturbances at both excitatory and inhibitory synapses. Adenosine receptors (ARs) regulate hippocampal glutamatergic and GABAergic signaling. Caffeine, a non-selective AR antagonist, has well-established neuroprotective actions. We examined whether caffeine attenuates amyloid-β (Aβ)-induced changes in neuronal viability, GABA handling, intrinsic excitability and synaptic excitation/inhibition (E/I) balance, and whether these functional effects occur alongside changes in AR and GABA transporter 1 (GAT-1) protein abundance. Primary mouse hippocampal cultures were exposed to Aβ1-42 (1nM) and/or caffeine (0.1, 1, 25, and 50µM) for culture-based assays, whereas acute hippocampal slices were exposed to Aβ1-42 (100nM) and/or caffeine (25µM) during whole-cell patch-clamp recordings from CA1 pyramidal neurons. In cultures, Aβ increased neuronal death, confirming previous reports, and caffeine co-treatment attenuated this effect. Total GAT-1, A1R and A2AR protein levels were unchanged, whereas Aβ reduced neuronal A1R immunoreactivity; this reduction was not observed with caffeine co-treatment. Radiometric assays identified treatment-associated differences in 1-h [3]H-GABA accumulation and basal [3]H-GABA outflow, including a non-significant trend toward increased accumulation after Aβ exposure and reduced accumulation in the Aβ+caffeine condition. In slices, Aβ flattened the frequency-current relationship and transiently reduced the E/I ratio, whereas these changes were not observed during caffeine co-application; subsequent caffeine exposure restored firing output after 30min of Aβ exposure. Further experiments are required to establish if changes in A1R immunoreactivity or radiometric GABA handling contribute to the electrophysiological effects.},
}

@article {pmid42906859,
year = {2026},
author = {Haller, OJ and Carr, LM and Semendric, I and George, RP and Whittaker, AL and Collins-Praino, LE},
title = {Evaluating the NLRP3 inflammasome in chemotherapy-induced cognitive impairment: A multi-timepoint study of methotrexate and 5-fluorouracil in female rats.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116542},
doi = {10.1016/j.bbr.2026.116542},
pmid = {42906859},
issn = {1872-7549},
abstract = {Chemotherapy-induced cognitive impairment (CICI) affects many cancer survivors, who often report cognitive difficulties during and/or after treatment that reduce quality of life. While the exact mechanisms that underlie CICI are unclear, neuroinflammation is widely proposed to contribute. One candidate mediator is the nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor protein 3 (NLRP3) inflammasome, which drives microglial inflammation and is implicated in Parkinson's and Alzheimer's disease. This study therefore investigated whether NLRP3 inflammasome components are altered in a rat model of CICI. Female Sprague Dawley rats were randomly allocated to receive methotrexate (MTX), 5-fluorouracil (5-FU) or saline (n = 18/treatment) and were euthanised at 96-hours, 31-days or 93-days post-treatment (n = 6/treatment/timepoint). This cohort was previously shown to develop cognitive deficits. In the prefrontal cortex and hippocampus, NLRP3 and pro-caspase-1 were measured by western blot, and interleukin-1β (IL-1β) by ELISA. Microglial number and activation were assessed by ionized calcium-binding adaptor molecule 1 (IBA1) immunohistochemistry (n = 4/treatment/timepoint). Compared with saline controls, neither chemotherapy altered NLRP3 or pro-caspase-1 in either brain region at any timepoint, and treatment effect sizes were small (ηp[2] ≤ 0.06). IL-1β, detectable only at 96-hours, was also unchanged. Similarly, there were no differences in either total microglial number or the percentage of activated microglia. These findings provide no evidence that NLRP3 inflammasome components are altered in this female rat model of CICI at the timepoints examined. However, as inflammasome assembly and activation were not directly assessed, future work should measure ASC speck formation, cleaved caspase-1 and mature IL-1β, and include earlier timepoints, particularly within the first two weeks after chemotherapy.},
}

@article {pmid42907679,
year = {2026},
author = {Wu, Y and Zhu, L and Chen, J and Liu, J and Yin, K and Yang, X},
title = {Real-world safety and efficacy of lecanemab in the treatment of Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42907679},
issn = {1432-1459},
support = {82560237，81960242//National Natural Science Foundation of China/ ; 202301AS070045//Applied Basic Research Foundation of Yunnan Province/ ; 202102AA310061//Yunnan Province Clinical Research Center for Neurological Disease/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Despite the approval of lecanemab for Alzheimer's disease (AD), evidence regarding its performance outside controlled trial settings remains scarce, leaving its real-world safety and clinical utility largely unknown.

METHODS: We searched PubMed, Embase, and Web of Science (through October 1, 2026) for real-world studies of lecanemab in AD. Outcomes included ARIA, discontinuation, infusion-related reactions, serious adverse events, MMSE, MoCA, CDR-SB, and amyloid PET. Random-effects models with REML and Hartung-Knapp adjustment were used. Subgroup analyses were stratified by region, APOE ε4 genotype, baseline CDR score, microhemorrhage, and white matter hyperintensity. Sensitivity analyses included leave-one-out and Egger's test. Scenario-based sensitivity analyses were also performed for overlapping cohorts. This study was registered with PROSPERO (No. CRD420261333493).

RESULTS: Thirty-seven studies were included. For overlapping cohorts, the largest dataset per outcome was retained after prioritizing peer-reviewed reports. Pooled incidence of any ARIA was 15.1% (US vs Asian studies 19.5% vs 9.7%), ARIA-E 6.5% (10.6% vs 2.5%), ARIA-H 11.5% (15.2% vs 7.0%), and symptomatic ARIA 1.3% (3.3% vs 0.1%). APOE ε4 homozygotes showed the highest rates across all three subtypes (any ARIA 34.1%, ARIA-E 10.3%, ARIA-H 18.9%), followed by heterozygotes (14.5%, 4.7%, 12.0%) and non-carriers (11.0%, 2.9%, 6.7%). Baseline microhemorrhage was associated with higher any ARIA (23.4% vs 11.5%) and ARIA-H (19.3% vs 4.2%), but not ARIA-E (5.4% vs 5.7%). ARIA incidence did not differ significantly by baseline CDR severity or deep white matter hyperintensity burden. Except for MoCA at ≤ 3 months (MD 0.515, 95% CI 0.451-0.578; 2 studies), no statistically significant changes were observed in cognitive outcomes. Amyloid PET decreased at 6 months (Centiloid MD -28.453, 95% CI -37.708 to -19.198) and 12 months (SUVR MD -0.171, 95% CI -0.291 to -0.052). Discontinuation rates were 3.5% (ARIA-related), 6.2% (adverse event-related), and 12.2% (total); infusion-related reactions were 18.5% and serious adverse events 2.8%. Sensitivity analyses supported robustness.

CONCLUSIONS: This is the first large-scale systematic review and meta-analysis of real-world studies of lecanemab reporting safety and efficacy outcomes. Safety outcomes particularly ARIA may be influenced by APOE ε4 genotype and baseline microbleeds. Cognitive outcomes lacking control data cannot confirm efficacy and longer-term cross-regional controlled studies are needed.},
}

Humans
*Alzheimer Disease/drug therapy

@article {pmid42908770,
year = {2026},
author = {Yoon, S and Ahn, J and Kim, S and Kim, K and Kim, SY and An, SK and Na, DG and Kim, YJ and Kwak, K and Seo, SW and Na, DL},
title = {Topography and risk factors of amyloid-related imaging abnormality: real-world data from 168 aducanumab-treated patients at a private clinic in South Korea.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70473},
pmid = {42908770},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid-related imaging abnormalities (ARIA) are a major safety concern in anti-amyloid therapy for Alzheimer's disease (AD), but real-world data remain limited. We investigated risk factors, temporal characteristics, and spatial distribution of ARIA in aducanumab-treated patients and assessed the safety of apolipoprotein E (APOE) genotype-tailored dosing.

METHODS: We retrospectively analyzed 168 patients with a Clinical Dementia Rating (CDR) of 0.5 to 2 treated with aducanumab between 2022 and 2024. Dosing was individualized by APOE genotype. Serial magnetic resonance imaging (MRI) detected ARIA, multivariable regression identified risk factors, and ARIA with edema or effusion (ARIA-E) lesions were manually segmented to generate topographical maps.

RESULTS: Among 164 patients, 33 (20.1%) developed ARIA-E, with incidence increasing by APOE ε4 status (12.5% non-carriers, 19.5% heterozygotes, 50.0% homozygotes; p = 0.002). Lesions showed posterior predominance. Independent risk factors included APOE ε4 homozygosity, CDR 2, and hypertension. Most cases did not require treatment discontinuation.

DISCUSSION: ARIA-E risk during aducanumab therapy was influenced by genetic and clinical factors, supporting genotype-tailored titration in practice.},
}

@article {pmid42909413,
year = {2026},
author = {Jie, S and Lei, Z},
title = {Pyroptosis: a potential target and research progress of exercise in ameliorating Alzheimer's disease pathology.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1983962},
pmid = {42909413},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), a debilitating neurodegenerative disorder that severely threatens elderly health, is clinically manifested as cognitive decline and driven by core pathological hallmarks including amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and chronic neuroinflammation. Recent studies have indicated that its pathophysiological process is closely associated with pyroptosis, and excessive activation of pyroptosis drives a vicious cycle of amplified inflammation and neuronal injury. Although accumulating evidence suggests that exercise serves as an effective non-pharmacological intervention to suppress pyroptosis and alleviate AD, the intrinsic interactive mechanisms among exercise, pyroptosis and the pathological progression of AD remain incompletely elucidated. Therefore, this review systematically summarizes the functional mechanisms of pyroptosis in the pathological progression of AD and discusses the potential neuroprotective effects of exercise intervention. It further focuses on analyzing the specific mechanisms by which exercise inhibits pyroptosis via regulating the NLRP3 inflammasome pathway, aiming to identify novel targets for the prevention and treatment of AD and provide a theoretical basis for formulating scientific exercise intervention strategies.},
}

@article {pmid42909680,
year = {2026},
author = {Sura, S and Jagadeesan, S and Masrudin, SS and Moklas, MAM and Nor, NHM},
title = {Cannabidiol in Alzheimer's disease: evidence-weighted molecular mechanisms and translational challenges.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42909680},
issn = {1573-4978},
support = {(Grant No. GP-IPM/2021/9700000)//Universiti Putra Malaysia through the Institutional Grant Scheme/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Cannabidiol/therapeutic use/pharmacology/metabolism ; Animals ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder in which amyloid-β accumulation, tau dysregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic loss and neurodegeneration interact to drive memory loss and cognitive decline. Despite advances in symptomatic therapies and anti-amyloid agents, clinical benefit remains modest, supporting interest in polypharmacological approaches. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that interacts with several signalling systems relevant to AD, including cannabinoid-related pathways, peroxisome proliferator-activated receptor-γ (PPARγ), transient receptor potential vanilloid 1 (TRPV1) channels, 5-HT1A signalling, fatty acid-binding proteins involved in anandamide transport, GPR55 and adenosine transporters. The most consistent preclinical findings indicate that CBD attenuates neuroinflammatory and oxidative responses and improves selected behavioural outcomes. Evidence for amyloid-related effects is supportive but heterogeneous. Direct evidence for tau modulation has expanded in transgenic and chemically induced models, but findings remain model-dependent, whereas mitochondrial rescue and adult hippocampal neurogenesis are less firmly established. Methodological variability in CBD source, formulation, dose, route, treatment window, sex, age and outcome selection limits direct comparison between studies. Work on other cannabinoids and CBD:Δ9-THC combinations is discussed for context, and current evidence does not establish CBD as a disease-modifying treatment in AD. Overall, current preclinical evidence supports continued investigation of CBD as a multi-target neuroprotective candidate in AD, provided that future studies use standardized, mechanism-focused and translationally relevant designs. This review compares preclinical evidence across pathological domains and identifies translational research priorities.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Cannabidiol/therapeutic use/pharmacology/metabolism
Animals
Oxidative Stress/drug effects
Amyloid beta-Peptides/metabolism
Signal Transduction/drug effects

@article {pmid42909797,
year = {2026},
author = {Cicin, FN},
title = {The Role of Digital Twins in Clinical Trials: A New Perspective on Methodological and Statistical Challenges.},
journal = {Therapeutic innovation & regulatory science},
volume = {},
number = {},
pages = {},
pmid = {42909797},
issn = {2168-4804},
abstract = {BACKGROUND: Randomized controlled trials (RCTs) remain the gold standard for evaluating medical interventions, yet they face persistent methodological challenges: patient dropout, inadequate sample sizes, premature termination, missing data, and the limitations of indirect treatment comparisons. The emergence of digital twin technology-computational patient representations that generate simulated clinical trajectories statistically indistinguishable from real-world data-offers a promising methodological complement to address these limitations.

APPROACH: We synthesize evidence from key methodological literature, regulatory guidance (ICH E9(R1), FDA, EMA), and proof-of-concept studies across oncology, neurology, and Alzheimer's disease. A taxonomy of in silico clinical trial approaches provides the organizational framework. This article is a narrative perspective rather than a systematic review; no predefined search strategy, database range, or inclusion/exclusion criteria were applied.

RESULTS: Digital twins may provide complementary methodological approaches across nine trial challenges: model-based sensitivity analyses for missing (MNAR) outcomes; Bayesian and posterior predictive modeling of partially observed longitudinal outcomes; prognostic covariate adjustment and virtual augmentation to improve efficiency; prospective simulation of futility stopping rules; prospective calibration of efficacy stopping boundaries; individualized control-arm (ICA) construction; hybrid augmented and synthetic control strategies; pre-trial protocol optimization through in silico simulation; and population-adjusted indirect treatment comparison.

CONCLUSIONS: Digital twins represent an emerging methodological ecosystem rather than isolated tools. Their methodological potential depends on consistent validation and explainability standards; frameworks for detecting algorithmic bias; clarification of regulatory acceptance criteria; and comprehensive data infrastructure addressing representativeness gaps. Digital twin approaches should be viewed as complementary to-not replacements for-established randomized trial methodology.},
}

@article {pmid42909824,
year = {2026},
author = {Liu, X and Du, X and Qi, S and Yuan, L and Liu, L and Zhang, K and Wang, L and Zhang, W and Liu, Q and Wu, M and Huang, Y},
title = {Circadian rhythms in health and disease.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {42909824},
issn = {2662-8651},
support = {82201594//National Natural Science Foundation of China/ ; 81502582//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Circadian Rhythm/physiology/genetics ; Animals ; },
abstract = {Circadian rhythms, serving as a crucial temporal bridge linking neural activity and pathological biology, are regulated by central pacemaker neurons to maintain cellular homeostasis and coordinate diverse biological processes. Circadian rhythm disruption is closely associated with various diseases, including neurodegenerative disorders, metabolic disorders, and cancer. Circadian rhythms are controlled by core clock genes, such as BMAL1 and CLOCK, modulating numerous physiological processes, encompassing metabolism, immune responses, neural activity, and hormone regulation. Circadian rhythms disruptions arising from shift work, jet lag, or inconsistent sleep schedules are implicated in both the onset and progression of numerous diseases, notably Alzheimer's disease, Parkinson's disease, diabetes, and cardiovascular disease. The article highlights how circadian dysregulation alters cellular processes to potentially accelerate disease progression. Circadian disruption results in impaired immune function, further promoting disease development and resistance to treatment. Potential therapeutic applications based on circadian biology, such as chronotherapy and personalized medicine, are also discussed. Recent technological advances, embodied in wearable devices and omics approaches, are increasingly providing deeper insights into circadian biology. Further unveiling the role of circadian in health and disease opens new avenues for tailoring treatment timing to patients' biological rhythms, thereby enhancing therapeutic outcomes across various diseases. By bridging fundamental circadian mechanisms with clinical pathology, this review provides a roadmap for future chronotherapeutic interventions in precision medicine.},
}

Humans
*Circadian Rhythm/physiology/genetics
Animals

@article {pmid42911093,
year = {2026},
author = {Smith, PJ and Ingle, KK and Nakamura, Z and Strauman, T and Keyserling, T and Parker, D and Nelson, C and Muoio, DM and Huffman, KM},
title = {Time restricted eating through self-regulatory behaviors for metabolic and cognitive health in mild cognitive impairment: Feasibility and acceptability findings from the TEMPO trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497622},
doi = {10.1177/13872877261497622},
pmid = {42911093},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) and Alzheimer's disease and related dementias (ADRD) occur at 1.5-2-fold higher rates among adults with obesity or metabolic syndrome. Time restricted eating (TRE) represents a portable and potentially effective strategy to enhance metabolic function and reduce ADRD risk.ObjectiveTo assess the feasibility and acceptability of TRE among older adults with MCI and metabolic risk.MethodsWe assessed a 16-18-h TRE protocol, implemented 2-3 days per week, among older adults (65-85 years of age) with MCI (proposed n = 40) and metabolic risk over 12-weeks. Feasibility was assessed by recruitment and completion of trial activities, while Acceptability was assessed using psychometric self-report. Cognitive function was assessed using a standard neuropsychological test battery, including tests of Executive Function/Processing Speed (Trail Making, Stroop, Controlled Oral Word Association Test, Animal Naming, Digit Span, and Digit Symbol Substitution Tests), Learning/Memory (Hopkins Verbal Learning Test-Revised and Benton Visual Memory Test-Revised. We also examined treatment- and state-dependent changes in metabolic and inflammatory biomarkers, including multiple ketone metabolites and pro-inflammatory cytokines, among others.ResultsFrom 9/28/23 until 3/25/25, thirty-three individuals (83% of target goal [n = 40]) were recruited. Enrolled participants completed all treatment sessions and assessments (100%) and self-reported Acceptability was high. Modification of study recruitment practices and inclusion criteria allowed for an increased screening-to-recruitment ratios over the course of the trial, rising from 1.3% to 11.1%, while still resulting in appropriate recruitment of individuals with MCI.ConclusionsTRE is a feasible and acceptable intervention among older adults with metabolic risk factors.},
}

@article {pmid42911292,
year = {2026},
author = {Ng, S and Somvanshi, RK and Kumar, U},
title = {Cannabidiol Regulates Amyloid-β Plaque Deposition and Astrogliosis in the 5xFAD Transgenic Mouse Model.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42911292},
issn = {1559-1166},
mesh = {Animals ; *Cannabidiol/pharmacology/therapeutic use ; Mice, Transgenic ; *Plaque, Amyloid/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; PPAR gamma/metabolism/genetics ; Mice ; Receptor, Cannabinoid, CB1/metabolism/genetics ; Receptor, Cannabinoid, CB2/metabolism/genetics ; Astrocytes/drug effects/metabolism ; Glial Fibrillary Acidic Protein/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; *Gliosis/drug therapy ; Cerebral Cortex/metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Alzheimer's Disease (AD) is marked by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuroinflammation. Cannabidiol (CBD), the major non-psychoactive compound of Cannabis, has demonstrated significant pharmacological potential for the treatment of AD. CBD is known to act on various receptors, including cannabinoid receptor 1 (CB1R) and 2 (CB2R), and peroxisome proliferator activated receptor γ (PPARγ). However, the precise changes in receptor expression in AD, as well as following CBD treatment, remain unclear and inconsistent in literature. To address this, we performed immunohistochemistry and immunoblotting in AD-compromised brain regions, specifically the cortex and the hippocampus. In 5xFAD transgenic (TG) mice, we noted strong deposition of Aβ plaques and glial fibrillary acidic protein (GFAP)- positive astrocytes. However, following CBD treatment, Aβ plaque burden and GFAP accumulation were significantly reduced. We observed increased CB1R expression in the cortex of TG mice, in comparison to age-matched wild-type control mice. CB2R expression changes were insignificant between the two groups, however, following CBD treatment, CB2R expression was significantly increased. Interestingly, we demonstrated PPARγ co-expressed with Aβ plaques in TG mice, and following CBD treatment, PPARγ co-expression increased. Lastly, we demonstrated dysregulations of the PI3K signaling pathway observed in TG mice was ameliorated with CBD treatment. In this study, we attributed the effects of CBD on AD-related biomarkers, particularly decreased Aβ plaque load and neuroinflammation, to the alterations in CB2R and PPARγ expression.},
}

Animals
*Cannabidiol/pharmacology/therapeutic use
Mice, Transgenic
*Plaque, Amyloid/drug therapy/metabolism
*Alzheimer Disease/drug therapy/metabolism
PPAR gamma/metabolism/genetics
Mice
Receptor, Cannabinoid, CB1/metabolism/genetics
Receptor, Cannabinoid, CB2/metabolism/genetics
Astrocytes/drug effects/metabolism
Glial Fibrillary Acidic Protein/metabolism/genetics
Amyloid beta-Peptides/metabolism
*Gliosis/drug therapy
Cerebral Cortex/metabolism/drug effects
Hippocampus/metabolism/drug effects
Amyloid beta-Protein Precursor/genetics

@article {pmid42893563,
year = {2026},
author = {Altas, B and Georgiou, P and Onisiforou, A},
title = {AI-bioinformatics synergy for precision medicine in brain diseases: integrating radiomics and multi-omics data.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {5},
pages = {},
pmid = {42893563},
issn = {1477-4054},
support = {//IDSA Foundation/ ; },
mesh = {Humans ; Radiomics ; *Precision Medicine/methods ; Multiomics ; *Computational Biology/methods ; *Artificial Intelligence ; *Brain Diseases/diagnostic imaging/genetics/metabolism ; Genomics ; Proteomics ; Brain Neoplasms/diagnostic imaging ; },
abstract = {The convergence of artificial intelligence (AI) and bioinformatics is reshaping the landscape of precision medicine in brain diseases, particularly in neurological diseases and brain tumors. Despite advances in both fields, the combined application of radiomics and multi-omics fusion remains underutilized, even though integrative frameworks are essential for addressing the complexity and heterogeneity of imaging and molecular data. This review examines how integrative AI-bioinformatics frameworks enable the fusion of radiomics with genomics, transcriptomics, proteomics, and other omics modalities to more comprehensively model disease complexity. Leveraging deep learning, graph neural networks, and advanced representation learning, these multimodal systems facilitate biomarker discovery, patient stratification, and personalized treatment strategies. We critically evaluate key challenges including data heterogeneity, limited interpretability, and barriers to clinical validation, and highlight emerging solutions aimed at enhancing reproducibility and translational readiness. Case studies in gliomas, Alzheimer's disease, and multiple sclerosis illustrate the clinical utility of unified imaging-omics architectures. Ultimately, this review positions radiomics and multi-omics integration as a foundational approach for the next generation of precision medicine in brain diseases by bridging the gap between computational innovation and clinical application.},
}

Humans
Radiomics
*Precision Medicine/methods
Multiomics
*Computational Biology/methods
*Artificial Intelligence
*Brain Diseases/diagnostic imaging/genetics/metabolism
Genomics
Proteomics
Brain Neoplasms/diagnostic imaging

@article {pmid42894266,
year = {2026},
author = {Hasegawa, C and Doi, Y and Hirano, T and Shirakawa, M and Tsuchiya, S and Yoshitsugu, H and Furihata, K and Miller, C and Singh, S and Cabalu, T and Yee, KL and Bueters, T and Alexopoulou, Z},
title = {A Phase 1 Study of MK-1942, a Negative Allosteric Modulator of mGluR2, in Healthy Japanese to Flexibly Assess Factors Including CYP2C19 Phenotype.},
journal = {Clinical and translational science},
volume = {19},
number = {11},
pages = {e70748},
pmid = {42894266},
issn = {1752-8062},
support = {//Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, New Jersey, USA/ ; },
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; Allosteric Regulation/drug effects ; Area Under Curve ; *Cytochrome P-450 CYP2C19/genetics/metabolism ; Double-Blind Method ; Healthy Volunteers ; Japan ; Phenotype ; *Receptors, Metabotropic Glutamate/metabolism/antagonists & inhibitors ; East Asian People/genetics ; },
abstract = {MK-1942 is a negative allosteric modulator of the metabotropic glutamate receptor 2 that was investigated for the treatment of Alzheimer's disease and depression. Nonclinical studies with recombinant human CYPs and genotyped human hepatocytes suggested that CYP2C19 is involved in the metabolism of MK-1942. Given the high incidence of different CYP2C19 polymorphisms in the Japanese population, a Phase 1 single and multiple dose study in healthy Japanese participants provided an opportunity to determine the involvement of CYP2C19 phenotype on the clinical PK of MK-1942. Also, since a first-in-human study in non-Japanese showed a decrease in exposures after administration with high-fat meal, we further tested an effect of low-fat meal on PK in the Japan study. The study was designed with flexibility which enabled dose selection for the multiple dose panels, based on the totality of safety and PK data. Oral administration of single and multiple doses of MK-1942 in Japanese participants was generally well tolerated. AUC0-inf was comparable between fasted and fed (low-fat meal) state. Following a single dose of MK-1942, AUC0-inf was ~70% increased in CYP2C19 poor metabolizer (PM) vs. extensive metabolizer (EM). Therefore, a decision was made to test the multiple dose separately for each CYP2C19 phenotype, rather than grouping them into a single panel. As opposed to the expectation from the single dose result, steady state exposures were similar among CYP2C19 phenotypes. These data supported the subsequent global Phase 2 study to permit a low-fat meal around dosing and no dose adjustment for any CYP2C19 phenotype.},
}

Adult
Female
Humans
Male
Middle Aged
Young Adult
Administration, Oral
Allosteric Regulation/drug effects
Area Under Curve
*Cytochrome P-450 CYP2C19/genetics/metabolism
Double-Blind Method
Healthy Volunteers
Japan
Phenotype
*Receptors, Metabotropic Glutamate/metabolism/antagonists & inhibitors
East Asian People/genetics

@article {pmid42894468,
year = {2026},
author = {Markus, HS},
title = {Vascular dementia and vascular cognitive impairment-current treatments and future prospects.},
journal = {International journal of stroke : official journal of the International Stroke Society},
volume = {21},
number = {9},
pages = {1200-1210},
pmid = {42894468},
issn = {1747-4949},
mesh = {Humans ; *Dementia, Vascular/therapy/physiopathology ; *Cognition Disorders/therapy/etiology ; },
abstract = {Vascular cognitive impairment (VCI) and vascular dementia (VaD) represent a substantial and growing global health burden, yet remain under-recognized and comparatively under-researched. Two broad categories are post-stroke cognitive impairment, and VCI secondary to chronic cerebrovascular disease of which the most common cause is cerebral small vessel disease (SVD). In addition, cerebrovascular pathology frequently coexists with Alzheimer's disease (AD), increasing the probability that AD pathology will manifest as clinical dementia. Current management focuses primarily on prevention through modification of cardiovascular risk factors and lifestyle interventions. Intensive blood-pressure control has shown the strongest evidence, reducing future all-cause dementia while slowing progression of white-matter abnormalities. Multidomain lifestyle interventions incorporating exercise, diet, cognitive training, and vascular risk monitoring may also preserve cognition, although results across trials remain variable. In established VCI and VaD, treatment options are limited; cholinesterase inhibitors and memantine lack convincing evidence of benefit, and no pharmacological therapy has definitively demonstrated symptomatic improvement or delayed disease progression. Advances in understanding SVD and VCI pathophysiology are, however, identifying promising therapeutic targets. Emerging evidence highlights endothelial dysfunction, impaired cerebral autoregulation, increased blood-brain barrier permeability, inflammation, and glymphatic dysfunction as possible mechanisms underlying SVD. Current trials are evaluating treatment approaches based on this framework including cerebral vasodilators such as cilostazol, isosorbide mononitrate and phosphodiesterase-5 inhibitors, anti-inflammatory therapies, glucagon-like peptide-1 receptor agonists, remote ischemic conditioning, and strategies targeting glymphatic function. Improved mechanistic understanding, appropriately targeted interventions, and adequately powered long-term clinical trials are required to translate these emerging approaches into effective treatments for VCI and VaD.},
}

Humans
*Dementia, Vascular/therapy/physiopathology
*Cognition Disorders/therapy/etiology

@article {pmid42895147,
year = {2026},
author = {Chaudhary, S and Dhankhar, S and Saini, M and Singh, TG and Chauhan, S and Kumar, V},
title = {Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273491538261009064612},
pmid = {42895147},
issn = {1996-3181},
abstract = {More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little effect on changing the course of the disease and are largely symptomatic. Psilocybin, a naturally occurring tryptamine alkaloid from psilocybin mushrooms, has become a promising medicinal agent because of its hallucinogenic, neuroprotective, and neuroplastic properties. After being metabolically transformed into its active form, psilocin, it primarily activates serotonin 5-HT2A receptors. This modulates glutamatergic neurotransmission and neurotrophic signaling pathways such as BDNF/TrkB and mTOR, which regulate synaptic remodeling, dendritic complexity, neurogenesis, neuroinflammatory response, and default mode network connectivity, all of which are linked to depression and dementia. Preclinical research studies demonstrate that psilocybin increases hippocampal plasticity, restores dendritic complexity, lowers proinflammatory cytokine levels, and promotes fear extinction in experimental models of stress, ischemic stroke, and neurodegeneration. Emerging clinical studies also indicate that individuals with moderate cognitive impairment, early-onset Alzheimer's disease, and Parkinson's disease may see long-term decreases in anxiety and depression as well as improvements in cognitive function, frequently after a single dose administration. Additionally, psilocybin has demonstrated promise in treating mental comorbidities that often accompany neurodegenerative illness, such as treatment-resistant depression, drug use disorders, and obsessive-compulsive disorder. However, there are still significant obstacles to overcome, such as optimizing dosing schedules, assessing safety issues such as temporary perceptual abnormalities and cardiovascular consequences, and translating preclinical results into extensive phase -III clinical studies. This review incorporates the most recent data on psilocybin's chemistry, pharmacology, metabolism, and mechanistic actions; it highlights the drug's therapeutic potential across a variety of neurodegenerative diseases and emphasizes the necessity of carefully planned randomized controlled trials to determine clinical efficacy, long-term safety, and its place in multimodal treatment approaches.},
}

@article {pmid42895489,
year = {2026},
author = {Liang, X and Jiang, C and Zhug, H and Sun, Y and Tu, S and Kang, J},
title = {Deep Cervical Lymphaticovenous Anastomosis (LVA) for Alzheimer's Disease: A Case Report.},
journal = {Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jopan.2026.08.005},
pmid = {42895489},
issn = {1532-8473},
abstract = {This case report describes the short-term observed clinical course of a 65-year-old patient with Alzheimer's disease (AD) who underwent deep cervical lymphaticovenous anastomosis (LVA) under general anesthesia, and summarizes the perianesthesia nursing care provided before, during, and after anesthesia. Neuropsychological assessments showed limited changes in cognitive scores at 1 month after surgery, including a 1-point increase in MMSE and a 1-point decrease in ADAS-Cog, while ADCS-ADL declined. The NPI score decreased from 21 preoperatively to 0 on postoperative day 3 and remained lower than baseline, with a score of 2 at 1 month. Given the single-case design, short follow-up period, and lack of a control condition, these observations should be interpreted cautiously and cannot establish treatment efficacy. Deep cervical LVA may warrant further investigation as an exploratory surgical approach for AD, and perianesthesia nursing care may support perioperative safety, recovery, and complication prevention in this context. Further controlled studies with longer follow-up are needed.},
}

@article {pmid42897209,
year = {2026},
author = {Santoro, JD and Abdel-Latif, S and Banerjee, AK and Mager, H and Silverman, M and Kazerooni, L and Otey, ST and Yousuf, MM and Lucas, MC and Schlachetzki, Z and Rissman, RA and Rafii, MS},
title = {Phosphorylated tau 217 in young adults with Down syndrome and Down syndrome regression disorder.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42897209},
issn = {2730-664X},
support = {K23 HL155898/HL/NHLBI NIH HHS/United States ; K23HL155898//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {BACKGROUND: Down syndrome regression disorder (DSRD) causes a rapid loss of cognitive, behavioral, and daily living skills, usually in adolescents and young adults with Down syndrome. Because people with Down syndrome have a high lifetime risk of Alzheimer's disease, we examined whether DSRD is associated with an Alzheimer-related pattern of tau pathology.

METHODS: In this prospective, single-center study, we measured plasma phosphorylated tau-217 (p-tau217), a blood marker of Alzheimer pathology, in 132 participants: 48 with DSRD, 39 with Down syndrome without regression (DSwR), and 45 neurodevelopmental controls. We compared p-tau217 concentrations across groups and examined relationships with demographic factors, medical conditions, treatment status, and diagnostic test abnormalities.

RESULTS: Median p-tau217 concentrations were similar in the DSRD (0.082 pg/mL), DSwR (0.084 pg/mL), and neurodevelopmental control (0.080 pg/mL) groups (overall comparison, p  =  0.57). Pairwise comparisons and models accounting for demographic and clinical factors also showed no statistically significant group differences. Among participants with DSRD, p-tau217 was not associated with treatment status or abnormalities on brain-wave testing, neuroimaging, or cerebrospinal fluid analysis. No clinical or demographic factor remained associated with p-tau217 after accounting for the number of analyses performed.

CONCLUSIONS: These findings provide no evidence of a group-level Alzheimer-related p-tau217 elevation in young people with DSRD and support DSRD as a condition distinct from Alzheimer's disease. However, a single blood measurement cannot exclude Alzheimer pathology in an individual. Longitudinal studies using several complementary biomarkers are needed.},
}

@article {pmid42897323,
year = {2026},
author = {Armbrust, F and Bruhn, H and Bickenbach, K and Steen, N and Shcoory, S and Afratis, N and Korn, N and Körschgen, H and Moali, C and Pietrzik, CU and Sagi, I and Becker-Pauly, C},
title = {Meprin β is specifically inhibited by its cognate synthetic propeptide.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {83},
number = {1},
pages = {},
pmid = {42897323},
issn = {1420-9071},
mesh = {*Metalloendopeptidases/antagonists & inhibitors/metabolism ; Humans ; Animals ; *Protease Inhibitors/pharmacology/chemistry ; *Peptides/pharmacology/chemistry/chemical synthesis ; Mice ; Hydroxamic Acids/pharmacology ; },
abstract = {Meprin β is a zinc-dependent metalloprotease of the astacin family highly expressed in kidney and intestine. Dysregulation of meprin β expression and activity was observed in several pathological conditions such as Alzheimer's disease, cancer, fibrosis, and inflammatory bowel disease. Therefore, inhibition of meprin β could be a promising therapeutic option to treat pathological conditions influenced by this protease. However, available small-molecule compounds such as the broad-spectrum metalloproteinases inhibitors marimastat or actinonin lack specificity. Hence, more selective meprin β inhibitors needs to be developed. Here, we provide evidence that the synthetically generated cognate meprin β propeptide serves as highly specific inhibitor for the protease (IC50 = 1.35 µM), while other related metalloproteases such as meprin α and a disintegrin and metalloproteinases (ADAMs) are not affected. Employing a targeted approach revealed that removal of the last four C-terminal amino acids of the propeptide significantly improved its inhibitory capacity (IC50 = 0.68 µM). In cell-based experiments, treatment with the propeptide resulted in diminished meprin β activity and decreased cleavage of its substrates, including the interleukin-6 receptor (IL-6R) and the G protein-coupled receptor latrophilin-3 (LPHN3). Suitability was further confirmed in ex vivo cultivated organotypic brain slices, where the administration of the propeptide also resulted in decreased meprin β activity and diminished latrophilin-3 cleavage. Thus, not only the synthetic wildtype propeptide but especially a C-terminally truncated propeptide of meprin β represent highly specific inhibitors with potential for therapeutic application.},
}

*Metalloendopeptidases/antagonists & inhibitors/metabolism
Humans
Animals
*Protease Inhibitors/pharmacology/chemistry
*Peptides/pharmacology/chemistry/chemical synthesis
Mice
Hydroxamic Acids/pharmacology

@article {pmid42897722,
year = {2026},
author = {Grewal, P and Seidman, MB and Chasen, J and Lench, D and Dickens, I and Brennan, EA and Rodriguez-Porcel, F and Kindred, J and George, MS and Kautz, S and Caulfield, KA and McTeague, LM},
title = {Brain Stimulation as a Treatment for Apathy: A Scoping Review of Effects and Safety.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20250297},
doi = {10.1176/appi.neuropsych.20250297},
pmid = {42897722},
issn = {1545-7222},
abstract = {OBJECTIVE: Apathy is a neuropsychiatric syndrome characterized by impairment of goal-directed behavior, cognition, and emotional responsiveness. In this scoping review, the authors evaluated the literature on brain stimulation for the treatment of patients with apathy across diagnostic categories and provide recommendations to guide future research and practice.

METHODS: The authors searched PubMed, Scopus, and PsycInfo for studies involving brain stimulation for apathy as a primary or secondary outcome.

RESULTS: From 1,209 records, 52 studies evaluating brain stimulation were included; of these, 10 systematic reviews or meta-analyses were synthesized separately. Modalities included repetitive transcranial magnetic stimulation (rTMS; N=26), deep brain stimulation (DBS; N=7), transcranial direct current stimulation (tDCS; N=6), electroconvulsive therapy (N=1), transcranial alternating current stimulation (N=1), and transcranial pulsating electromagnetic field therapy (N=1). Populations included patients with schizophrenia (N=477), Parkinson's disease (PD; N=289), depression (N=288), Alzheimer's disease (AD) and mild cognitive impairment (MCI) (N=210), Huntington's disease (N=42), PD with MCI (N=28), traumatic brain injury (N=28), stroke (N=14), COVID-19 (N=12), and dementia with Lewy bodies (N=6) (total N=1,366). rTMS improved apathy measures, most consistently in AD, with positive trends in depression, MCI, stroke, and schizophrenia. tDCS showed variable effects, with some benefits for schizophrenia. DBS showed mixed results, varying with stimulation location. Observed adverse events were mild and modality specific.

CONCLUSIONS: Investigations into brain stimulation as a treatment for apathy show some promise. Conclusions were limited by small sample sizes, heterogeneous study designs, and variable outcome measures. Randomized trials with common validated apathy instruments, standardized stimulation parameters, and harmonized diagnostic measures may help advance the field.},
}

@article {pmid42897836,
year = {2026},
author = {Kumari, P and Sathyanarayanan, A and Pimpalkar, K and Kumar, A and Kumar, D and Chopade, S},
title = {Design, In Silico Targeting, and Characterization of Curcumin-Ibuprofen Prodrug Microspheres for Brain-Specific Delivery in Alzheimer's Therapy.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128447768260915075822},
pmid = {42897836},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a complex neurodegenerative condition characterized by limited treatment effectiveness, attributed to inadequate Blood-Brain Barrier (BBB) permeability and low medication absorption. Curcumin and ibuprofen possess anti-inflammatory and neuroprotective properties but are limited by pharmacokinetic constraints. This study aimed to synthesize a curcumin-ibuprofen mutual prodrug (CIP), formulate it into chitosan-based microspheres (CIPM), and evaluate its neuroprotective potential for brain-targeted delivery in AD.

METHODS: CIP was synthesized via ethylenediamine carbodiimide (EDCI) mediated esterification and confirmed through IR, NMR, LC-MS, and DSC. CIPM microspheres were prepared using emulsion crosslinking, characterized by scanning electron microscopy, drug entrapment efficiency (85.5%), zeta potential, particle size analysis, and DSC. In silico tools (SwissADME, ProTox-II) and molecular docking were used to assess ADMET profiles and target binding (AChE, BACE1, β-secretase). Network pharmacology identified overlapping targets between curcumin and AD. In vivo evaluation was conducted in a TMT (Trimethyltin)- induced neurodegeneration rat model through behavioral Morris Water Maze (MWM), Novel Object Recognition (NOR), Social Recognition Test (SRT), and biochemical and histological assessments.

RESULTS: CIP demonstrated strong binding affinity with AD-related targets (-10.0 to -8.5 kcal/mol) and favorable ADMET properties. Network analysis identified 226 overlapping targets and key hub genes. CIPM significantly improved cognitive performance, antioxidant enzyme levels, and neuronal integrity compared to individual drugs and showed comparable efficacy to donepezil.

DISCUSSION: The present study demonstrates that the curcumin-ibuprofen conjugate, when delivered through chitosan-based microspheres, effectively enhances brain targeting and overcomes pharmacokinetic barriers. The formulation not only improved drug bioavailability but also showed superior neuroprotective and cognitive benefits compared to individual drugs. Molecular docking and network pharmacology further confirmed its multi-target potential, suggesting a synergistic mechanism in modulating key AD pathways. These outcomes highlight CIPM as a promising candidate that warrants further pharmacokinetic and clinical validations for Alzheimer's therapy.

CONCLUSION: The curcumin-ibuprofen prodrug-loaded microspheres present a promising brain-targeted treatment approach for Alzheimer's disease by improving bioavailability, engaging multiple targets, and providing neuroprotection.},
}

@article {pmid42898005,
year = {2026},
author = {Rosenberg, A and Rennie, A and Ekman, U and Daniilidou, M and Hall, A and Matton, A and Solomon, A and Wahlund, LO and Kivipelto, M and Westman, E},
title = {Real-World Patient Eligibility for Alzheimer's Disease Anti-Amyloid Therapy in Seven Swedish Memory Clinics.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70786},
pmid = {42898005},
issn = {1468-1331},
support = {101112145//Innovative Health Initiative/ ; 101132933//Innovative Health Initiative/ ; //Region Stockholm (ALF)/ ; FoUI-104172//Center for Innovative Medicine/ ; 357810//EU Joint Programme - Neurodegenerative Disease Research/ ; AF-1031812//Alzheimerfonden/ ; 2025-02405//Vetenskapsrådet/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; FO2026-0228//Hjärnfonden/ ; 2025-02071//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; 2025-03749//VINNOVA/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Sweden ; Female ; Male ; Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; *Cognitive Dysfunction/drug therapy/cerebrospinal fluid ; *Eligibility Determination ; Cohort Studies ; },
abstract = {BACKGROUND: Anti-amyloid therapies lecanemab and donanemab are the first potentially disease-modifying treatments for Alzheimer's disease (AD) approved in Europe. We estimated real-world eligibility for these treatments in a large multicenter memory clinic patient cohort in Sweden (MemClin).

METHODS: MemClin included patients with a first diagnostic visit between 2016 and 2022 at seven specialist memory clinics in Stockholm, Sweden. To estimate eligibility for anti-amyloid therapy, we applied key inclusion/exclusion criteria from the lecanemab and donanemab appropriate use recommendations. Eligible patients were required to have (1) a clinical diagnosis of AD-type dementia or mild cognitive impairment (MCI), (2) confirmed Aβ pathology (abnormal CSF Aβ42) and (3) no apparent medical exclusion criteria. Eligibility was calculated for different scenarios to provide both upper-bound estimates (main analysis) and more conservative, implementation-ready estimates of near-term treatable patients (sensitivity analysis).

RESULTS: Cohort consisted of 2126 patients (mean age 77.1 ± 6.6 years; 61.8% MCI, 24.2% dementia, 13.7% subjective cognitive impairment). In the main analysis, 11.5% of the whole cohort was estimated to be eligible for either treatment (lecanemab 10.6%, donanemab 11.5%). Most eligible patients had early-stage disease (61.9% MCI vs. 38.1% dementia) and an A + T- biomarker profile, that is, normal biomarker of tau (57.9%). Eligibility was markedly lower in sensitivity analyses (e.g., 2.7% when all patients without MRI were assumed ineligible).

CONCLUSIONS: Even upper-bound estimates indicate that a minority of real-world memory clinic patients may currently qualify for anti-amyloid therapy. These findings provide timely evidence to inform the ongoing debate on the implementation of anti-amyloid therapy in public healthcare.},
}

Humans
*Alzheimer Disease/drug therapy/cerebrospinal fluid
Sweden
Female
Male
Aged
*Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
*Cognitive Dysfunction/drug therapy/cerebrospinal fluid
*Eligibility Determination
Cohort Studies

@article {pmid42898907,
year = {2026},
author = {Wicker, A and Courtright-Lim, A and Tilburt, J},
title = {Ethical challenges in the clinical translation of anti-amyloid monoclonal antibodies for Alzheimer's disease: a scoping review.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1953954},
pmid = {42898907},
issn = {1664-0640},
abstract = {BACKGROUND: The development and evaluation of anti-amyloid beta monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease have been accompanied by extensive ethical debate spanning clinical trials, regulatory processes, prescribing practices, and healthcare delivery. This scoping review examined literature published between 2006 and 2026 to identify and clarify the landscape of ethical considerations surrounding the implementation, prescribing, and delivery of anti-amyloid mAbs across both research and clinical settings.

METHODS: We searched PubMed, Scopus, Web of Science, Embase, and Ovid EBM Reviews (including CENTRAL and CDSR) from 2006 to March 2026 using a structured search strategy. Eligible publications focused on ethical issues associated with the clinical translation of anti-amyloid mAbs. Two reviewers independently screened titles, abstracts, and full-text articles, with duplicate extraction performed on an initial subset of publications. The review was conducted using JBI guidance and reported according to PRISMA-ScR.

RESULTS: We identified 84 publications from 23 countries published between 2014 and 2026, including 12 original research studies, 1 systematic review, and 71 commentaries, narrative reviews, legal analyses, or practice guidelines. Analysis identified 32 subthemes, which were synthesized into 7 overarching themes: (1) beneficence and nonmaleficence, (2) respect for persons, (3) equity and accessibility, (4) evidence and trial integrity, (5) governance and stewardship, (6) relational and social impacts, and (7) health system readiness and sustainability. Among the 32 subthemes, uncertain clinical benefit and risk of harm (both within the beneficence and nonmaleficence theme) were discussed most frequently within the literature, each appearing in 61 publications.

CONCLUSIONS: The biomedical literature documents a broad range of ethical considerations relating to anti-amyloid mAbs. Despite this growing literature, it is primarily based on commentary, with few empirical studies, and even fewer incorporating the perspectives of patients, families, and clinicians. Doing so may add further context and nuance to ethical discussion about mAbs in the years ahead.},
}

@article {pmid42899916,
year = {2026},
author = {Vasenina, EE},
title = {[Mild cognitive impairment as a heterogeneous condition: From diagnostic algorithm - to individualized therapeutic approaches].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {9},
pages = {42-51},
doi = {10.17116/jnevro202612609142},
pmid = {42899916},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/drug therapy/etiology/therapy/epidemiology ; Disease Progression ; Algorithms ; Neuropsychological Tests ; Risk Factors ; Precision Medicine ; Dementia/etiology/prevention & control ; },
abstract = {Mild cognitive impairment (MCI) is a prevalent syndrome affecting approximately 10-15% of the global population. In the Russian Federation, the estimated number of individuals with MCI may reach 5 million, with continued growth projected. Subjective cognitive deficits are linked to an increased risk of dementia, although memory complaints are often regarded as a normal aspect of aging. Standard neuropsychological assessments, including the Mini-Mental State Examination (MMSE), Mini-Cog, and Montreal Cognitive Assessment (MoCA), often lack sufficient sensitivity to detect MCI, particularly in individuals with high cognitive reserve. MCI has multiple etiologies, including depression and other affective disorders, severe somatic diseases, traumatic or toxic brain injury, and neurodegenerative or vascular pathologies of the central nervous system. This etiological diversity leads to variable clinical outcomes: cognitive function may return to age-appropriate norms in some instances, while in others, early impairment progresses to dementia. High-risk factors for conversion from MCI to dementia include the amnestic subtype of cognitive impairment, slow gait, coexisting affective disorders, sensory deficits, senile preasthenia and asthenia, and sleep disturbances. Accurate prediction of disease progression is critical for informing therapeutic strategies. For patients at elevated risk of progression, pharmacological interventions should be selected not only for symptomatic management but also for their potential to delay conversion. In Russia, Miladean, a combination of memantine and melatonin, is approved for use in patients with MCI. In addition to its symptomatic benefits, Miladean exhibits neuroprotective and endothelioprotective properties, supporting its use as the preferred treatment for patients at high risk of MCI progression.},
}

Humans
*Cognitive Dysfunction/diagnosis/drug therapy/etiology/therapy/epidemiology
Disease Progression
Algorithms
Neuropsychological Tests
Risk Factors
Precision Medicine
Dementia/etiology/prevention & control

@article {pmid42900219,
year = {2026},
author = {Giri, N and Chakraborty, A},
title = {Nanomaterial Design for Macrophage Reprogramming: Emerging Strategies and Mechanistic Insights for Inflammation and Tumor Therapy.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01937},
pmid = {42900219},
issn = {2576-6422},
abstract = {Macrophages play a paradoxical role in inflammation and tumor. They can protect the host during acute inflammation but act as the main driver for the chronic inflammation which is a common characteristic of several diseases including rheumatoid arthritis, atherosclerosis, type 2 diabetes, inflammatory bowel disease, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In the tumor microenvironment, macrophages switch their phenotype to the immunosuppressive M2 state that promotes tumor growth, angiogenesis, and metastasis. Emerging nanomaterial platforms are trying to offer transformative solutions by enabling the precise delivery of immunomodulatory drugs directly to disease-site macrophages. This review will provide comprehensive comparative analysis of these emerging nanomaterial designs strategies across two disease paradigms: inflammatory diseases and tumor. The discussion will focus on various strategies which include inhibiting chemokine axis (CCL2-CCR2 axis), selective elimination of macrophages through apoptosis, metabolic reprogramming, biomimetic and apoptotic cell-inspired nanoparticles leveraging natural macrophage clearance pathways to promote M2 polarization in inflammation, and the activation of tumor-associated macrophages via TLR and STING agonist. We highlight the role of nanoparticle surface chemistry, composition, and targeting ligands in achieving the two opposite therapeutic outcomes of these two diseases while maintaining some common design principles including EPR-mediated accumulation at the disease sites and biomimetic modifications. We also mentioned novel next-generation nanoparticle-based platforms that are currently in clinical trials for the treatment of tumor and inflammatory diseases. Finally, we discuss the barriers that limit the clinical translational potential of broad nanoparticles, with particular emphasis on nanoparticle-related immunotoxicity, macrophage heterogeneity, and manufacturing reproducibility of the nanoparticles.},
}

@article {pmid42900250,
year = {2026},
author = {Páez, A and Piñol-Ripoll, G and Dakterzada, F and Dang-Vu, TT},
title = {Sleep Spindles and Slow Oscillations as Potential Biomarkers and Therapeutic Targets in Mild-to-Moderate Alzheimer's Disease.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42900250},
issn = {1534-6293},
mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy/diagnosis ; Biomarkers ; *Sleep/physiology ; Animals ; },
abstract = {PURPOSE OF REVIEW: This review critically evaluates evidence on sleep spindles (SP), slow oscillations (SOs), and their coordination in mild-to-moderate Alzheimer's disease (AD), focusing on their relationships with cognition, AD biomarkers, and their therapeutic potential.

RECENT FINDINGS: Longitudinal studies associate greater SP and/or SO activity with better cognition and favourable amyloid and tau profiles after clinical onset. Spindle and SO coupling may index network integrity. Preserved NREM sleep oscillations are associated with lower orexin concentrations and weaker adverse relationships between orexin and cognitive and neuropsychiatric outcomes. Closed-loop acoustic stimulation and slow-oscillatory transcranial direct-current stimulation can modify SO activity, spindle activity, and coupling, although cognitive and biomarker benefits remain uncertain. Spindle-SO activity, including their temporal coupling, are associated with cognition and AD biomarkers across the disease continuum. Closed-loop acoustic and electrical stimulation can modify these oscillations, but biomarker-characterized trials in MCI and AD are needed to determine whether treatment produces durable cognitive and biomarker benefits.},
}

Humans
*Alzheimer Disease/physiopathology/therapy/diagnosis
Biomarkers
*Sleep/physiology
Animals

@article {pmid42901167,
year = {2026},
author = {Perneczky, R and Schöll, M and Rauchmann, BS and Hofmann, A},
title = {More than just accuracy: A pathway-level framework for implementing blood and digital biomarkers for Alzheimer's disease care.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.006},
pmid = {42901167},
issn = {1097-4199},
abstract = {Blood biomarkers are transforming Alzheimer's disease diagnostics by enabling a scalable, minimally invasive assessment of pathology. Food and Drug Administration clearances and European market certifications of different plasma tests mark a shift toward biological diagnosis in routine care. However, clinical implementation is not guided by diagnostic accuracy alone but will depend on improved patient-centered and pathway-level outcomes, including diagnostic confidence, the appropriate use of CSF and PET assessments, time to diagnosis, amyloid-targeting treatment eligibility assessment, and trial recruitment. Digital biomarkers may complement blood tests by providing repeated measures of cognition, speech, and mobility. Yet, their evidence base remains more heterogeneous regarding construct validity, supervision requirements, device dependence, adherence burden, cultural portability, interpretability, and regulatory classification. This review defines how combined blood-digital workflows could be evaluated beyond accuracy, including the context of use, downstream decisions, ethical aspects, governance, and post-market monitoring, ultimately aiming to translate biomarker innovation into meaningful benefits for patients and health systems.},
}

@article {pmid42901789,
year = {2026},
author = {Maekawa, H},
title = {[Intravenous Thrombolysis for Acute Ischemic Stroke: Current Evidence and Perspectives].},
journal = {No shinkei geka. Neurological surgery},
volume = {54},
number = {5},
pages = {996-1004},
doi = {10.11477/mf.030126030540050996},
pmid = {42901789},
issn = {0301-2603},
mesh = {Humans ; Administration, Intravenous ; *Brain Ischemia/drug therapy ; Fibrinolytic Agents/administration & dosage/therapeutic use ; *Ischemic Stroke/drug therapy ; *Thrombolytic Therapy/methods ; Tissue Plasminogen Activator/therapeutic use/administration & dosage ; },
abstract = {Since its introduction, intravenous thrombolysis (IVT) with alteplase has remained a mainstay of reperfusion therapy in the hyperacute management of acute ischemic stroke (AIS). Recent clinical evidence has driven a major paradigm shift from a strictly "time-based" approach to a "tissue-based" approach. Advanced neuroimaging techniques, including diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR mismatch) and perfusion mismatch analyses, have enabled extension of the treatment window beyond 4.5 h and treatment of patients with strokes of unknown onset, particularly benefiting those who are ineligible for endovascular thrombectomy (EVT). Furthermore, the treatment criteria have been refined to recommend IVT for disabling deficits regardless of the baseline stroke severity score while withholding it from patients with minor, nondisabling presentations. An emerging challenge in clinical practice is determining whether IVT should be contraindicated in patients receiving novel amyloid-targeting therapies for Alzheimer's disease. Meanwhile, prehospital protocols involving mobile stroke units (MSUs) may help reduce onset-to-needle time in selected regions. IVT continues to evolve through personalized patient selection aimed at maximizing safety and improving functional outcomes.},
}

Humans
Administration, Intravenous
*Brain Ischemia/drug therapy
Fibrinolytic Agents/administration & dosage/therapeutic use
*Ischemic Stroke/drug therapy
*Thrombolytic Therapy/methods
Tissue Plasminogen Activator/therapeutic use/administration & dosage

@article {pmid42885677,
year = {2026},
author = {Pandey, JP},
title = {Immunoglobulin GM (γ marker) allotypes as potential genetic markers of efficacy of lecanemab therapy in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500140},
doi = {10.1177/13872877261500140},
pmid = {42885677},
issn = {1875-8908},
abstract = {Lecanemab is a humanized IgG1 monoclonal antibody that targets amyloid-β (Aβ) aggregates, a pathological hallmark of Alzheimer's disease (AD). In the largest clinical trial of its kind to date, lecanemab slowed cognitive decline by 27% in patients with early-stage AD. Lecanemab has also been shown to reduce cerebral Aβ deposition. Lecanemab expresses the immunoglobulin GM 3 allotype, which is defined by an arginine residue in the CH1 region of the γ1 chain and is potentially immunogenic in individuals who lack this allotype. I hypothesize that anti-GM 3 antibodies, generated either following lecanemab administration or acquired previously through maternal-fetal incompatibility or transfusion of allotype-incompatible blood products, may form immune complexes with the therapeutic antibody. These immune complexes could be cleared by phagocytic cells, including microglia, thereby reducing the availability and efficacy of lecanemab and contributing to therapeutic nonresponsiveness. If validated, GM allotypes could serve as genetic markers for predicting response to lecanemab therapy and may help guide personalized treatment strategies in AD.},
}

@article {pmid42885691,
year = {2026},
author = {Alavi, A and Høilund-Carlsen, PF},
title = {The critical role of PET-based assessment of cerebrovascular disease in the management of patients with cognitive impairment and dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497232},
doi = {10.1177/13872877261497232},
pmid = {42885691},
issn = {1875-8908},
abstract = {A recent survey provides valuable insights into French practitioners' preparedness for implementing anti-amyloid immunotherapy (AAI) for Alzheimer's disease. It highlights the need for education but also underscores a broader challenge: clinicians must understand not only treatment protocols but also unresolved issues regarding diagnostic specificity, efficacy, safety, and cost-effectiveness. Amyloid biomarkers should not be considered definitive indicators of disease causality or treatment response. Greater attention should also be given to functional imaging approaches and cerebrovascular pathology, which may contribute to a more comprehensive understanding of cognitive decline. A balanced, evidence-based approach is essential before widespread adoption of AAI.},
}

@article {pmid42885915,
year = {2026},
author = {Gries, M and Schäfer, KH and Endres, K},
title = {Targeting the microbiota-gut-brain axis in Alzheimer's and Parkinson´s disease: recent therapeutic approaches.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2748747},
pmid = {42885915},
issn = {1744-7631},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders with limited disease-modifying treatment options. Evidence suggests that the microbiota-gut-brain axis (MGBA) plays a role in these diseases by facilitating communication between the gut and the central nervous system. Associations have been found between altered gut microbiota composition and function, impaired barrier integrity, dysregulated metabolite production, and immune activation to neuroinflammation and progressive neurodegeneration.

AREAS COVERED: This review summarizes and critically assesses recent studies from the past year to provide an updated overview of therapeutic strategies targeting the MGBA in both diseases. We discuss dietary interventions, probiotics, postbiotics, microbial metabolites, and approaches targeting gut barrier function. We also highlight strategies such as fecal transplantation, photobiomodulation, and PD-targeted metabolism therapies using butyrate and resistant starch.

EXPERT OPINION: While these interventions have shown promising results in preclinical and early clinical trials, their clinical application is limited by methodological heterogeneity, interindividual variability and a lack of standardized protocols. Successful implementation requires carefully designed clinical trials, particularly longitudinal studies of presymptomatic cohorts, standardized microbiome analyses, and integrated multi-omics approaches to elucidate causal relations and facilitate personalized treatment strategies.},
}

@article {pmid42887669,
year = {2026},
author = {Otto, B and Zantvoord, JB and Siskind, D and Vermeulen, JM},
title = {Modulating neuroinflammation with glucagon-like peptide-1 receptor agonists: a scoping review exploring their therapeutic potential in schizophrenia.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111978},
doi = {10.1016/j.pnpbp.2026.111978},
pmid = {42887669},
issn = {1878-4216},
abstract = {Neuroinflammation is a key contributor to the pathophysiology and symptomatology of schizophrenia spectrum disorders. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), clinically approved anti-diabetic and -obesity medication, have been associated with anti-inflammatory properties. It remains unclear whether GLP-1RA treatment can improve neuroinflammation within psychiatric disorders, including schizophrenia. This scoping review synthesizes evidence from clinical and preclinical studies on the anti-inflammatory effects of GLP-1RAs in psychiatric, neurodegenerative and neurological disease models, identifying crucial research gaps and providing future recommendations to guide potential clinical translation. The literature search was conducted in PubMed, Embase and PsycINFO and included outcomes of cytokine levels within blood and brain samples. Within the 40 included studies, two were clinical (schizophrenia and alcohol-use disorder) and 38 were preclinical models of psychiatric diseases, Alzheimer's -, Parkinson's Disease, Multiple Sclerosis, Epilepsy and lipopolysaccharide (LPS)-induced neuroinflammation. Preclinical studies showed anti-(neuro)inflammatory effects of GLP-1RAs, whereas the two available clinical studies found no significant changes in peripheral inflammatory markers. As these trials were not primarily designed or powered to test neuroinflammatory effects, the clinical findings remain inconclusive. Differences in study design, inflammatory measurements, pharmacokinetics and dosing may have contributed to the discrepancy between preclinical and clinical findings. Future research should prioritize early-phase dose-finding trials in non-diabetic, or -overweight patients diagnosed with schizophrenia spectrum disorders, evaluating the effects of alternative GLP-1RA regimens on neuroinflammatory markers, safety and clinical symptomatology. This is an essential step to determine their potential mental health-enhancing effects through the modulation of neuroinflammation within schizophrenia spectrum disorders.},
}

@article {pmid42887705,
year = {2026},
author = {Roy, J and Tsui, KC and Poon, CH and Zhang, J and Lai, Y and Wong, KY and Mihardja, M and Tse, V and Li, PC and Au, C and Ng, J and Kocabicak, E and Aquili, L and Wong, KH and Lu, Z and Temel, Y and Fung, ML and Lim, LW},
title = {Melatonin ameliorates behavioral deficits in 5xFAD mice through modulation of neurogenesis, neuroimmune responses, neurotransmission, and metabolic pathways.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {107077},
doi = {10.1016/j.bbi.2026.107077},
pmid = {42887705},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with limited disease-modifying treatment options. Melatonin, an endogenous hormone, has been shown to have therapeutic effects on amyloid deposition, oxidative stress, and neuroinflammation in AD. However, the mechanisms of its neuroprotective effects in the hippocampus remain largely unknown. This study aimed to investigate the multi-mechanistic neuroprotective effects of melatonin in AD. Eight-month-old female 5xFAD transgenic mice were treated with melatonin (10 mg/kg) for 4 weeks. Temozolomide and bromodeoxyuridine were used to block neurogenesis and to label proliferating neurons, respectively. Our results showed that 5xFAD mice treated with melatonin exhibited improved exploratory behavior, enhanced memory performance, reduced depressive-like symptoms, and decreased levels of stress hormones. At the molecular level, melatonin reduced amyloid-beta (Aβ) plaque accumulation, elevated hippocampal neurogenesis markers (DCX and BrdU), increased Trem2 expression and anti-inflammatory microglial activation, restored serotonergic, dopaminergic, catecholaminergic, and GABAergic neurotransmission, and partially normalized broader hippocampal metabolic pathways. Notably, temozolomide treatment abrogated the beneficial effects of melatonin on memory performance and depressive-like behavior in 5xFAD mice, indicating a neurogenesis-dependent mechanism. Collectively, these findings suggest that melatonin ameliorates behavioral deficits in 5xFAD mice through both neurogenesis-independent (reduced Aβ plaque accumulation, Trem2-microglial activation, neurotransmission restoration, and metabolic remodeling) and hippocampal neurogenesis-dependent mechanisms. Overall, melatonin holds therapeutic potential for attenuating the neuropathology and behavioral deficits in AD.},
}

@article {pmid42888370,
year = {2026},
author = {Porsteinsson, AP and Chumki, SR and Palma, AM and Zhang, Z and Wang, D and Such, P and Montano, CB},
title = {Brexpiprazole for Individual Agitation Symptoms in Alzheimer's Dementia: A Caregiver-Centered Post Hoc Analysis.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42888370},
issn = {2193-8253},
abstract = {INTRODUCTION: People with Alzheimer's dementia commonly experience agitation symptoms, which are distressing to caregivers and can influence long-term care decisions. The aim of this exploratory post hoc analysis was to test the hypothesis that brexpiprazole can improve individual agitation symptoms over 12 and 24 weeks, including symptoms that caregivers find the most distressing.

METHODS: Data were included from two phase 3, 12-week, randomized (brexpiprazole or placebo), double-blind trials and a phase 3, 12-week, brexpiprazole-treatment extension trial. Participants had Alzheimer's dementia with agitation, and lived at home or in long-term care. The frequency of 29 agitation symptoms over 12 and 24 weeks was assessed using Cohen-Mansfield Agitation Inventory (CMAI) item scores. The focus of this post hoc analysis was the 11 CMAI agitation symptoms that caregivers found the most distressing in a prior survey.

RESULTS: Among 610 participants (median age 74 years, 55.5% female, 44.5% male), each of the 11 most-distressing agitation symptoms reduced in frequency from baseline to Week 12, with further improvements to Week 24 (n = 159). Improvements over 12 weeks were numerically greater with brexpiprazole 2 or 3 mg/day (n = 363) compared with placebo (n = 247) on 9 of 11 symptoms: cursing or verbal aggression, spitting, repetitive sentences or questions, hitting, constant unwarranted requests for attention/help, trying to get to a different place, pacing or aimless wandering, grabbing onto people or things, and kicking. Each of the 18 other agitation symptoms (beyond the most distressing) also reduced in frequency. After 24 weeks, 15 of 29 agitation symptoms occurred less than once a week.

CONCLUSION: Brexpiprazole was associated with improvement in a range of agitation symptoms in people with Alzheimer's dementia, including those that are the most distressing to caregivers. These exploratory results suggest that brexpiprazole may improve the specific agitation symptoms that can have the biggest impact on the caregiver experience.

TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, NCT03594123.},
}

@article {pmid42889642,
year = {2026},
author = {Wenhua, Y and Wenjing, M and Yan, D and Fei, L and Juan, C and Xia, T and Yu, G and Xin, L and Yanlin, H and Ya, G and Xuelin, Y and Jing, L and Meimin, J and Wenyi, L and Yilin, K and Hongke, L and Yating, L},
title = {Should ApoE4 gene editing therapy be approached with caution when AD is accompanied by retinal neurodegenerative diseases?.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1934307},
pmid = {42889642},
issn = {1664-2295},
mesh = {Humans ; *Apolipoprotein E4/genetics ; *Gene Editing/methods ; *Alzheimer Disease/genetics/therapy/complications ; *Genetic Therapy/methods ; Animals ; *Neurodegenerative Diseases/genetics/therapy/complications ; *Retinal Diseases/genetics/therapy/complications ; Macular Degeneration/genetics/therapy ; },
abstract = {Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD), and ApoE4-directed gene editing and gene therapy have emerged as promising therapeutic strategies for AD, although they remain investigational and are not yet an established mainstream treatment. Interestingly, however, ApoE4 is reported to be associated with a reduced risk of retinal degenerative diseases such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Therefore, should ApoE4 gene editing therapy be approached with caution when AD occurs concurrently with glaucoma, AMD, or DR? In view of these and based on the existing literature, the present study detailed the distinct roles of ApoE4 in AD, glaucoma, AMD, and DR, with a purpose to offer valuable insights into subsequent ApoE4 gene editing therapies. We also summarise the ApoE-targeted therapeutic programmes currently in preclinical and early clinical development, delineate the remaining translational challenges, and discuss how patients with coexisting retinal neurodegenerative disease might be evaluated and monitored.},
}

Humans
*Apolipoprotein E4/genetics
*Gene Editing/methods
*Alzheimer Disease/genetics/therapy/complications
*Genetic Therapy/methods
Animals
*Neurodegenerative Diseases/genetics/therapy/complications
*Retinal Diseases/genetics/therapy/complications
Macular Degeneration/genetics/therapy

@article {pmid42890205,
year = {2026},
author = {Ji, H and Yang, Y and Wu, X and Bao, E},
title = {Safety of lecanemab in real-world patients with Alzheimer's disease: a prospective, observational case series supported by FAERS signal analysis.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1977226},
pmid = {42890205},
issn = {1662-5196},
abstract = {OBJECTIVE: Lecanemab, a humanized immunoglobulin monoclonal antibody, has been approved for the treatment of Alzheimer's disease (AD). Although clinical trials have demonstrated its favorable safety profile, real-world studies are crucial for identifying rare adverse events (AEs) and evaluating post-marketing safety. This study aimed to evaluate the safety of lecanemab by combining a clinical prospective, observational case cohort with data from the FAERS database, thereby providing a robust basis for the identification of potential safety signals.

METHODS: A prospective and observational study was conducted on patients with mild-to-moderate AD receiving lecanemab treatment at a tertiary medical center in China from July 2024 to February 2026. Extracted data included demographic characteristics, time to onset of AEs, and clinical symptoms. Exposure-adjusted incidence rates were calculated per 100 patient-years (PYs). Disproportionality analysis was performed using the US Food and Drug Administration Adverse Event Reporting System (FAERS), and safety signals for AEs observed in the cohort were evaluated utilizing reporting odds ratios (RORs) and proportional reporting ratios (PRRs). Additionally, data from these two real-world sources were compared and cross-validated.

RESULTS: The single-center prospective study enrolled a total of 91 patients. The median duration of lecanemab treatment was 185 days. Thirteen AEs were recorded (56.48/100 PYs), with the most frequent being amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H; defined as microhemorrhages and hemosiderin deposition) (12.39/100 PYs) and infusion-related reactions (IRRs) (8.85/100 PYs). In the FAERS database, the most frequently reported preferred terms (PTs) included headache, amyloid-related imaging abnormalities-edema/effusion (ARIA-E), ARIA-H, and IRRs. The majority of AEs occurred within the first 1-2 months after initiating lecanemab treatment (n = 393, 45.65%). Furthermore, FAERS analysis revealed a potential safety signal for cerebral infarction. However, this finding must be interpreted cautiously due to the lack of complete data on traditional stroke risk factors and concomitant antithrombotic use in spontaneous reports.

CONCLUSION: In this single-center prospective observational study, lecanemab demonstrated a generally favorable safety profile. Patients with AD aged 65 to 85 years represent a high-risk demographic for AEs. Particular clinical vigilance is required regarding the occurrence of AEs within the first two months of lecanemab initiation. Notably, ARIA (including both ARIA-E and ARIA-H) can occur at any phase during the treatment course.},
}

@article {pmid42890315,
year = {2026},
author = {Cutler, J and Tran, BA and Bullers, K and Fox, C},
title = {Lecanemab-Monoclonal Antibodies for the Treatment of Early Alzheimer's Disease.},
journal = {The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians},
volume = {},
number = {},
pages = {87551225261492568},
pmid = {42890315},
issn = {8755-1225},
abstract = {OBJECTIVE: Review the pharmacology, efficacy, and safety of lecanemab, a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody, for the treatment of early Alzheimer's disease (AD).

DATA SOURCES: Comprehensive search of Embase, PubMed, International Pharmaceutical Abstracts, Cochrane CENTRAL, Scopus, Web of Science, and Google Scholar were conducted from inception through December 2025.

Phase I-III clinical trials, systematic reviews, and meta-analyses evaluating lecanemab pharmacology, pharmacokinetics, efficacy, and safety were included. Product labeling was reviewed to supplement clinical data.

DATA SYNTHESIS: In the phase III Clarity AD trial, patients were randomized 1:1 to lecanemab 10 mg/kg every 2 weeks or placebo. The primary endpoint was change from baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) score at 18 months. Lecanemab demonstrated a mean change of 1.21 versus 1.66 with placebo (difference, -0.45; 95% CI, -0.67 to -0.23; P < .001). Secondary endpoint, amyloid burden via positron emission tomography (PET) scans (n = 698) showed -55.48 centiloids with lecanemab versus 3.64 with placebo (difference -59.12 centiloids; 95% CI, -62.64 to -55.6; P < .001). Additional endpoints included changes in ADAS-cog 14, ADCOMS, and ADCS-MCI-ADL scores favoring lecanemab over placebo. Lecanemab was well tolerated; infusion site reactions occurred in 26.4%. Amyloid-related imaging abnormalities (ARIA-E) occurred in 12.6% of participants.

CONCLUSION: Compared to placebo, lecanemab demonstrated statistically significant slowing of cognitive decline on CDR-SB and secondary endpoints, including amyloid burden reduction. However, its clinical benefit must be weighed against ARIA risk and substantial financial burden. Current evidence supports its use in carefully selected patients with early AD under close supervision.},
}

@article {pmid42890532,
year = {2026},
author = {Xi, Q and Wang, S and Shi, Q and Wang, H and Sun, P and Jin, Y and Ma, Y},
title = {Emerging roles of plant-derived extracellular vesicles in the management of dental diseases.},
journal = {Extracellular vesicles and circulating nucleic acids},
volume = {7},
number = {3},
pages = {1600-1624},
pmid = {42890532},
issn = {2767-6641},
abstract = {Dental diseases, including dental caries, pulpitis, and periodontitis, can cause pain and tooth loss, compromising mastication, speech, aesthetics, and quality of life. These diseases have also been associated with systemic disorders, including Alzheimer's disease. Conventional interventions, such as restorative procedures, root canal treatment, and periodontal scaling, have inherent limitations, underscoring the clinical need for novel therapeutic strategies. Plant-derived extracellular vesicles (PDEVs) have recently attracted considerable attention owing to their wide availability, cost-effectiveness, favourable biosafety profile, and capacity to mediate cross-kingdom communication. PDEVs exert diverse biological effects, including antimicrobial, anti-inflammatory, immunomodulatory, and tissue-regenerative activities. For example, ginger-derived PDEVs suppress the growth and virulence of Porphyromonas gingivalis through their lipid and miRNA cargoes, thereby alleviating periodontitis in mice. Given that effective dental therapy requires antimicrobial action, anti-inflammatory effects, immunomodulation, and tissue regeneration, PDEVs are promising therapeutic modalities. This review summarises the isolation, characterisation, composition, and biological functions of PDEVs, and discusses their potential applications in the management of dental diseases.},
}