@article {pmid42695408,
year = {2026},
author = {Li, Y and Fan, H and Han, X and Ni, M and Hou, X and Xia, H and Shi, Y and Zhang, L and Sun, J},
title = {Effect of MALT1 inhibition by MI‑2 on the microglial phenotype switch, inflammatory cytokine secretion, neuronal loss and oxidative stress in Alzheimer's disease.},
journal = {International journal of molecular medicine},
volume = {58},
number = {5},
pages = {},
doi = {10.3892/ijmm.2026.5973},
pmid = {42695408},
issn = {1791-244X},
mesh = {*Microglia/metabolism/drug effects/pathology ; *Oxidative Stress/drug effects ; *Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors/metabolism ; *Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Neurons/metabolism/pathology/drug effects ; Animals ; *Cytokines/metabolism ; Mice ; Phenotype ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Cell Line ; Amyloid beta-Peptides ; Cell Survival/drug effects ; },
abstract = {Mucosa‑associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key paracaspase enzyme regulating immune responses, inflammation and oxidative stress. The present study aimed to investigate the effect of MALT1 inhibition on neuroinflammation, neuronal loss and oxidative stress in Alzheimer's disease (AD). A co‑culture system involving microglia and neuron cells under β‑amyloid (Aβ) intervention was used to establish AD cellular models using human microglia HMC3 cells and neuroblastoma SH‑SY5Y cells and mouse microglia BV‑2 and hippocampal neuron HT‑22 cells. The inhibition of MALT1 proteolytic activity was achieved by MALT1 inhibitor 2 (MI‑2) treatment, and the NF‑κB pathway was activated by phorbol 12‑myristate 13‑acetate (PMA) treatment in HMC3 and BV‑2 cells. Western blotting, ELISA, Cell Counting Kit‑8, EdU staining, reactive oxygen species (ROS) detection and reduced glutathione (GSH) assays were performed to evaluate molecular changes, inflammatory responses, neuronal viability and oxidative stress. MALT1 expression was upregulated following Aβ treatment in HMC3 and BV‑2 cells. MALT1 inhibition by MI‑2 suppressed the microglial M1 phenotype but enhanced the M2 phenotype, reduced the levels of the proinflammatory cytokines TNF‑α and IL‑1β and inactivated the NF‑κB pathway in HMC3 and BV‑2 cells. Moreover, microglial MALT1 inhibition elevated cell viability (verified by Cell Counting Kit‑8 and EdU assays), increased the level of reduced glutathione and decreased the levels of reactive oxygen species in SH‑SY5Y and HT‑22 cells. NF‑κB activation by PMA attenuated the effects of MALT1 inhibition on the microglial phenotype switch and proinflammatory cytokine secretion in HMC3 and BV‑2 cells, as well as cell viability and oxidative stress in SH‑SY5Y and HT‑22 cells. The present study reveals that MALT1 inhibition may suppress microglial M1 phenotype, neuroinflammation, neuronal loss and oxidative stress by inactivating the NF‑κB pathway in AD.},
}

*Microglia/metabolism/drug effects/pathology
*Oxidative Stress/drug effects
*Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors/metabolism
*Alzheimer Disease/metabolism/pathology/drug therapy
Humans
*Neurons/metabolism/pathology/drug effects
Animals
*Cytokines/metabolism
Mice
Phenotype
Reactive Oxygen Species/metabolism
NF-kappa B/metabolism
Cell Line
Amyloid beta-Peptides
Cell Survival/drug effects

@article {pmid42695591,
year = {2026},
author = {Lu, M and Zheng, Y and Chen, T and Wu, Y and Li, Z and Zheng, T and Chen, Q and Peng, X and Shi, L and Pan, Y and Xu, Y and Wei, D},
title = {Quantitative Assessment of Cerebrospinal Fluid-Vascular Association in Alzheimer's Disease Using Phase-Contrast and 4D-Flow Magnetic Resonance Imaging.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {235},
pages = {},
doi = {10.3791/71768},
pmid = {42695591},
issn = {1940-087X},
mesh = {*Alzheimer Disease/cerebrospinal fluid/physiopathology/pathology ; Humans ; *Magnetic Resonance Imaging/methods ; Glymphatic System/pathology ; *Cerebrospinal Fluid/physiology ; },
abstract = {From a neuropathological perspective, the most well-known pathological change in Alzheimer's disease (AD) to date is primarily tau protein hyperphosphorylation, which leads to the formation of intracellular neurofibrillary tangles (NFTs) and amyloid protein deposition-namely, the accumulation of amyloid protein (Aβ) and other protein aggregates outside cells, resulting in neurofibrillary tangles. The glymphatic system, driven by arterial pulsation, clears waste, including amyloid-β, via perivascular spaces (PVS). In AD, vascular dysfunction and slow-wave sleep speculation have been separately observed, and both are hypothesized to impair glymphatic clearance. However, causal links among these factors remain unproven, and the proposed self‑reinforcing cycle-where vascular failure may aggravate protein deposition and further vascular damage-is speculative. This study utilized two-dimensional cine phase-contrast MRI (PC-MRI) and four-dimensional flow MRI (4D-Flow) to quantify hydrodynamic parameters, including cerebrospinal fluid (CSF) flow in the cerebral aqueduct (CA) and blood flow in the internal carotid artery (ICA). Altered CSF-vascular association was observed in AD, suggesting possible glymphatic involvement. The integration of CSF and vascular flow metrics provides a promising biomarker framework for early AD detection and monitoring. PC-MRI and 4D-Flow reveal altered CSF-vascular association in Alzheimer's disease, reflecting potential glymphatic alteration and offering a non-invasive, quantitative method for potential adjunctive biomarker and disease monitoring.},
}

*Alzheimer Disease/cerebrospinal fluid/physiopathology/pathology
Humans
*Magnetic Resonance Imaging/methods
Glymphatic System/pathology
*Cerebrospinal Fluid/physiology

@article {pmid42696024,
year = {2026},
author = {Sultana, SM and Kong, CY and Badhulika, S},
title = {Simultaneous Detection of Dopamine and Xanthine in Human Sweat by Ultrasensitive MoB-MBene/PVA Sponge-like Hydrogel Grown on a Porous Nickel Substrate.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01330},
pmid = {42696024},
issn = {2576-6422},
abstract = {Dopamine and xanthine are essential biomolecules for neurological disorders and oxidative stress, respectively, and their abnormal concentrations are associated with Parkinson's disease, schizophrenia, Alzheimer's disease, and renal dysfunction. To overcome the limitations of invasive conventional diagnostics, a flexible MoB/PVA hydrogel on nickel foam is fabricated for the simultaneous, non-invasive electrochemical detection of dopamine and xanthine in human sweat. It is prepared through selective alkali etching and solvothermal synthesis. Characterization of the optimized MoB-MBene hydrogel (7 wt %), such as FTIR, confirms characteristic Mo-B vibrational bands, while SEM analysis reveals a sponge-like porous morphology favorable for rapid ion transport and enhanced electroactive sites. Using the DPV technique, the MoB/PVA hydrogel/NF sensor, which has a higher active surface area, demonstrates the simultaneous detection of dopamine, with a linear range from 50 nM to 500 μM, detection limit of 0.35 nM, and sensitivity of 158 μA nM-1 cm-2, and xanthine, with a linear range of 100 nM to 1 mM, detection limit of 0.098 nM, and sensitivity of 95.2 μA nM-1 cm-2, with a peak separation (ΔEp) of 285 mV. The superior electrochemical performance is attributed to the synergistic effect arising from abundant active sites in the ion-rich MoB/PVA hydrogel, facilitating higher charge-transfer kinetics and resulting in enhanced peak currents and well-resolved peaks for simultaneous sensing with 99.6-101.3% recovery for dopamine and 99.3-101.4% recovery for xanthine. Repeatability tests (N = 4) yielded dopamine with a 0.6% RSD and xanthine with a 1.93% RSD. The flexible sensor exhibits excellent selectivity and stability for up to 4 weeks and holds potential for point-of-care and flexible wearable devices.},
}

@article {pmid42696146,
year = {2026},
author = {Zhou, Y and Del Toro, S and Zeng, MY},
title = {Nutritional regulation of gut-brain immune crosstalk across the lifespan.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2725371},
doi = {10.1080/19490976.2026.2725371},
pmid = {42696146},
issn = {1949-0984},
mesh = {Humans ; *Brain/immunology ; Animals ; *Gastrointestinal Microbiome ; Aging/immunology ; *Gastrointestinal Tract/immunology ; *Brain-Gut Axis ; },
abstract = {The gut-brain immune axis integrates microbial, immune, and neural signals to regulate neurodevelopment, homeostasis, and disease susceptibility. Early-life nutrition, particularly human milk oligosaccharides, shapes beneficial microbiota composition, enhances hippocampal plasticity, promotes anti-inflammatory microglia polarization, and fosters immune tolerance. Gut microbiota-derived metabolites, including short-chain fatty acids, tryptophan derivatives and secondary bile acids, regulate microglia maturation, astrocyte function, T cell differentiation, neurotransmitter production, and vagus nerve signaling. These processes influence synaptic pruning, neurogenesis, and neuroinflammation. Adaptive immune cells in the central nervous system, notably meningeal and infiltrating CD4 T cells, further connect peripheral immunity to neuronal responses through cytokines, such as IL-4, IFNγ, and IL-17A. Nutritional imbalances may exacerbate disease-associated microglia and pathogenic T cell activity in Multiple Sclerosis, Alzheimer's disease, and autism spectrum disorders. In aging, diet helps mitigate "inflammaging" by countering metabolic shifts in microglia and lymphocytes. This review examines how nutrition modulates bidirectional gut-brain immune crosstalk across the lifespan.},
}

Humans
*Brain/immunology
Animals
*Gastrointestinal Microbiome
Aging/immunology
*Gastrointestinal Tract/immunology
*Brain-Gut Axis

@article {pmid42696208,
year = {2026},
author = {Chauhdary, Z and Masood, MS and Irfan, M and Shafi, A and Rafique, D and Arif, A and Akmal, M},
title = {Molecular target for neuroinflammation and pain management: transient receptor potential vanilloid 1.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42696208},
issn = {1568-5608},
abstract = {Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel and polymodal sensor of noxious heat, protons, capsaicin and endogenous lipids. The wide variety of functions of TRPV1 in pain transmission, inflammatory pathways and neurological disorders has triggered efforts to understand the molecular mechanisms underlying these functions, particularly pain and neuroinflammation. The molecular structure and its tetrameric structure, temperature and ligand dependent activation and post-translational modification are discussed. It also covers the Ca[2][+]-dependent signalling pathways such as CaMKII/Nrf2, MAPK, NF-κB and PI3K/ERK, and the localization of TRPV1 in sensory neurons, microglia, astrocytes, T lymphocytes and brain tissues. Other notable mentions are the involvement of TRPV1 in acute inflammatory, neuropathic, and visceral pain as well as in neuroinflammatory and neurodegenerative diseases like multiple sclerosis, Alzheimer's disease and Parkinson's disease. Evidence that comes from the various studies suggests that TRPV1 may cause a number of different responses depending on the cell and disease context, whether pro-inflammatory or neuroprotective. Therapeutic strategies directed to TRPV1 such as desensitizing agents, allosteric and state-selective modulators, peptide-based and natural-product based ligands, and gene-directed strategies, are also taken into account. To conclude, the context-dependent activity of TRPV1 signalling holds promise for therapeutic applications, and highlights the importance for context-specific, local and precise targeting of TRPV1 in clinical practice.},
}

@article {pmid42696209,
year = {2026},
author = {Wasim, R},
title = {Targeting cytokine-driven neuroinflammation in Alzheimer's disease: mechanistic insights and pharmacological strategies.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42696209},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia worldwide. Although the classical pathological hallmarks of AD include extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, increasing evidence indicates that neuroinflammation plays a central role in disease initiation and progression. Among the key mediators of neuroinflammatory responses, cytokines have emerged as critical regulators of immune communication within the central nervous system. Activated microglia and reactive astrocytes release a wide range of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and interferon-γ, which contribute to synaptic dysfunction, neuronal injury, and amplification of inflammatory signaling pathways. Conversely, anti-inflammatory cytokines such as interleukin-10, interleukin-4, and transforming growth factor-β participate in regulating immune homeostasis and may exert neuroprotective effects by suppressing excessive inflammatory responses. This review provides a comprehensive overview of cytokine-mediated neuroinflammation in Alzheimer's disease, focusing on the cellular sources of cytokine production within the brain, including microglia, astrocytes, neurons, and endothelial cells. Key intracellular signaling pathways involved in cytokine activity, such as nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK-STAT), and mitogen-activated protein kinase (MAPK) pathways, are also discussed in relation to their roles in inflammatory amplification and neurodegeneration. Furthermore, the complex interactions between cytokine signaling, amyloid-β accumulation, and tau pathology are examined to highlight the interconnected mechanisms underlying disease progression. Finally, emerging therapeutic strategies targeting cytokine-driven neuroinflammatory pathways are explored, emphasizing their potential in the development of novel anti-inflammatory and disease-modifying treatments for Alzheimer's disease.},
}

@article {pmid42696253,
year = {2026},
author = {Bianchessi, C and Serpente, M and Ferri, E and Giudici, G and Arcaro, M and Borracci, V and Visconte, C and Buccellato, F and Sacchi, L and Pintus, M and Arosio, B and Arighi, A and Fenoglio, C and Galimberti, D},
title = {Microglia-derived extracellular vesicles uncover early alterations of inflammatory signaling in Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42696253},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a neurodegenerative disorder associated with chronic low-grade inflammation and age-related immune dysregulation. Microglial-derived extracellular vesicles (MDEVs) are emerging as important mediators of neuroimmune communication and potential biomarkers reflecting pathological processes occurring within the central nervous system (CNS). However, how EV-associated inflammatory signalling changes across different stages of AD remains poorly understood. In this study, we characterized the inflammatory molecular profile of serum-derived MDEVs in 22 AD patients, 19 prodromal AD subjects, and 23 healthy controls (HC). Cytokine concentrations were also evaluated in paired serum and cerebrospinal fluid (CSF) samples to compare vesicle-associated and soluble inflammatory signals across biological compartments. MDEVs were isolated by size exclusion chromatography followed by TMEM119-based immunoenrichment. Cytokine quantification was performed using the Ella Simple Plex automated immunoassay platform. MDEVs from AD patients showed a generalized reduction in both pro- and anti-inflammatory cytokines compared to HC, including IL-1β, TNF-α, IL-2, IFN-γ, IL-6, IL-12p70, IL-10, and IL-4. Notably, several alterations were already detectable at the prodromal stage. In contrast, soluble cytokines in serum and CSF displayed a predominantly pro-inflammatory profile in AD patients, with increased levels of IL-1β, TNF-α, and IL-12p70. No significant correlations were observed between cytokine levels measured in MDEVs and those detected in serum or CSF. Overall, these findings support the presence of a compartment-specific reorganization of inflammatory signalling during AD progression. Early alterations in MDEV inflammatory cargo may reflect disrupted EV-mediated neuroimmune communication and highlight the potential of MDEVs as accessible peripheral biomarkers of neuroinflammatory processes in AD.},
}

@article {pmid42696260,
year = {2026},
author = {Nakaoka, Y and Sohara, K and Matsuda, H and Mizumura, S and Suda, M and Imai, S and Sekine, T and Ando, T and Tanaka, A and Ishiwata, A and Tateno, A and Koeda, M and Saito, T and Suda, S and Yamazaki, A and Hayashi, H and Kumita, S},
title = {Association of global gray matter volume and cortical thickness with cognitive function stratified by amyloid PET status.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {42696260},
issn = {1864-6433},
support = {Nihon Medi-Physics//Nihon Medi-Physics/ ; },
abstract = {OBJECTIVE: Structural magnetic resonance imaging (MRI) measures may relate to cognition differently depending on the underlying biological context. We examined the associations of global gray matter volume and cortical thickness with cognitive performance after stratification by amyloid positron emission tomography (PET) status.

METHODS: This cross-sectional study included 113 participants (mean age 76.3 ± 7.8 years; 68.1% female) who underwent amyloid PET, structural MRI, and Mini-Mental State Examination (MMSE). Amyloid burden was quantified on the Centiloid scale, with positivity defined as > 25 (44 amyloid-negative, 69 amyloid-positive). Global gray matter volume normalized by total intracranial volume (GM/TIV) and global cortical thickness were derived with CAT12/SPM12. Multivariable linear regression was used to assess associations with the MMSE score after adjustment for age, sex, and amyloid burden, with prespecified stratification by amyloid status. Formal interaction analyses tested effect modification.

RESULTS: In the overall cohort, GM/TIV was independently associated with the MMSE score (β = 0.35, p = 0.007), whereas cortical thickness was not (β = 0.02, p = 0.844). In exploratory stratified analyses, GM/TIV was associated with the MMSE score in amyloid-positive participants (β = 0.48, p = 0.003) but not in amyloid-negative participants (β = 0.05, p = 0.835). Age was associated with the MMSE score in amyloid-negative participants (β = -0.33, p = 0.041) but not in amyloid-positive participants (β = 0.11, p = 0.377). Formal interaction analyses were not significant.

CONCLUSIONS: In this cohort, global GM/TIV was associated with cognitive performance more consistently than global cortical thickness. Exploratory stratified analyses suggested different association patterns according to amyloid PET status; however, formal interaction analyses were not significant. These findings should therefore be interpreted cautiously and validated in larger longitudinal studies.},
}

@article {pmid42696296,
year = {2026},
author = {Rubin, R},
title = {Nearly Half of Dementia Cases May Be Preventable-Here's What the Research Says So Far.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.9439},
pmid = {42696296},
issn = {1538-3598},
}

@article {pmid42696736,
year = {2026},
author = {Yao, YH and Xu, S and Kim, ES and Kim, EA and Wang, YX and Kim, HS and Kim, DH and Liang, JG and Shin, YK and Kim, NY},
title = {Electroencephalography Functional Network Responses to Immersive Virtual Reality in Alzheimer Disease and Mild Cognitive Impairment: Exploratory Single-Session 3-Group Repeated-Measures Study.},
journal = {JMIR serious games},
volume = {14},
number = {},
pages = {e95160},
doi = {10.2196/95160},
pmid = {42696736},
issn = {2291-9279},
abstract = {BACKGROUND: Alzheimer disease (AD) is increasingly conceptualized as a disorder of large-scale brain network disruption rather than isolated regional dysfunction. Immersive virtual reality (VR) may provide a controlled sensory challenge for neurophysiological assessment, but its association with whole-brain electroencephalography (EEG) functional network organization across AD and mild cognitive impairment (MCI) remains insufficiently characterized.

OBJECTIVE: This study examined whether immersive VR exposure was associated with state-dependent changes in EEG-derived functional network organization among older adults with AD, MCI, and normal cognition (NC).

METHODS: This exploratory single-session, 3-group repeated-measures EEG study included 60 older adults: 20 with AD, 20 with MCI, and 20 participants with NC. During a single visit, participants underwent repeated within-session EEG recordings during pre-VR resting, immersive VR exposure, and post-VR resting states. VR was delivered through a head-mounted display presenting a passive first-person roller-coaster environment. Functional connectivity was quantified using phase-locking value (PLV) across multiple frequency bands, and global efficiency (GE), modularity, and nodal strength were calculated to characterize network topology. Between-group differences within each state were assessed using 1-way ANOVA with post hoc pairwise comparisons, whereas within-group state changes were evaluated using paired-sample 2-tailed t tests. Benjamini-Hochberg false discovery rate (FDR) correction was applied to inferential graph-theoretical analyses. PLV matrices, nodal strength maps, and connectivity graphs were interpreted descriptively.

RESULTS: In the broadband range, GE was higher in the AD group than in the NC group during the pre-VR resting state (raw P=.009; FDR-adjusted P=.04), whereas the AD-NC difference was not statistically significant during VR exposure or the post-VR resting state. Baseline modularity was also higher in AD than in NC and remained significant after FDR correction; no significant between-group modularity differences were detected during VR exposure. Within-group analyses showed an FDR-corrected increase in GE from pre-VR to VR in NC participants and from pre-VR to post-VR in participants with MCI. No within-group GE change in AD remained significant after FDR correction. Descriptive PLV, nodal strength, and connection maps suggested state-associated changes in hemispheric distribution and high-frequency connectivity patterns. However, high-frequency GE findings did not remain significant after FDR correction and were therefore interpreted as exploratory.

CONCLUSIONS: In this exploratory single-session, 3-group repeated-measures EEG study, immersive VR exposure was associated with short-term, state-dependent changes in PLV-derived EEG functional network organization among older adults with AD, MCI, and NC. Graph-theoretical analysis demonstrated the feasibility of using repeated within-session VR-EEG measurements to characterize acute network responsiveness across cognitive groups. However, descriptive connectivity maps were not treated as confirmatory evidence, and the absence of a non-VR comparison condition and concurrent cognitive or clinical outcomes precludes conclusions regarding causality or therapeutic efficacy. Larger controlled and longitudinal studies are needed to establish the reproducibility and clinical relevance of these findings.},
}

@article {pmid42696905,
year = {2026},
author = {Nie, W and Liang, Z and Fu, Q and Tan, Y and Wang, L and Wu, W and Liang, J},
title = {Linking behavioral and psychological symptoms to nutritional status in Alzheimer's disease: Clinical correlations and implications.},
journal = {Acta psychologica},
volume = {270},
number = {},
pages = {107768},
doi = {10.1016/j.actpsy.2026.107768},
pmid = {42696905},
issn = {1873-6297},
abstract = {OBJECTIVE: Behavioral and Psychological Symptoms of Dementia (BPSD) are highly prevalent in Alzheimer's disease (AD) and constitute a major therapeutic challenge. Although nutritional deficiencies are common among AD patients, their relationship with BPSD remains poorly understood. This cross-sectional study aimed to examine the association between multidimensional nutritional characteristics and BPSD in patients with AD.

METHODS: A total of 102 patients with Alzheimer's disease were enrolled in this study and stratified into two groups based on the presence or absence of BPSD, as determined by comprehensive psychiatric assessment. We integrated Mini Nutritional Assessment (MNA) with a panel of serological biomarkers reflecting protein-energy status, glucose metabolism, and systemic homeostasis. Multivariate regression analyses were employed to identify nutritional factors associated with BPSD.

RESULTS: AD patients with BPSD exhibited a distinct nutritional and metabolic profile, characterized by poorer MNA scores and lower prealbumin (PAB), as well as lower MMSE and ADL scores, and longer disease duration. Critically, after rigorous adjustment for confounders, higher MNA scores and higher PAB were independently associated with lower odds of BPSD.

CONCLUSION: Our findings revealed that poorer nutritional status, particularly lower MNA scores and lower prealbumin levels, was associated with higher likelihood of BPSD. Integrating multidimensional nutritional assessment into clinical practice may help identify at-risk patients and inform therapeutic strategies. However, due to the cross-sectional design and sample imbalance, these findings are hypothesis-generating and require prospective validation.},
}

@article {pmid42697072,
year = {2026},
author = {Wu, Q and Li, L and Lei, Y and Zhou, T and Tang, H and Zhang, B and Lu, Y and Salvatore, M and Zhang, D and Tong, J and Wang, T and Chen, S and Li, H and Xu, Z and Huang, Y and Hu, Y and Hong, N and Zhou, Y and Lin, F and O'Brien, KS and Chen, Y and Li, R and Xu, H and Wang, F and Bian, J and Wolk, DA and Chen, Y},
title = {Discovering repurposable drugs for Alzheimer's disease and related dementias: target trial emulation using decentralised real-world data.},
journal = {EBioMedicine},
volume = {132},
number = {},
pages = {106466},
doi = {10.1016/j.ebiom.2026.106466},
pmid = {42697072},
issn = {2352-3964},
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) affect nearly 6.9 million Americans, with the number expected to triple by 2050, while disease-modifying therapies remain unavailable. Drug repurposing, which identifies new indications for already approved medications, offers a more efficient and cost-effective pathway to accelerate development of effective therapies for ADRD. The aim of this study is to identify potential drug repurposing signals by systematically screening routinely prescribed drugs for associations with progression from mild cognitive impairment (MCI) to ADRD.

METHODS: We conducted a multi-site target trial emulation using electronic health record (EHR) data from four decentralised databases: INSIGHT Clinical Research Network, OneFlorida + Clinical Research Consortium, the University of Pennsylvania Health System, and Yale New Haven Health System. We performed an independent validation using EHR data from the TriNetX Research Network and a genetic risk-stratified sensitivity analysis in the Penn Medicine BioBank (PMBB) database. Eligible participants were adults aged 50 years or older at the time of MCI diagnosis, with no prior diagnosis of ADRD and no prior use of the trial drugs. Initiation of each of 181 routinely prescribed drugs was compared with two active control groups defined by initiation of supplements or cardiovascular medications. Risk ratios (RRs) and 95% CIs were estimated using a federated target trial emulation framework (LATTE) with stabilised inverse probability of treatment weighting and Poisson regression.

FINDINGS: A total of 122,972 eligible patients were identified from the four decentralised databases, 335,506 patients identified from the TriNetX network for validation and 898 from PMBB database. Federated, multi-site target trial emulation identified 20 drug repurposing hypotheses with statistically significant protective effects, including anti-inflammatory and pain-modulating agents (celecoxib: RR 0.43; 95% CI: 0.23-0.81; dexamethasone RR 0.46; 95% CI: 0.29-0.73; gabapentin: RR 0.55; 95% CI: 0.36-0.83; ketorolac: RR 0.50; 95% CI: 0.31-0.80; methylprednisolone: RR 0.43; 95% CI: 0.24-0.76; prednisone: RR 0.48; 95% CI: 0.28-0.83; pregabalin: RR 0.53; 95% CI: 0.35-0.79), antimicrobial and microbiome-associated agents (cefazolin: RR 0.62; 95% CI: 0.45-0.84; clavulanate: RR 0.56; 95% CI: 0.44-0.71; fluconazole: RR 0.36; 95% CI: 0.23-0.58), neuromodulators and adrenergic agents (epinephrine: RR 0.42; 95% CI: 0.31-0.56; propranolol: RR 0.56; 95% CI: 0.37-0.85; salmeterol: RR 0.49; 95% CI: 0.32-0.74; tizanidine: RR 0.29; 95% CI: 0.14-0.57), vascular, metabolic, and hormonal modulators (empagliflozin: RR 0.29; 95% CI: 0.17-0.50; oestradiol: RR 0.47; 95% CI: 0.28-0.81; ezetimibe: RR 0.69; 95% CI: 0.52-0.91; sodium bicarbonate: RR 0.49; 95% CI: 0.29-0.84; spironolactone: RR 0.43; 95% CI: 0.31-0.60), and histamine-related and gastrointestinal agents (famotidine: RR 0.64; 95% CI: 0.55-0.74). Results were consistent in the independent validation using TriNetX network and sensitivity analysis in PMBB database.

INTERPRETATION: 20 widely used medications may be associated with reduced progression from MCI to ADRD and represent promising candidates for clinical evaluation as repurposed therapies for dementia.

FUNDING: National Institutes of Health.},
}

@article {pmid42697176,
year = {2026},
author = {Bellelli, G and Brignoli, O and Canevelli, M and Cherubini, A and Clegg, A and Dubois, B and Ferrara, MC and Fratiglioni, L and Frisoni, GB and Grande, G and Jessen, F and Kennelly, SP and Magni, A and Marelli, M and Marengoni, A and Velilla, NM and Shenkin, SD and Suárez-Calvet, M and Timmons, S and Padovani, A},
title = {Integrating frailty into decision-making for disease-modifying therapies in Alzheimer's disease: a proposed expert-opinion based approach.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100666},
doi = {10.1016/j.tjpad.2026.100666},
pmid = {42697176},
issn = {2426-0266},
abstract = {The introduction of disease-modifying therapies for Alzheimer's disease (AD-DMTs) is reshaping clinical practice, raising critical questions about patient selection, diagnostic pathways, treatment appropriateness, and equity of access. Frailty, a multidimensional condition of reduced physiological reserve and increased vulnerability to stressors, is common in older adults with AD, yet has not been systematically assessed in AD-DMTs trials, limiting the generalizability of trial findings to real-world populations. In this review, we examine the role of frailty in the emerging era of AD-DMTs, summarizing evidence on its prevalence and prognostic relevance, approaches to its assessment, and its potential impact on treatment safety and effectiveness. We propose that regular frailty assessment should inform decision-making in both clinical trials and clinical practice, while frailty-informed management-including medication review and multidomain interventions-may support more appropriate, individualized care.},
}

@article {pmid42697335,
year = {2026},
author = {Li, X and Wan, R and Wu, Y and Zhao, Y and Chen, X and Li, Y and Yang, R and Zhang, D and Li, Q and Luo, C},
title = {Targeting the mitochondrial functional network: Decoding upstream pathological mechanisms and novel therapeutic paradigms for Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103359},
doi = {10.1016/j.arr.2026.103359},
pmid = {42697335},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Conventional downstream interventions targeting β-amyloid (Aβ) and tau proteins have repeatedly failed in clinical practice, and mitochondrial functional decline has been identified as the core upstream driver of AD pathogenesis. Focusing on the mitochondrial functional network as the core target, this paper systematically dissects the key molecular mechanisms of mitochondrial dysfunction during AD progression, including oxidative phosphorylation impairment, mitochondrial DNA (mtDNA) mutations and genetic defects, excessive reactive oxygen species (ROS) production, mitochondrial dynamics imbalance, mitophagy dysfunction, calcium homeostasis dysregulation, mitochondrial transport defects, and the bidirectional regulatory pathway of tau pathology, and elucidates the pathological network featured by cascade amplification and reciprocal regulation among these abnormal mechanisms. It also comprehensively summarizes mitochondria-targeted intervention strategies for AD, analyzes the research limitations in this field such as model heterogeneity, lack of specific biomarkers and inefficient drug delivery, and prospects future research directions by integrating cutting-edge technologies including cell reprogramming and artificial intelligence (AI). This study provides a novel interpretation of the aging-related pathogenic mechanisms of AD from a mitochondrial perspective, lays a theoretical foundation for the development of precise and efficient mitochondria-targeted therapeutic strategies for AD, and offers a new paradigm for breaking through the bottlenecks of clinical diagnosis and treatment of AD.},
}

@article {pmid42697346,
year = {2026},
author = {Cai, J and Luo, J and Cai, Y and Xu, Y and Ran, R and Xiao, M and Ye, Q and Zheng, W and Li, S},
title = {Artemether alleviates Aβ1-42-induced neuronal cell damage via PGC-1α-mediated mitochondrial homeostasis in Alzheimer's disease.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112879},
doi = {10.1016/j.cellsig.2026.112879},
pmid = {42697346},
issn = {1873-3913},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia. Mitochondrial dysfunction is a key pathogenic event that drives neuronal damage and disease progression. Thus, protecting against mitochondrial damage in neuronal cells has become a critical therapeutic target for AD prevention and treatment. Our previous research has shown that artemether can protect PC12 cells from oxidative stress damage induced by Aβ and oxygen-glucose deprivation, but its underlying regulatory mechanisms remain elusive. Therefore, it is essential to elucidate the role and mechanism of artemether in Aβ-induced mitochondrial damage.

OBJECTIVE: Evaluate the protective effects of artemether on Aβ-induced mitochondrial dysfunction and the underlying molecular mechanism in AD.

METHODS: The HT-22 cell line and primary hippocampal neurons were employed in the present study owing to their greater physiological relevance to hippocampal neuronal injury. In order to evaluate the protective effects of artemether against mitochondrial damage in neuronal cells, we performed Cell Counting Kit-8 assays to assess cell viability and LDH release assays to measure cytotoxicity. Furthermore, we evaluated mitochondrial membrane potential, quantified ATP content, and detected ROS production in Aβ-induced neuronal cell damage. In addition, we used transmission electron microscopy to observe mitochondrial ultrastructural changes and performed immunofluorescence staining to analyze mitochondrial protein localization and morphology. In the AD mouse model, we conducted behavioral tests to assess cognitive function, while using H&E staining, immunohistochemistry, and TUNEL staining to evaluate artemether's effects on AD-related pathological hallmarks. Furthermore, Western blot analysis was performed to dissect the molecular mechanism underlying artemether's protective effect against Aβ-induced mitochondrial damage, focusing on the expression of key proteins in the PGC1/ERRα/TFAM signaling pathway.

RESULTS: Artemether protects against Aβ1-42 induced mitochondrial damage in HT-22 cells and alleviates Aβ1-42 injection induced memory deficits, mitochondrial dysfunction and neuroinflammation in the AD mice model. Mechanistically, artemether treatment upregulated the protein levels of PGC1, which contributes to mitochondrial homeostasis and further activation of the ERRα/TFAM signaling pathway. Moreover, Inhibition of PGC1α abrogates artemether's protective effects.

CONCLUSION: Our findings indicate that neuronal mitochondrial dysfunction serves as a central driver in AD pathogenesis, and activating the PGC1α/ERRα/TFAM axis through artemether offers an effective and feasible strategy for the prevention and treatment of AD.},
}

@article {pmid42697379,
year = {2026},
author = {Mohammad, SI and Vasudevan, A and Oriquat, G and Gajjar, TB and Hanumanthayya, M and Shukla, SK and Tailor, NK and Baig, MR and Fadaam, O and Abdul, AS},
title = {Extracellular Vesicles in Neurodegenerative Diseases: A New Frontier in Diagnosis and Therapy.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116455},
doi = {10.1016/j.bbr.2026.116455},
pmid = {42697379},
issn = {1872-7549},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.},
}

@article {pmid42697420,
year = {2026},
author = {Escarcega, RD and Vijay Kumar, MJ and Abdul, A and Bommineni, R and Manwani, B and Jung, SY and Tsvetkov, AS},
title = {HUWE1 interactomes reveal sex-specific networks of nucleic acid-binding proteins.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104115},
doi = {10.1016/j.mcn.2026.104115},
pmid = {42697420},
issn = {1095-9327},
abstract = {HUWE1 (HECT, UBA, and WWE domain-containing protein 1) is an X-linked E3 ubiquitin ligase that regulates a broad range of substrates through both degradative and non-degradative ubiquitination. The essential role of HUWE1 is underscored by the neonatal lethality of Huwe1 knockout mice. Although HUWE1 has been extensively studied in cancer and neurodevelopment, its functions in brain aging and neurodegeneration remain poorly understood. Here, we used cross-linking-assisted immunoprecipitation coupled with mass spectrometry to characterize HUWE1 interactomes in 26-month-old wild-type and Tg-SwDI mouse brains. HUWE1 interactomes were enriched for proteins involved in gene expression, translation, synaptic signaling, and nucleic acid metabolism. HUWE1-associated protein complexes contained an extensive network of nucleic acid-binding proteins, including the G-quadruplex-associated helicases DDX5, DDX3X, DDX3Y, and DDX17, the nucleic acid-binding proteins nucleolin and FUS, and the DNA topology regulator TOP2B. These interactomes exhibited both disease- and sex-specific organization. Independent biochemical validation confirmed the association between HUWE1-containing complexes and the G-quadruplex helicase DDX5. In addition, APOE was uniquely detected in Tg-SwDI HUWE1 interactomes and was more abundant in females than in males, suggesting a disease- and sex-specific association between HUWE1-containing complexes and APOE. Taken together, these findings identify HUWE1 as a component of sex-specific nucleic acid-binding protein networks in the aging brain and provide new insights into its potential roles in neurodegeneration.},
}

@article {pmid42697424,
year = {2026},
author = {Jia, B and Zulalai, A and Tang, H and Xiao, J and Zhang, R and Bao, X and Chen, J and Deng, S and Xu, Y and Yu, L and Zhu, X},
title = {Targeting of NLRP3 Gln624/Ser658 by Carabrone attenuates inflammatory diseases.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179299},
doi = {10.1016/j.ejphar.2026.179299},
pmid = {42697424},
issn = {1879-0712},
abstract = {The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in host defense; however, its aberrant activation leads to excessive release of pro-inflammatory cytokines, triggering inflammatory responses and tissue damage in human diseases. In this study, the inhibitory effect and anti-inflammatory potential of carabrone on the NLRP3 inflammasome were systematically evaluated. Carabrone suppressed lipopolysaccharide (LPS) + ATP/Nigericin-induced IL-1β secretion, Caspase-1 activation, and apoptosis-associated speck-like protein (ASC) speck formation. Mechanistic investigations revealed that carabrone inhibited the NLRP3-NEK7 interaction and bound to Gln 624 and Ser 658 within the NACHT domain of NLRP3, thereby stabilizing the local conformation and inhibiting inflammasome activation. In addition, carabrone showed protective effects in Alzheimer's disease (AD) models, which were associated with NLRP3 inflammasome inhibition. Similar effects were also observed in other NLRP3 inflammasome-related disease models, including sepsis, gouty arthritis, and acute peritonitis. Collectively, these results indicate that carabrone might act as a modulator of NLRP3 inflammasome activation across multiple inflammatory disease contexts.},
}

@article {pmid42697496,
year = {2026},
author = {Zhang, J and Chen, X and Hu, Z and Zhang, J and Wu, T and Zhou, J and Song, B and Xu, Y and Yang, H and Zhu, X},
title = {Breaking the autophagy-oxidative stress vicious cycle in Alzheimer's disease: Lactiflorin unlocks P62 dual phosphorylation via ULK1 targeting.},
journal = {Journal of ethnopharmacology},
volume = {374},
number = {Pt 1},
pages = {122367},
doi = {10.1016/j.jep.2026.122367},
pmid = {42697496},
issn = {1872-7573},
abstract = {The dried root of Paeonia lactiflora Pall. has a long history of medicinal use in traditional Chinese medicine. Classical materia medica and traditional practice describe Paeonia-related medicinal materials for headache, dizziness, restlessness, and other neurological or behavioral manifestations, particularly in disorders traditionally associated with blood or yin deficiency and liver-yang hyperactivity. Modern pharmacological studies have further demonstrated neuroprotective and antioxidant effects of Paeonia lactiflora and its bioactive monoterpene glycosides. Lactiflorin (LAC) is a naturally occurring monoterpene glycoside reported as a constituent of Paeonia lactiflora and exhibits antioxidant and cytoprotective properties; however, its therapeutic potential and underlying mechanisms in Alzheimer's disease (AD) remain unclear. This study therefore investigated the protective effects of LAC against AD and explored its underlying mechanisms.

AIM OF THE STUDY: This study investigated whether LAC could break the self-reinforcing vicious cycle between autophagic dysfunction and oxidative stress in AD by engaging ULK1 to promote P62 phosphorylation at two key residues.

MATERIALS AND METHODS: APP/PS1 transgenic mice and Aβ1-42-treated HT22 cells served as in vivo and in vitro AD models, respectively, with cognitive performance assessed through a battery of behavioral tests. Integrated bioinformatics and machine-learning analyses were applied to map AD-related molecular networks and prioritize candidate targets. Aβ deposition, autophagic flux, and oxidative stress were evaluated by immunofluorescence, Western blotting, biochemical assays, and the mCherry-EGFP-LC3 tandem fluorescent reporter system. The interaction between LAC and ULK1 was subsequently evaluated by molecular docking, molecular dynamics simulation, thermal shift assay, DARTS, and SPR.

RESULTS: LAC alleviated cognitive deficits in male APP/PS1 mice and reduced hippocampal Aβ deposition. Bioinformatics analysis subsequently suggested that LAC may regulate AD-related pathology mainly through autophagy- and oxidative stress-associated networks. Consistent with these predictions, LAC increased the LC3-II/LC3-I ratio and decreased P62 expression, while also alleviating redox imbalance and lipid peroxidation in brain tissue and HT22 cells, as evidenced by decreased malondialdehyde (MDA) levels and restored superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Mechanistically, LAC engaged ULK1 via a His24-dependent interaction, thereby enhancing P62 phosphorylation at Ser403/Ser351, activating the Keap1/Nrf2/HO-1 pathway, and restoring the Beclin-1/VPS34-associated autophagy-initiation machinery.

CONCLUSIONS: LAC alleviated Aβ deposition, oxidative injury, and cognitive dysfunction by engaging ULK1, suggesting its potential as a promising natural compound for AD treatment.},
}

@article {pmid42697520,
year = {2026},
author = {Sharma, A and Jatana, N},
title = {Microbiota-derived metabolite-GPCR signalling in neurodegeneration.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.09.001},
pmid = {42697520},
issn = {1873-7544},
abstract = {The gut microbiome acts as a primary regulator of host homeostasis, influencing the entire body through bidirectional communication along the gut-brain axis (GBA). Dysbiosis, which is defined as a state of microbial imbalance involving alterations in community composition and function, can disrupt the synthesis of important microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids and neurotransmitter precursors. This can lead to impaired essential host signalling pathways. There is growing evidence that metabolic alterations associated with dysbiosis contribute to the onset and progression of neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). In this context, G protein-coupled receptors (GPCRs) act as essential molecular transducers that link microbial metabolites to intracellular signalling networks. Aberrant GPCR activation, driven by altered metabolite profiles, modulates key downstream pathways including cAMP, MAPK, PI3K/Akt, NF-κB and Ca2 + signalling. This promotes neuroinflammation, oxidative stress, mitochondrial dysfunction and pathological protein aggregation - hallmark processes underlying neurodegeneration. By identifying convergent and disease-specific signalling pathways, the review highlights mechanistic nodes of therapeutic relevance and discusses GPCR-centric emerging and other microbiome-targeted strategies aimed at restoring metabolic and signalling homeostasis in neurodegenerative disorders.},
}

@article {pmid42697521,
year = {2026},
author = {Alreshidi, NF and Al-Qahtani, SA and Almasoudi, KS and Mirza, IM and Abdulhag, MM and Alsaidan, AA and Jumah, JB and , },
title = {Lower serum serotonin is associated with greater cardiovascular risk burden and poorer cognitive outcomes in mild cognitive impairment and amyloid-positive participants.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.09.005},
pmid = {42697521},
issn = {1873-7544},
abstract = {Both serum serotonin and cardiovascular-risk (CVR) burden are implicated in Alzheimer's disease (AD)-related vascular and neurodegenerative processes, yet their interrelationship across the AD continuum remains unclear. This cross-sectional study examined whether serum serotonin was associated with three complementary measures of CVR burden across the AD continuum and according to CSF amyloid status in 428 participants (138 cognitively normal [CN] individuals, 206 participants with mild cognitive impairment [MCI], and 84 participants with AD), using covariate-adjusted regression models with FDR correction. Following covariate-adjusted analyses, serum serotonin declined progressively from CN to MCI and AD, whereas all CVR measures were higher in MCI and AD than in CN participants. Among participants with MCI and pooled amyloid-positive (Aβ+) participants, greater CVR burden was consistently associated with lower serum serotonin across the Framingham Risk Score (FRS), pooled PCA-derived CVR score, and cohort-specific PCA-derived CVR score. Together, these within-group findings suggest that lower serum serotonin accompanies greater vascular-risk burden in clinically and biologically vulnerable individuals. However, CVR × diagnosis and CVR × amyloid-status interaction tests were not significant after FDR correction. Besides, lower serum serotonin and greater CVR burden were separately associated with poorer cognitive and functional outcomes in both MCI and Aβ+ participants. In short, greater CVR burden was associated with lower serum serotonin, particularly within MCI and Aβ+ groups, and both factors were related to less favorable clinical outcomes, underscoring the need for longitudinal and mechanistic studies to define serotonin's role at the vascular-neurodegenerative interface in AD.},
}

@article {pmid42697812,
year = {2026},
author = {Clark, ED and Perin, J and Devanand, DP and Padala, PR and Shade, DM and Lyketsos, CG and Porsteinsson, AP and , },
title = {Effects of Escitalopram on Neuropsychiatric Symptoms in Alzheimer Disease: A Secondary Analysis From the S-CitAD Study.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.08.011},
pmid = {42697812},
issn = {1545-7214},
abstract = {OBJECTIVE: Using Neuropsychiatric Inventory (NPI) data from the Escitalopram for agitation in Alzheimer disease (S-CitAD) study, the authors explored the potential impact of escitalopram on neuropsychiatric symptom domains and caregiver distress scores outside of agitation.

METHODS: Caregiver-rated scores were compared from baseline to week 12 in 173 participants receiving escitalopram (5-15 mg/day) or placebo examining the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and median NPI domain severity scores between groups at week 12. Caregiver distress scores were additionally examined by NPI domain at baseline and at week 12 for between group changes.

RESULTS: Statistical significance was seen in the depression/dysphoria domain median scores favoring the escitalopram group at week 12. Caregiver distress scores in the domains of apathy/indifference and irritability/lability favored escitalopram at week 12; however, the median NPI domain scores in these domains weren't statistically different from placebo. In evaluating the emergence of new symptoms over the 12-week period, no participants (0%) in the escitalopram group reported new hallucinations versus 5 participants (7%) in the placebo group.

CONCLUSION: Escitalopram may have an impact on the severity of symptoms of depression/dysphoria in AD. No new symptoms of hallucinations in the escitalopram group throughout the 12 week trial suggest a possible direction for future research into selective serotonin reuptake inhibitors (SSRIs) and the treatment and/or delaying of psychotic symptoms in AD. As this was an exploratory analysis involving multiple comparisons, findings may be spurious.},
}

@article {pmid42697987,
year = {2026},
author = {Joly, J and Budamagunta, V and Zhang, Z and Nortman, B and Jouzi, M and Bhatnagar, R and Egertson, JD and Flaster, ME and Grothe, R and Guha, S and Kaneshige, K and McVey, K and Nelson, N and Perera, RT and Tan, SJ and Trinh, T and Arnott, D and Lipka, J and Pandya, NJ and Rougé, L and Wendorff, TJ and Kirkpatrick, DS and Rohou, A and Butler, DC and Lotz, S and Forton, A and Sartori, ER and Schwarz, JE and Brereton, PS and Chen, K and Darcy, MA and Golnabi, HR and Hartley, R and Indermuhl, PF and Inman, CE and Jin, KM and Katsyuk, S and Kota, R and Lowry, B and Menger, JC and Miller, DA and Newman, MR and Ogunyemi, A and Robinson, JK and Steiner, N and Sun, J and Tabakman, SM and Wang, L and Wang, Z and Wilcox, SK and , and Kapp, GT and Patel, S and Temple, S and Bertucci, T and Blanchard, J and Huhmer, AFR and Sankar, SV and Juneau, K and Mallick, P},
title = {Large-scale single-molecule analysis of tau proteoforms.},
journal = {Nature methods},
volume = {23},
number = {9},
pages = {1786-1797},
pmid = {42697987},
issn = {1548-7105},
support = {RF1NS123568//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 1RF1NS142335//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 1RF1NS142335//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 80ARC022CA004//National Aeronautics and Space Administration (NASA)/ ; 80ARC022CA004//National Aeronautics and Space Administration (NASA)/ ; R01AG089533//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {*tau Proteins/metabolism/chemistry ; Animals ; Humans ; Phosphorylation ; *Single Molecule Imaging/methods ; Alzheimer Disease/metabolism ; Mice ; Brain/metabolism ; Protein Processing, Post-Translational ; Protein Isoforms/metabolism ; },
abstract = {Proteins exist as diverse proteoforms resulting from a combination of genetic variation, alternative splicing and post-translational modifications. Current methods struggle to capture this complexity at the single-molecule level. Here we introduce Iterative Mapping of proteoforms, a method that enables massively parallel interrogation of millions to billions of single-protein molecules through iterative probing with fluorescently labeled antibodies. We applied Iterative Mapping to tau, a key protein in neurodegenerative diseases, using 12 site-specific antibodies. The tau proteoform assay demonstrates high sensitivity (detecting proteoforms at 0.1% abundance), high reproducibility (median coefficient of variation <5.5%) and broad dynamic range (>3 orders of magnitude), outperforming conventional techniques in resolving closely related proteoform groups. Analysis of relevant biological samples, including organoids, mouse brains and human Alzheimer's disease samples, revealed 130 distinct tau proteoform groups with as many as six phosphorylation events. The nonrandom distribution of these phosphorylation events suggests ordered and site-specific modification processes rather than random, stochastic accumulation. Iterative Mapping provides insights into proteoform complexity at the single-molecule level, with implications for understanding protein regulation in neurodegenerative diseases and beyond.},
}

*tau Proteins/metabolism/chemistry
Animals
Humans
Phosphorylation
*Single Molecule Imaging/methods
Alzheimer Disease/metabolism
Mice
Brain/metabolism
Protein Processing, Post-Translational
Protein Isoforms/metabolism

@article {pmid42698179,
year = {2026},
author = {Dhar, A and Sharar, AD and Papisetty, S and Bydon, M and Moinuddin, FM},
title = {The Therapeutic Potential of Purmorphamine Across Disease Models.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {17},
pages = {e71349},
doi = {10.1111/jcmm.71349},
pmid = {42698179},
issn = {1582-4934},
mesh = {Humans ; Animals ; *Purines/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Hedgehog Proteins/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Morpholines ; },
abstract = {Purmorphamine (PUR) is a trisubstituted purine compound that selectively activates Smoothened receptor, thereby initiating Sonic Hedgehog (Shh) signalling-a pathway critical for embryonic patterning, neuronal specification and tissue regeneration across multiple organ systems. Dysregulation of Shh signalling has been implicated in degenerative diseases yet therapeutic interventions targeting this pathway remain limited. PUR demonstrates broad therapeutic efficacy across diverse preclinical disease models by activating both canonical GLI-mediated transcription and non-canonical Shh pathways, resulting in neuroprotection, reduced neuroinflammation, enhanced blood-brain barrier integrity and tissue regeneration. In contrast to previous assumptions that Shh pathway activation requires endogenous ligand binding, PUR bypasses this requirement through direct Smoothened engagement, offering a pharmacologically tractable approach to pathway modulation. Preclinical studies demonstrate that PUR enhances motor neuron survival in amyotrophic lateral sclerosis models, protects dopaminergic neurons in Parkinson's disease, reverses behavioural abnormalities in autism spectrum disorder, promotes neurovascular repair following stroke, restores myelin integrity in multiple sclerosis models and drives osteogenic differentiation in bone tissue engineering applications. Beyond its established Smoothened agonist activity, recent evidence identifies PUR as a positive allosteric modulator of the secretin receptor, expanding its therapeutic scope to include cardiovascular applications such as hypertension management through enhanced nitric oxide bioavailability.},
}

Humans
Animals
*Purines/therapeutic use/pharmacology
Signal Transduction/drug effects
Hedgehog Proteins/metabolism
Disease Models, Animal
Neuroprotective Agents/pharmacology/therapeutic use
Morpholines

@article {pmid42698301,
year = {2026},
author = {Chen, Y and Du, X and Li, F and Yuan, S and Wang, W and Zhu, Z and Wang, M and Gu, C},
title = {P7C3 Compounds as Targeted Mitochondrial Therapeutics for Brain Disorders.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71139},
doi = {10.1002/cns.71139},
pmid = {42698301},
issn = {1755-5949},
support = {32200775//National Natural Science Foundation of China/ ; (2021) 31576//Jiangsu Innovative and Enterpreneurial Talent Programme/ ; SYW2025109//Suzhou Medical Health Science and Technology Innovation Project/ ; GSWS2023102//Suzhou Health Talent Plan Talent Research Project/ ; },
mesh = {Humans ; Animals ; *Carbazoles/therapeutic use/chemistry/pharmacology/administration & dosage ; *Mitochondria/drug effects/metabolism ; *Brain Diseases/drug therapy/metabolism ; Nicotinamide Phosphoribosyltransferase/metabolism ; *Neuroprotective Agents/administration & dosage/pharmacology ; Cytokines/metabolism ; },
abstract = {BACKGROUND: P7C3 compounds are aminopropyl carbazole derivatives identified through phenotypic screening for proneurogenic activity. They directly activate nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD[+] salvage pathway. However, a comprehensive synthesis of their mechanisms and therapeutic potential across neurological disorders is currently lacking.

METHODS: A systematic literature review was conducted in PubMed, Web of Science, and Scopus to synthesize the discovery trajectory, structure-activity relationships, molecular mechanisms, and preclinical efficacy of P7C3 compounds. The following keyword combinations were used: ("P7C3" OR "P7C3 compound") AND ("NAMPT" OR "NAD+" OR "sirtuin" OR "mitochondria") AND ("neuroprotection" OR "neurodegenerative").

RESULTS: P7C3 elevates intracellular NAD[+] levels, engages SIRT1 and SIRT3 deacetylase cascades, enhances mitochondrial quality control and attenuates oxidative stress. This review discusses the discovery, structure-activity relationships, and molecular mechanisms of P7C3, with a particular emphasis on mitochondrial dynamics and redox homeostasis. The efficacy of P7C3 in preclinical studies was evaluated across Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI), ischemic stroke, depression, and chemotherapy-induced neuropathy. These neuroprotective effects occur independently of disease-specific aggregates. Challenges hindering clinical application include the on-target safety of NAMPT activation given the concurrent development of NAMPT inhibitors for tumorigenesis, the absence of validated predictive biomarkers, and the failure of prior NAMPT-targeting trials.

CONCLUSIONS: P7C3 illustrates how phenotypic screening coupled with target deconvolution can yield therapeutic candidates with potential applications across a broad spectrum of neurological disorders.},
}

Humans
Animals
*Carbazoles/therapeutic use/chemistry/pharmacology/administration & dosage
*Mitochondria/drug effects/metabolism
*Brain Diseases/drug therapy/metabolism
Nicotinamide Phosphoribosyltransferase/metabolism
*Neuroprotective Agents/administration & dosage/pharmacology
Cytokines/metabolism

@article {pmid42698645,
year = {2026},
author = {Husted, GE and Cassels, SL and Ackert, ES and Bendlin, BB},
title = {Long-Term Industrial Emissions Exposure and Cognitive Impairment in Older U.S. Adults: A Longitudinal Cohort Study.},
journal = {Health science reports},
volume = {9},
number = {9},
pages = {e73185},
doi = {10.1002/hsr2.73185},
pmid = {42698645},
issn = {2398-8835},
abstract = {BACKGROUND: The demographic shift toward an older global population is increasing the burden of Alzheimer's Disease and Related Dementias (ADRD). While age is the strongest risk factor, environmental toxicants are increasingly recognized as contributors to cognitive decline. Plastics and rubber manufacturing facilities emit neurotoxic chemicals, yet their relationship to ADRD risk remains understudied. This study assesses whether exposure to plastics/rubber industry emissions is associated with ADRD risk and whether sociodemographic factors influence this relationship.

METHODS: We linked geocoded Environmental Protection Agency (EPA) Toxic Release Inventory (TRI) data with Panel Study of Income Dynamics (PSID) records and Neighborhood Change Database (NCDB) Census data. Historical exposure to plastics/rubber emissions and time-varying sociodemographic characteristics were measured from 1990 to 2017, leveraging PSID's longitudinal structure to capture residential mobility. ADRD risk was defined as a positive AD8 screen (≥ 2 endorsed cognitive challenges) in 2017, 2019, 2021, or 2023. Logistic regression models estimated ADRD risk as a function of average total pounds of chemicals released from the nearest TRI facility to each individual's census tract of residence over time, adjusting for individual and neighborhood characteristics.

RESULTS: Moderate emissions exposure was significantly associated with elevated ADRD risk (OR = 1.34), independent of income and neighborhood disadvantage. Neighborhood disadvantage was also strongly predictive of ADRD risk.

CONCLUSIONS: Environmental emissions may represent a modifiable risk factor for ADRD and contribute to disparities in cognitive aging.},
}

@article {pmid42698704,
year = {2026},
author = {Takahashi, F and Yamamura, T and Oki, S},
title = {Coincidence of L1 retrotransposition and DNA repair deficiency elicits synthetic lethality in S-phase mature neurons.},
journal = {iScience},
volume = {29},
number = {9},
pages = {117335},
doi = {10.1016/j.isci.2026.117335},
pmid = {42698704},
issn = {2589-0042},
abstract = {Neurodegeneration involves the entangled processes of cell-autonomous and non-cell-autonomous neuronal cell death, which leads to a collapse in the integrity of the neural network and causes behavioral symptoms. Here, we demonstrate that aberrant cell cycle re-entry (CCR) is prominent in mature neurons and that the replication fork acts as a target site for long interspersed nuclear element-1 (L1) retrotransposition during neurodegeneration. The fatal susceptibility of S-phase neurons in 5xFAD mice is attributed to a DNA repair deficiency in response to L1-mediated replication stress. Impaired sirtuin 6 expression seems to allow stochastic L1 activation and enhanced retrotransposition. Reduced estrogen/prolactin signaling correlates well with reduced Brca1 expression that is thought to protect neurons from replication stress. Importantly, L1-mediated pathogenesis correlates well with conventional Alzheimer's disease pathology. In summary, the combination of enhanced L1 retrotransposition and DNA repair deficiency elicited synthetic lethality in S-phase neurons, highlighting a previously unknown pathogenic mechanism of neurodegeneration.},
}

@article {pmid42698737,
year = {2026},
author = {Xie, B and Zhang, W and Zhang, Y and Liu, L and You, J and Li, Q},
title = {Translating blood-based biomarkers into Alzheimer's disease clinical practice: screening, diagnosis, and longitudinal monitoring.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1852137},
doi = {10.3389/fnagi.2026.1852137},
pmid = {42698737},
issn = {1663-4365},
abstract = {Blood-based biomarkers (BBMs) are increasingly being integrated into Alzheimer's disease (AD) clinical pathways by providing scalable tools to track amyloid, tau, neurodegeneration, and inflammation dimensions of the ATN-I framework. As biological characterization and biomarker-informed assessment are increasingly integrated into AD care, there is growing interest in clinically applicable blood-based approaches capable of reflecting AD-related biological changes across different disease stages. This review examines recent advances in BBMs through the ATN-I framework while emphasizing their clinical decision value, analytical feasibility, economic considerations, and implementation barriers across different healthcare settings. Building on these findings, we examine the evidence supporting clinical use, with a focus on appropriate use criteria, clinical validation, laboratory feasibility, and consistent interpretation methods. Furthermore, this review explores how integrating BBMs with traditional cerebrospinal fluid and neuroimaging tests may support symptom-driven clinical triage, probability refinement, and early evaluation in selected individuals, improving clinical workflow efficiency and accessibility. Finally, the article addresses remaining challenges related to clinical validation, platform accessibility, cost-effectiveness, and equitable deployment, highlighting how emerging biomarker strategies may contribute to more scalable AD assessment.},
}

@article {pmid42698748,
year = {2026},
author = {Alkam, T and Tarshizi, E and Van Benschoten, AH},
title = {Data-driven subtyping of Alzheimer's emergency presentations using unsupervised machine learning.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {687-697},
doi = {10.1016/j.ibneur.2026.08.016},
pmid = {42698748},
issn = {2667-2421},
abstract = {BACKGROUND: Older adults with Alzheimer's disease (AD) frequently present to emergency departments (EDs) with multiple coexisting conditions. However, age-specific patterns of multimorbidity in AD-related ED encounters remain incompletely characterized.

OBJECTIVE: To identify and describe age-specific multimorbidity subtypes among AD-associated ED encounters using unsupervised machine learning and heatmap-based diagnostic profiling.

METHODS: We conducted a cross-sectional analysis of the 2022 Nationwide Emergency Department Sample. AD-associated encounters were identified by an ICD-10-CM G30.x diagnosis code in any diagnosis field. The cohort included 125,461 ED encounters and was stratified into four age groups: 60-64, 65-74, 75-84, and ≥ 85 years. For each age group, the 30 most frequent co-occurring diagnoses were converted into binary indicators. KMeans clustering with eight clusters per age group was used for heatmap-based subtyping, while Uniform Manifold Approximation and Projection and Hierarchical Density-Based Spatial Clustering of Applications with Noise were used to visualize diagnostic structure.

RESULTS: Distinct multimorbidity profiles were identified across all age groups. Among adults aged 60-74 years, clusters commonly included psychiatric and metabolic conditions, such as depression, anxiety, diabetes, chronic kidney disease, substance-use diagnoses, and dehydration. Among adults aged ≥ 75 years, clusters more frequently included cardiorenal disease, urinary tract infection, metabolic encephalopathy, respiratory failure, do-not-resuscitate status, and palliative care. The cohort had a mean age of 81.7 ± 7.2 years, and 62.6% of encounters involved women.

CONCLUSION: Patterns of coexisting conditions in AD-related ED visits differed substantially by age. Adults aged 60-74 years more often showed psychiatric and metabolic combinations, whereas those aged ≥ 75 years more often showed infection, cardiorenal disease, respiratory failure, and end-of-life care markers. Recognizing these age-related patterns may help clinicians anticipate common care needs when evaluating patients with AD in the ED.},
}

@article {pmid42699154,
year = {2026},
author = {Rouault, M and Kindler, DR and Ni, R and Liberale, L and Seiler, R and Ielacqua, GD and Nitsch, R and Pryce, C and Camici, GG and Kulic, L and Klohs, J},
title = {Coagulation factor XII deficiency alleviates vascular dysfunction and cognitive impairment in a mouse model of cerebral β-amyloidosis and cerebral amyloid angiopathy.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100167},
doi = {10.1016/j.nbas.2026.100167},
pmid = {42699154},
issn = {2589-9589},
abstract = {Amyloid-β (Aβ) can activate the factor XII (FXII)-driven contact system, which exerts several downstream effects on Alzheimer's disease (AD) pathology associated with cognitive impairment. Here, using genetically modified FXII deficient mice crossed with arcAβ mice, we show that genetic deletion of FXII ameliorates β-amyloidosis-mediated susceptibility to arterial thrombus formation, blood-brain barrier leakage, and cerebral microbleed load. Furthermore, we show that genetic deletion of FXII improves cognitive deficits, without affecting Aβ deposition. Thus, the FXII-driven contact system constitutes an important pathway contributing to vascular dysfunction and cognitive impairment in AD, independent of Aβ neuropathology, with important implications for the diagnosis and treatment of the disease.},
}

@article {pmid42699166,
year = {2026},
author = {Mughal, EU and Naeem, N and Kılınç, N and Ahmed, I and Zaki, MEA and Fathalla, M and Sadiq, A and Hefnawy, M},
title = {Dual-acting flavonol analogues as cholinesterase inhibitors and anticonvulsant agents: integrated in vitro, in vivo, and in silico studies.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ra06819g},
pmid = {42699166},
issn = {2046-2069},
abstract = {Neurological disorders such as Alzheimer's disease and epilepsy are complex, multifactorial conditions that require therapeutic agents capable of acting through multiple mechanisms. In the present study, a series of structurally diverse flavonol analogues was synthesized and evaluated for their dual cholinesterase inhibitory and anticonvulsant potential through integrated in vitro, in vivo, and in silico approaches. The compounds were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities using standard spectrophotometric assays. Selected derivatives demonstrating significant enzyme inhibition were further assessed for anticonvulsant efficacy in maximal electroshock seizure (MES) and pentylenetetrazole (PTZ)-induced seizure models. Several compounds exhibited noteworthy inhibition of both cholinesterase enzymes, with the most active derivatives displaying low micromolar potency. In anticonvulsant studies, the leading compounds produced dose-dependent protection against electrically and chemically induced seizures, significantly reducing seizure severity, prolonging seizure latency, and increasing protection rates in both experimental models. To the best of our knowledge, this is among the first reports evaluating the anticonvulsant activity of this specific flavonol scaffold in both MES and PTZ models. Computational investigations, including induced-fit docking, MM-GBSA binding free-energy calculations, molecular dynamics simulations, ADME prediction, and density functional theory (DFT) analyses, revealed favorable enzyme-binding interactions, stable ligand-protein complexes, and acceptable drug-like characteristics. The convergence of biological and computational findings identified compound 8 as the most promising multifunctional candidate, exhibiting potent dual cholinesterase inhibition, pronounced anticonvulsant activity, and sustained target engagement. These results demonstrate that flavonol-based scaffolds represent attractive lead structures for the development of multifunctional therapeutic agents targeting neurodegenerative disorders and epilepsy.},
}

@article {pmid42690834,
year = {2026},
author = {Lin, J and Vassilaki, M and St Sauver, J and Petersen, RC and Wi, CI and Juhn, YJ and Chen, J and Sham, Y and Sohn, S},
title = {Differential associations of individual- and neighborhood-level socioeconomic status with mortality in dementia: Findings from the Mayo Clinic Study of Aging.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261482043},
doi = {10.1177/13872877261482043},
pmid = {42690834},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and related dementias are leading causes of death worldwide. While socioeconomic status (SES) is a critical determinant, its impact on mortality after diagnosis remains understudied.ObjectiveTo investigate the roles of neighborhood-level and individual-level SES in predicting mortality risk among older adults with incident dementia.MethodsWe analyzed data from 924 participants with incident dementia from the Mayo Clinic Study of Aging (N = 6909), a cohort with clinical follow-up visits every 15 months. We assessed mortality risk using Cox's time-varying survival regression, adjusting for time-fixed and time-varying covariates. Primary predictors were neighborhood-level SES (Area Deprivation Index [ADI]) and individual-level SES (housing-based SES index [HOUSES], education, and occupation). We also applied a random survival forest model to assess the predictive contribution of SES indicators and identify influential predictors.Results857 participants (92.7%) died, with a median time from dementia diagnosis to death of 29 months (IQR: 12-54). Lower SES measured by HOUSES was associated with increased mortality risk (HR 1.28, 95% CI 1.07-1.52). Conversely, ADI, education, and occupation were not associated with mortality. Male sex, older age, congestive heart failure and diabetes were associated with higher mortality risk. In predictive analysis, HOUSES ranked among the top 10 contributors to mortality risk.ConclusionsAmong older adults with dementia, lower HOUSES was associated with higher mortality risk beyond neighborhood-level deprivation, education, and occupation. Integrating this housing-based individual-level SES measure into dementia care planning may help identify patients with greater socioeconomic vulnerability and inform mortality risk stratification.},
}

@article {pmid42691074,
year = {2026},
author = {Fernandez, FX and Burke, SN and Nadel, L},
title = {Aging as a Continuation of Development: A Hypothesis and Framework.},
journal = {Perspectives on psychological science : a journal of the Association for Psychological Science},
volume = {},
number = {},
pages = {17456916261469175},
doi = {10.1177/17456916261469175},
pmid = {42691074},
issn = {1745-6924},
abstract = {Prevailing theories of cognitive aging depict late life as a period of compensatory decline-an effort to preserve performance despite progressive neural deterioration. We propose instead that aging represents a continuation of development: a genetically conserved, adaptive reorganization of memory systems that parallels the brain's earlier-life transitions. Drawing on convergent molecular, network, behavioral, and comparative evidence, we argue that the well-documented decline in episodic-memory precision reflects a deliberate recalibration of plasticity from hippocampal to cortical circuits, favoring semantic integration and schematic stability over rapid encoding of novel details. This shift, we suggest, is not a workaround for loss but an evolved optimization suited to the cognitive ecology of late life, when accumulated knowledge, social insight, and intergenerational teaching become primary adaptive functions. The resulting semantic mode of cognition supports narrative coherence, emotional regulation, and wisdom, distinguishing normal aging from pathological derailments such as Alzheimer's disease. We outline testable predictions across longitudinal, neuroimaging, and computational domains and reinterpret constructs like cognitive reserve as expressions of this developmental reallocation. By reframing aging as purposeful maturation rather than compensation, the adaptive-aging hypothesis positions late-life cognition as a distinct, evolutionarily honed phase of human development.},
}

@article {pmid42691219,
year = {2026},
author = {Iqbal, T and Tabassum, S and Imran, M and Tang, S and Xiao, P and Wei, T and Hailaiti, D and Fan, P and Lu, W and Li, H and Huang, J},
title = {The Glymphatic and Meningeal Lymphatic Systems: Gatekeepers of Brain Health in Aging and Neurodegeneration.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0009},
pmid = {42691219},
issn = {2152-5250},
abstract = {The discovery of the glymphatic system and of meningeal lymphatic vessels has substantially revised our understanding of how the central nervous system clears waste and maintains neuroimmune homeostasis. Acting in series, these two pathways remove interstitial solutes, metabolic by-products, and neurotoxic proteins such as tau and amyloid-β from the brain parenchyma and deliver them to the peripheral lymphatic system. Converging experimental and clinical evidence indicates that both pathways decline with age, and that impaired clearance contributes to the onset and progression of Alzheimer's disease, Parkinson's disease, and stroke, although the direction of causality in these associations is not yet fully resolved. In this review, we summarize current knowledge of the anatomy and physiology of the glymphatic and meningeal lymphatic systems; examine the molecular and cellular mechanisms by which their function deteriorates with age; appraise the imaging modalities and fluid biomarkers used to assess them; and evaluate the therapeutic strategies being developed to restore them. A clearer understanding of this clearance pathways may open new avenues for the treatment of age-related neurodegenerative disease.},
}

@article {pmid42691403,
year = {2026},
author = {Jain, M and Matysiak, S},
title = {Calcium Reshapes Aβ Aggregation at Anionic Lipid Membranes.},
journal = {The journal of physical chemistry. B},
volume = {130},
number = {35},
pages = {8770-8781},
doi = {10.1021/acs.jpcb.6c02606},
pmid = {42691403},
issn = {1520-5207},
support = {CHE-2202281//Division of Chemistry/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Calcium/chemistry/metabolism ; Molecular Dynamics Simulation ; *Lipid Bilayers/chemistry/metabolism ; Anions/chemistry ; Phosphatidylcholines/chemistry ; *Peptide Fragments/chemistry/metabolism ; Hydrophobic and Hydrophilic Interactions ; Protein Aggregates ; Phosphatidylserines/chemistry ; Static Electricity ; },
abstract = {Dysregulated calcium homeostasis is a hallmark of neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. In Alzheimer's disease (AD), the aggregation of amyloid beta (Aβ) peptides at neuronal membranes is shown to be modulated by the presence of Ca2+ ions, yet the molecular mechanism by which Ca2+ reshapes Aβ aggregation at anionic membrane surfaces remains poorly understood. To address this knowledge gap, we employed coarse-grained molecular dynamics simulations to investigate the aggregation of the model amyloidogenic K16LVFFAE22 fragment of Aβ (Aβ16-22), on a mixed bilayer composed of 30% anionic phosphatidylserine (PS) and 70% zwitterionic phosphatidylcholine (PC) (30% POPS, 70% POPC) in the presence of Ca2+ ions. We find that Ca2+ ions screen the surface charge and reduce hydrophobic packing defects at the membrane surface. Since peptide binding is primarily driven by electrostatic interactions between positively charged residues and anionic lipids, followed by hydrophobic interactions, these Ca2+-induced changes delay peptide adsorption onto the bilayer, promoting the formation of larger aggregates in solution that subsequently adsorb as preformed aggregates. This is in contrast with the no-Ca2+ condition, where peptides bind earlier as small oligomers and aggregate on the bilayer. Following adsorption, PS-Ca2+-PS ionic bridges rapidly condense PS lipids around peptide aggregates and reduce their lateral mobility. This leads to larger, less ordered aggregates with shallower insertion and hydrophobic residues exposed to the solution, a structural feature associated with seeding-active aggregates. These findings align with Western blot analyses showing enhanced Aβ aggregation with Ca2+ ions and provide a molecular basis for the observed aggregation behavior. Together, our results provide mechanistic insight into how calcium alters the membrane-mediated aggregation pathway of amyloidogenic peptides, potentially informing therapeutic strategies against amyloid pathology.},
}

*Amyloid beta-Peptides/chemistry/metabolism
*Calcium/chemistry/metabolism
Molecular Dynamics Simulation
*Lipid Bilayers/chemistry/metabolism
Anions/chemistry
Phosphatidylcholines/chemistry
*Peptide Fragments/chemistry/metabolism
Hydrophobic and Hydrophilic Interactions
Protein Aggregates
Phosphatidylserines/chemistry
Static Electricity

@article {pmid42691413,
year = {2026},
author = {Mo, Y and Hou, Y and Su, R and Huang, Z and Tang, G and Du, L and Lu, Y},
title = {Conformational Features of Aβ25-35 and Its Mutants Suggest Toxic Structural Determinants: Insights from REST2 Simulations.},
journal = {The journal of physical chemistry. B},
volume = {130},
number = {35},
pages = {8855-8866},
doi = {10.1021/acs.jpcb.6c04178},
pmid = {42691413},
issn = {1520-5207},
support = {2018GXNSFBA050028//Natural Science Foundation of Guangxi Zhuang Autonomous Region/ ; 12464018//National Natural Science Foundation of China/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/genetics/toxicity/metabolism ; *Peptide Fragments/chemistry/genetics/toxicity/metabolism ; *Molecular Dynamics Simulation ; Mutation ; Hydrophobic and Hydrophilic Interactions ; Hydrogen Bonding ; Protein Conformation ; Humans ; },
abstract = {The Aβ25-35 fragment is the shortest proteolytic fragment retaining the core neurotoxicity of full-length Alzheimer's amyloid-β (Aβ). To elucidate the structure-neurotoxicity relationships, we performed replica exchange with solute tempering 2 (REST2) simulations on wild-type (WT), N27A (less toxic), and M35A (more toxic) Aβ25-35 hexamers in explicit solvent. Our simulations show that N27A, WT, and M35A hexamers predominantly adopt 4-stranded, 6-stranded, and 5-stranded β-barrels, respectively, driven by hydrophobic interactions within residues I30-G33. Hydrogen bond counts and binding energies for adjacent peptide contacts and peptide-water interactions indicate that both β-barrel disassembly propensity and N-terminal hydration (residues G25-K28) correlate with the cytotoxicity trend (N27A < WT < M35A). Integrating our findings with established membrane damage mechanisms, we propose that (I) the disassembly propensity of dominant β-barrels governs their transition from off-pathway states to cytotoxic oligomers, and (II) N-terminal domain exposure (G25-K28) in on-pathway intermediates modulates peptide-membrane interactions. To reduce Aβ25-35 oligomeric toxicity, we recommend inhibiting hydrophobic core residues (A30-G33) to suppress aggregation and modulating N-terminal contacts to limit solvent exposure and membrane binding. Our simulations provide new insights into WT and mutant Aβ25-35 cytotoxicity and suggest therapeutic strategies for its attenuation.},
}

*Amyloid beta-Peptides/chemistry/genetics/toxicity/metabolism
*Peptide Fragments/chemistry/genetics/toxicity/metabolism
*Molecular Dynamics Simulation
Mutation
Hydrophobic and Hydrophilic Interactions
Hydrogen Bonding
Protein Conformation
Humans

@article {pmid42691466,
year = {2026},
author = {Beaufort, Q and Charbonnier, C and Ruellan, P and Ozkul-Wermester, O and Amar, V and Turpin, D and Quillard-Muraine, M and Gerardin, E and Dufour, D and Charidimou, A and Balageas, AC and Boulouis, G and Pasi, M and Wallon, D and Grangeon, L},
title = {Evaluation of Disease Severity Using CSF Biomarkers in Patients With Probable Cerebral Amyloid Angiopathy.},
journal = {Neurology},
volume = {107},
number = {6},
pages = {e218458},
doi = {10.1212/WNL.0000000000218458},
pmid = {42691466},
issn = {1526-632X},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging ; Female ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; *tau Proteins/cerebrospinal fluid ; Retrospective Studies ; Aged ; *Severity of Illness Index ; *Peptide Fragments/cerebrospinal fluid ; Magnetic Resonance Imaging ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy (CAA) is currently diagnosed using MRI-based Boston criteria. However, imaging markers represent downstream consequences of vascular injury and may not fully reflect disease severity. CSF biomarkers, particularly β-amyloid 1-42 (Aβ42) and β-amyloid 1-40 (Aβ40), may provide a more direct measure of vascular amyloid burden. We investigated the association between CSF biomarkers and hemorrhagic and nonhemorrhagic MRI markers of disease severity in probable CAA.

METHODS: We conducted a retrospective multicenter cohort study including consecutive patients diagnosed with probable CAA according to Boston criteria v2.0 at 2 tertiary centers (2014-2023) who underwent lumbar puncture (LP) as part of clinical evaluation. CSF Aβ42, Aβ40, total tau, and phosphorylated-tau 181 (p-tau181) were measured using standardized immunoassays. MRI markers included lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), white matter hyperintensity burden, Fazekas score, and enlarged perivascular spaces in the centrum semiovale. Multivariable linear regression models were adjusted for age, sex, MRI sequence type, and delay between onset and LP. False discovery rate correction was applied for multiple testing. We also used principal component analysis to explore associations between MRI and CSF biomarkers.

RESULTS: A total of 102 patients were included (mean age at LP 72.0 ± 7.5 years; 65% male). Initial presentations were cognitive impairment in 53%, intracerebral hemorrhage in 34%, and transient focal neurologic episodes in 13%. Lower CSF Aβ40 and Aβ42 levels were significantly associated with greater cSS burden (standardized β -0.49 [95% CI -0.8 to -0.17], p = 0.002 and -0.42 [-0.73 to -0.11], p = 0.007, respectively) and higher Fazekas score (β -0.18 [-0.33 to -0.03], p = 0.02 and -0.23 [-0.38 to -0.08], p = 0.002) but not with CMB count. No significant association was found between tau species and MRI markers. Associations remained significant after stratification by CSF Aβ42/Aβ40-defined Alzheimer-like profile.

DISCUSSION: In probable CAA, lower CSF Aβ40 and Aβ42 levels are associated with established MRI markers of disease severity, independently of clinical presentation and concomitant Alzheimer-like profile. These findings suggest that CSF Aβ levels may reflect vascular amyloid burden rather than downstream neurodegeneration. Prospective longitudinal studies are needed to determine their prognostic value.},
}

Humans
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging
Female
Male
*Amyloid beta-Peptides/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
*tau Proteins/cerebrospinal fluid
Retrospective Studies
Aged
*Severity of Illness Index
*Peptide Fragments/cerebrospinal fluid
Magnetic Resonance Imaging
Aged, 80 and over
Middle Aged

@article {pmid42691539,
year = {2026},
author = {Hsu, EC and Carder, P and Smith, L and Zhou, ZE and Yakusheva, O and Beeber, A and Jutkowitz, E and Thomas, KS},
title = {A Profile of Assisted Living Direct Care Workforce Training Requirements Across the United States.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {10},
pages = {106445},
doi = {10.1016/j.jamda.2026.106445},
pmid = {42691539},
issn = {1538-9375},
abstract = {OBJECTIVES: To characterize assisted living (AL) direct care worker (DCW) training requirements across the United States and how these regulations have changed over time. Specifically, we examine state-level profiles of training regulations, including duration, frequency, content, source of materials, evaluation, and changes in regulatory coverage.

DESIGN: Cross-sectional and longitudinal descriptive study using state policy data and AL directories from 2019, 2021, and 2023.

SETTING AND PARTICIPANTS: All US states' AL training-related regulations; all ALs and AL beds governed by those regulations.

METHODS: We used a mixed-methods approach with an explanatory sequential design (QUAN → qual), first conducting health services regulatory analysis followed by qualitative content analysis.

RESULTS: In 2023, 43 states (90% of ALs, nationally) required DCW training, 29 states required annual training frequency, 28 states specified training hours (median 10 hours), 28 required dementia-specific content, and 29 required training to cover at least 5 topics when onboarding. Common training topics included resident rights, emergency response, infection control, and personal care; dementia-specific training topics included Alzheimer's disease, behavior, communication, and dignity of residents, with only 2 states requiring training that addressed DCWs' well-being. Ten states mandated use of professionally designed courses, and 5 states required DCWs to complete an exam. From 2019 to 2023, 6 states made changes to the scope of dementia-specific training.

CONCLUSIONS AND IMPLICATIONS: While most states mandate DCW training and over half require annual frequency, duration, and cover 5 topic areas, few states specify sources of training materials or require competency checks. Lack of specificity in training requirements requires AL operators to determine what constitutes adequate training for DCWs to be successful. To better prepare the AL workforce for growing resident complexity, policymakers should consider promoting specific training requirements that ensure both onboarding and continuous education for DCWs, particularly around dementia care and workforce well-being.},
}

@article {pmid42691626,
year = {2026},
author = {Singh, R and Paliwal, T and Joshi, R and Paliwal, V and Dubey, P and Bhardwaj, S and Jain, S and Paliwal, S and Sharma, S},
title = {Targeting the protein tyrosine phosphatase 1B signaling axis in Alzheimer's disease: Emerging therapeutic potential of ivermectin.},
journal = {Biochemical and biophysical research communications},
volume = {835},
number = {},
pages = {154524},
doi = {10.1016/j.bbrc.2026.154524},
pmid = {42691626},
issn = {1090-2104},
abstract = {This study attempts to repurpose ivermectin (IVM) for AD by inhibiting the PTP1B enzyme. IVM is a widely known, commercially approved antiparasitic drug. The PTP1B enzyme dephosphorylates multiple kinase substrates and is responsible for metabolic regulation by the PI3K/AKT downstream signaling cascade. A similar signaling pathway is present in the brain. We assessed binding affinity in BIOVIA Discovery Studio Visualizer version 2021 and inhibitory activity using a commercially available ELISA kit. The streptozotocin (3 mg/kg, intracerebroventricularly)- induced AD mouse model was used to study the biological effects of IVM using NOR and Y-maze behavioral assays. Multiple disease physiologies, such as oxidative stress, mitochondrial complex (I-IV) dysfunction, brain insulin resistance, neuroinflammation, Aβ aggregation, apoptosis, and autophagy signaling cascade, were studied by assessing various biomarkers to generate a proof-of-concept. The docking study demonstrated potential interactions of IVM with the catalytic pocket of PTP1B enzyme, yielding a docking score of -8.0. To validate the docking protocol, the re-docked ligand was superimposed on the crystallographic ligand, resulting in an RMSD of 0.000 Å, therefore confirming the reliability of the computational approach. The calculated IC50 value of IVM by ELISA inhibitory assay was found 4.58 μM. The in vivo study of IVM (10 mg/kg) in the mouse model showed improvement in cognitive deficits on behavioral assays and was comparable to donepezil and DPM1001. The preliminary screening investigations through in vitro enzyme inhibition and molecular-level studies showed promising improvements in multiple physiological parameters that progressed to AD. The IHC showed a reduction in the Aβ plaque load and activated microglia cell count. These preliminary data demonstrate that IVM exhibits considerable PTP1B inhibitory potential and require further exploration in a robust, statistically powered preclinical study, followed by clinical trials, to repurpose it in AD and related conditions.},
}

@article {pmid42691699,
year = {2026},
author = {Reinhardt, AM and Theron, A and Tantoh, ALA and Malan, FP and Panayides, JL and Riley, DL},
title = {Integrated computational and automated flow synthesis platform for the rapid discovery of N-benzylpiperidine acetylcholinesterase inhibitors.},
journal = {European journal of medicinal chemistry},
volume = {319},
number = {},
pages = {119259},
doi = {10.1016/j.ejmech.2026.119259},
pmid = {42691699},
issn = {1768-3254},
abstract = {The principal constraint on early-stage medicinal chemistry in an academic setting is rarely the supply of chemical ideas, but the cycle time required to convert them into tested compounds. Here we benchmark an integrated platform that couples ensemble virtual screening, automated continuous-flow library synthesis with inline scavenging, and biological profiling. The platform was evaluated deliberately on a target-scaffold combination for which the pharmacology is already established: the N-benzylpiperidine carboxamide class, identified in our earlier virtual screening campaign against acetylcholinesterase (AChE)[1] and structurally anchored to the approved therapeutic donepezil (1). This choice makes platform performance, the measured variable. An 84-member virtual library was designed, triaged by ensemble docking, and synthesized on an automated flow platform; 54 members were isolated in ≥95% purity. Single-point screening at 5 μM identified ten compounds with ≥70% AChE inhibition, and dose-response determination against electric eel AChE (eeAChE) gave three sub-200 nM inhibitors: 69 (91 nM), 8 (93 nM) and 12 (117 nM), each exceeding galantamine (237 nM) and approaching donepezil (1, 42 nM) under identical assay conditions. Cytotoxicity against VERO cells was uniformly low (IC50 > 250 μM), giving selectivity indices above 2000. Molecular dynamics simulations and twelve single-crystal X-ray structures provide a structural basis for the observed structure-activity relationships, identifying a C-Br···O halogen bond to Asp72 as the origin of the ortho-bromo preference, and a binding-mode reversal that accounts for the loss of potency on benzylpiperazine extension. The complete cycle was executed in under three months by a three-person team. We report this as a measured platform capability rather than as accelerated drug discovery allowing the rapid generation of first-round leads.},
}

@article {pmid42691714,
year = {2026},
author = {Chen, J and Li, X and He, C and Yao, L and Han, T and Han, Q and Huang, J and Li, C and Song, X},
title = {Photoelectrochemical highly efficient detection of β-amyloid 1-42 based on in-situ grown donor-acceptor covalent organic frameworks combined with dual-aptamer sandwich amplification strategy.},
journal = {Talanta},
volume = {312},
number = {Pt C},
pages = {130537},
doi = {10.1016/j.talanta.2026.130537},
pmid = {42691714},
issn = {1873-3573},
abstract = {A highly sensitive dual-aptamer sandwich-type photoelectrochemical (PEC) sensor was developed for detecting β-amyloid 1-42 (Aβ42), whose abnormal accumulation in the brain has been considered as the molecular driver of Alzheimer's (AD) pathogenesis and progression. The sensor was constructed based on in-situ grown covalent organic frameworks (COFs) films. Using a simple room-temperature in-situ synthesis method, TAPB-TFPA COFs (TAPB: 1,3,5-tris(4-aminophenyl)benzene, TFPA: tris(4-formylphenyl)amine) films were successfully fabricated on indium tin oxide (ITO) electrodes. By exploiting the specific recognition between two aptamers and Aβ42, a sandwich complex was formed on the electrode surface. This architecture induces pronounced steric hindrance that impedes interfacial charge transfer, resulting in substantial attenuation of the photocurrent response and enabling highly specific detection of Aβ42. The PEC sensing platform exhibited a good linear response to Aβ42 in the concentration range of 1 pM to 1 μM, with a detection limit of 0.86 pM. Meanwhile, the sensor possessed excellent selectivity, reproducibility, and stability, and showed satisfactory detection accuracy in real human serum samples. This work provides a novel method for the detection of Aβ42 in the early diagnosis of AD, and also sheds light on the construction of high-performance PEC sensors and the application expansion of COF materials.},
}

@article {pmid42691753,
year = {2026},
author = {Ilaghi-Hoseini, S and Garkani-Nejad, Z},
title = {Comparative QSAR and Q-RASAR modeling of benzimidazole derivatives as dual AChE/BuChE inhibitors and design of novel anti- Alzheimer drug candidates supported by molecular docking, ADMET and molecular dynamic simulation.},
journal = {Journal of molecular graphics & modelling},
volume = {149},
number = {},
pages = {109550},
doi = {10.1016/j.jmgm.2026.109550},
pmid = {42691753},
issn = {1873-4243},
abstract = {Alzheimer's disease is a progressive neurological disorder characterized by memory loss, cognitive decline, and behavioral changes, and is one of the most important causes of dementia. Benzimidazole derivatives, as bioactive compounds, are promising candidates for the design of new anti-Alzheimer drugs due to their diverse biological activities. In this study, a dataset of 193 benzimidazole derivatives, whose IC50 values were experimentally measured and previously reported, was used to investigate anti-Alzheimer activity. All modeling and computational analyses were performed based on these experimental data. First, a comparative study between Quantitative Structure-Activity Relationship (QSAR) and Quantitative Read-Across Structure-Activity Relationship (Q-RASAR) methods was conducted using Multiple Linear Regression (MLR) and Support Vector Regression (SVR). Model performance was evaluated using statistical parameters such as Q[2], RMSE, and R, showing that Q-RASAR models had better predictive accuracy, stability, and interpretability. Molecular docking studies were then performed to investigate ligand-target interactions. Based on the results, a set of new compounds was designed and their biological activities were predicted using the developed models. Selected compounds were further validated through molecular docking and molecular dynamics simulations to assess complex stability. In addition, ADMET analyses were conducted to evaluate pharmacokinetic properties and toxicity. Among the designed compounds, compound 5 showed the best overall profile and was introduced as a lead candidate for further studies. This work provides valuable insights for the rational design of benzimidazole-based anti-Alzheimer agents and supports future research in this field.},
}

@article {pmid42691804,
year = {2026},
author = {Sato, S and Sasabuchi, Y and Yamana, H and Kohro, T and Yasunaga, H},
title = {Treatment Duration of Cholinesterase Inhibitor Formulations in Alzheimer's Disease.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {11},
pages = {106481},
doi = {10.1016/j.jamda.2026.106481},
pmid = {42691804},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine treatment duration of oral and transdermal cholinesterase inhibitor formulations in older adults with severe Alzheimer's disease (AD) in routine clinical practice.

DESIGN: Retrospective population-based cohort study.

SETTING AND PARTICIPANTS: Linked medical and long-term care insurance claims databases from Tochigi Prefecture, Japan, between April 2019 and October 2023. We included patients aged ≥65 years with AD who were certified at care needs level 4 or 5 (indicating complete dependence in activities of daily living) or were institutionalized under the Japanese Long-Term Care Insurance system.

METHODS: Patients were classified according to the initial cholinesterase inhibitor formulation: oral formulations (donepezil or galantamine) or transdermal patches (rivastigmine or donepezil). The primary outcome was duration of treatment with the initial formulation. Continuous treatment was defined using a 30-day grace period. Kaplan-Meier analysis and Cox proportional hazards models were used to compare treatment discontinuation between groups. Hospitalization and mortality were evaluated as exploratory outcomes.

RESULTS: Among 8117 eligible patients, 6467 initiated oral formulations and 1650 initiated transdermal patches. Mean treatment duration was longer in the oral group than in the patch group (1.5 vs 0.6 years; log-rank P < .001). In adjusted Cox regression analysis, the patch group showed a higher risk of discontinuation than the oral group (hazard ratio, 11.3; 95% CI, 10.2-12.4). Hospitalization and mortality rates were lower in the oral group than in the patch group (236 vs 272 and 210 vs 272 per 1000 person-years, respectively).

CONCLUSIONS AND IMPLICATIONS: In older adults with severe AD, oral cholinesterase inhibitor formulations were continued substantially longer than transdermal patches. Given the limited evidence supporting prolonged cholinesterase inhibitor use in severe AD, these findings raise concerns regarding long-term prescribing practices in advanced dementia care.},
}

@article {pmid42692040,
year = {2026},
author = {Maure-Blesa, L and Carmona-Iragui, M and Barroeta, I and Arranz, J and Fernández, S and Rodríguez-Baz, Í and Benejam, B and Videla, L and Arriola-Infante, JE and Del Hoyo Soriano, L and Pertierra, L and Vaqué-Alcázar, L and Sanjuan, A and Bueno, A and Aranha, MR and Lorente, O and Morcillo-Nieto, AO and Ros-Castelló, V and Sierra-Marcos, A and Sánchez-Moreno, B and Lisgaras, CP and Blessing, E and Osorio, RS and Estanga, A and García-Sebastián, M and Ros, N and Stockbauer, AC and Nuebling, G and Remi, JM and McCarron, M and Lima, K and Dunne, P and Sirisi, S and Dols-Icardo, O and Belbin, O and Alcolea, D and Bejanin, A and Lleó, A and Giménez, S and Montes, N and de Asua, DR and McGlinchey, E and Levin, J and Rebillat, AS and Altuna, M and Fortea, J},
title = {Natural history and clinical impact of epilepsy in adults with Down syndrome: a multicentre clinical study.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)00980-3},
pmid = {42692040},
issn = {1474-547X},
abstract = {BACKGROUND: As individuals with Down syndrome age, they face high risks of Alzheimer's disease and epilepsy. With symptomatic Alzheimer's disease, late-onset myoclonic epilepsy in Down syndrome (LOMEDS) often emerges. We aimed to examine how epilepsy develops in Down syndrome, its timing relative to Alzheimer's disease symptom onset, and its effect on prognosis.

METHODS: We conducted a multicentre, observational, longitudinal study across seven international cohorts with an aggregate observation window from Oct 24, 2012, to July 28, 2025. We included adults with Down syndrome aged at least 18 years and with at least one longitudinal clinical assessment. Alzheimer's disease staging was done by clinical consensus. Active epilepsy required an epilepsy diagnosis plus ongoing antiseizure medication or at least one seizure within the past 5 years. We analysed active epilepsy prevalence, incidence and cumulative incidence, its timing with respect to symptomatic Alzheimer's disease, and its effect on survival and cognitive trajectories as well as electroencephalogram (EEG) abnormalities.

FINDINGS: We included 4804 adults with Down syndrome (mean age 43 years [SD 13]): 3238 (67·4%) were cognitively stable, 267 (5·6%) had non-degenerative cognitive decline, 321 (6·7%) had prodromal Alzheimer's disease, and 978 (20·3%) had Alzheimer's disease dementia. Intellectual disability was mild in 1020 (24·6%) participants, moderate in 2352 (56·7%), and severe to profound in 779 (18·8%). Active epilepsy prevalence was 145·2 per adults with Down syndrome overall but significantly increased with age, particularly with symptomatic Alzheimer's disease, when epilepsy manifested mostly as myoclonic or tonic-clonic seizures. Cumulative incidence of epilepsy increased linearly after symptomatic Alzheimer's disease, from 9·5% (95% CI 7·8-11·3) at diagnosis to 56·9% (51·7-61·7) after 9 years. Risk of epilepsy increased with time since Alzheimer's disease diagnosis (adjusted odds ratio 1·33 per year [95% CI 1·22-1·45]; p<0·0001), severe-to-profound intellectual disability (2·14 per year [1·25-3·70]; p=0·0057), and APOE ε4 carriership (1·61 per year [1·04-2·49]; p=0·034), independent of age. LOMEDS was associated with increased mortality (hazard ratio 2·10 [95% CI 1·57-2·82]; p<0·0001), and faster cognitive decline. Interictal EEG abnormalities showed little diagnostic utility.

INTERPRETATION: Epilepsy increases sharply after symptomatic Alzheimer's disease onset in people with Down syndrome. The association of epilepsy with reduced survival and accelerated cognitive decline underscores the need for targeted preventive and therapeutic strategies against Alzheimer's disease-related epileptogenesis and hyperexcitability.

FUNDING: See Acknowledgments for funders.},
}

@article {pmid42692041,
year = {2026},
author = {Schlachetzki, Z and Rafii, MS},
title = {Late-onset seizures as a sentinel of Alzheimer's disease progression in Down syndrome.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)00959-1},
pmid = {42692041},
issn = {1474-547X},
}

@article {pmid42692204,
year = {2026},
author = {Camargo, LC and Jonas, A and Gering, I and Schemmert, S and Jacobs, D and Schäfer, M and Willbold, D and Willuweit, A and Kutzsche, J},
title = {Pharmacokinetic properties of the clinical drug candidate PRI-002 with regard to genotype, sex, age, dose-dependence and food effects in mice.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {},
number = {},
pages = {107649},
doi = {10.1016/j.ejps.2026.107649},
pmid = {42692204},
issn = {1879-0720},
abstract = {The d-enantiomeric peptide RD2 (named Contraloid or PRI-002 in clinical trials) was developed for the direct disassembly of toxic amyloid-β (Aβ) oligomers, which are the most neurotoxic aggregate species and play a key role in the development and progression of Alzheimer´s disease (AD). PRI-002/RD2 already demonstrated its safety and tolerability in three phase I clinical trials in young healthy volunteers and patients with mild neurocognitive impairment (MCI) or mild dementia due to AD. Results from a phase II clinical trial with PRI-002/RD2 are expected this year, which was designed to demonstrate safety and efficacy of PRI-002/RD2 in patients at an early stage of AD. The objective of this study was to evaluate the effect of age, sex, genotype and food on the pharmacokinetics of intravenous or orally administered RD2 in male and female transgenic APPswe/PS1ΔE9 (APP PS1) (n=62) or wild type (wt) mice (n=169) under fed and fasted conditions. Age and concomitant food intake influenced the pharmacokinetics of RD2. Slightly higher plasma and brain levels were observed in young compared to old wt mice. However, the effect of food on plasma levels depended on the RD2 dose administered. While at lower doses (200 mg/kg) the effect was substantial, plasma levels were 15 times higher in fasted than in non-fasted animals, the effect was only minor at higher RD2 doses (600 mg/kg). The results of this study indicate the important influence of prior food intake on the bioavailability of the compound, which may also apply to patients and is therefore of interest in further clinical development.},
}

@article {pmid42692292,
year = {2026},
author = {Chen, H and Cui, XN and Deng, MY},
title = {Astrocyte Lipid Metabolism: From Physiological Homeostasis to Reactive Phenotype Plasticity in Neurodegeneration.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106255},
doi = {10.1016/j.neuint.2026.106255},
pmid = {42692292},
issn = {1872-9754},
abstract = {Astrocytes are one of the most abundant types of glial cells in the central nervous system (CNS) and play pivotal roles in metabolic support, synaptic regulation, and neurotransmitter homeostasis. Astrocytic dysfunction is closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), and lipid metabolism constitutes a central axis for maintaining astrocyte function and CNS homeostasis. Here, we provide a systematic review of recent advances in astrocyte lipid metabolism, summarizing the fundamental roles of astrocytes in the CNS and focusing on the biosynthesis, degradation, and trafficking mechanisms of fatty acids, cholesterol, and the tightly linked organelles known as lipid droplets. We further analyze the relationships and potential pathogenic mechanisms linking lipid metabolic disturbances, such as impaired fatty acid β-oxidation, cholesterol accumulation, and dysregulated lipid droplet dynamics, to neurodegeneration. The review also presents current frameworks for classifying reactive astrocytes, including the classical A1/A2 paradigm and more recently identified subtypes, and examines how lipid metabolic processes influence phenotype transitions. Finally, we propose a regulatory axis: lipid metabolism dysregulation leads to cellular phenotype conversion, which in turn drives disease progression, to emphasize the central role of lipid metabolism in astrocyte reactivity and neuropathology. This synthesis fills a gap in the literature at the interface of lipid metabolism and astrocyte functional regulation, and it offers a conceptual framework and candidate targets to guide future investigation into metabolic mechanisms of neurodegeneration and the development of precision therapeutic strategies.},
}

@article {pmid42692374,
year = {2026},
author = {Huang, X and Wang, J and Guo, W and Ye, W and Hu, X and Zhou, X and Xu, B and Cheng, A and Qian, PY},
title = {Spectinabilin mitigates Aβ-associated proteotoxic stress and preserves synaptic protein expression in cellular and Caenorhabditis elegans models.},
journal = {Pharmacological research},
volume = {232},
number = {},
pages = {108421},
doi = {10.1016/j.phrs.2026.108421},
pmid = {42692374},
issn = {1096-1186},
abstract = {Solubleamyloid-β(Aβ) assemblies, glutamate-associated injury, mitochondrial dysfunction, and synaptic failure are closely connected processes in Alzheimer's disease. Here, we investigated the neuroprotective activity of spectinabilin, a natural product isolated from the marine-derived bacterium Streptomyces spectabilis, using biochemical assays, neuronal cell models, and Caenorhabditis elegans (C. elegans) models of Aβ proteotoxicity. Spectinabilin directly associated with both monomeric and oligomer-enriched FITC-Aβ42 under microscale thermophoresis conditions, with apparent dissociation constants of 13.9 and 2.72 µM, respectively, and reduced the accumulation of ThT-positive β-sheet-rich assemblies and elongated fibrils in vitro. In differentiated HT22 cells and primary cortical neurons, spectinabilin attenuated glutamate- and oligomer-enriched Aβ42-associated reductions in cell viability and preserved mitochondrial membrane potential during Aβ42 exposure. In Aβ-expressing C. elegans, spectinabilin reduced ThS-reactive deposits and oxidative-stress-associated fluorescence, delayed paralysis, extended lifespan, and improved chemotaxis. Integrated transcriptomic analysis showed that spectinabilin partially opposed Aβ-model-associated alterations, particularly in synaptic signaling, G protein-coupled receptor-associated signaling, and membrane-potential-related pathways. Spectinabilin also increased synaptic and cAMP-related transcripts and restored Rab3A and VAMP2 expression while normalizing stress-associated CREB phosphorylation. H89 prevented the recovery of CREB regulation and presynaptic proteins, indicating a requirement for PKA-associated signaling. Together, these findings identify spectinabilin as a marine-derived small-molecule scaffold that modifies Aβ42 assembly and preserves mitochondrial and synaptic homeostasis across cellular and C. elegans models.},
}

@article {pmid42692748,
year = {2026},
author = {Hong, J and Silverman, DHS},
title = {FDG-PET in Cognitive Impairment and Dementia.},
journal = {PET clinics},
volume = {21},
number = {4},
pages = {483-497},
doi = {10.1016/j.cpet.2026.07.001},
pmid = {42692748},
issn = {1879-9809},
mesh = {Humans ; *Fluorodeoxyglucose F18 ; *Positron-Emission Tomography/methods ; *Dementia/diagnostic imaging ; *Radiopharmaceuticals ; *Cognitive Dysfunction/diagnostic imaging ; Brain/diagnostic imaging ; },
abstract = {Neuroimaging is crucial in early and accurate assessment of diagnosis, prognosis, and therapy optimization in patients with declining cognitive abilities. Imaging modalities now available for clinical indications related to neurodegenerative processes include Computed Tomography (CT), MR imaging, and PET imaging with 6 positron-emitting radiotracers approved at this time by the US Food and Drug Administration. The central focus of this article is the role of FDG-PET in clinical and research applications of patients with cognitive problems, and how the derived information may be effectively integrated with information acquired from other neuroimaging modalities.},
}

Humans
*Fluorodeoxyglucose F18
*Positron-Emission Tomography/methods
*Dementia/diagnostic imaging
*Radiopharmaceuticals
*Cognitive Dysfunction/diagnostic imaging
Brain/diagnostic imaging

@article {pmid42692750,
year = {2026},
author = {Sanchez, M and Kuret, J},
title = {Lysine methylation is an endogenous post-translational modifications of tau protein in human brain and a modulator of aggregation propensity.},
journal = {Methods in enzymology},
volume = {734},
number = {},
pages = {1-28},
doi = {10.1016/bs.mie.2026.05.044},
pmid = {42692750},
issn = {1557-7988},
mesh = {Humans ; *tau Proteins/metabolism/isolation & purification/chemistry/genetics ; *Protein Processing, Post-Translational ; Methylation ; *Brain/metabolism/pathology ; *Lysine/metabolism ; Protein Aggregates ; Alzheimer Disease/metabolism/pathology ; Protein Aggregation, Pathological/metabolism ; Tauopathies/metabolism/pathology ; Recombinant Proteins/metabolism/isolation & purification/chemistry/genetics ; Proteomics/methods ; Mass Spectrometry/methods ; },
abstract = {Tau protein undergoes a broad range of post-translational modifications in the brain, influencing its structure, solubility, and propensity to aggregate. This chapter presents an integrated methodological framework for characterizing tau methylation and evaluating its impact on tau biology. We describe procedures for isolating soluble and filamentous tau from post-mortem human brain tissue while preserving modifications for proteomic analysis. These approaches support precise mapping of methylation sites alongside other co-occurring modifications. To model methylation under controlled conditions, we outline protocols for recombinant tau expression, purification, and chemical reductive methylation, including radiolabeled assays for determining modification stoichiometry. We then detail biophysical assays used to assess how methylation alters tau conformation and aggregation propensity. This methodological framework supports experimentation seeking insight into mechanisms relevant to Alzheimer's disease and related tauopathies.},
}

Humans
*tau Proteins/metabolism/isolation & purification/chemistry/genetics
*Protein Processing, Post-Translational
Methylation
*Brain/metabolism/pathology
*Lysine/metabolism
Protein Aggregates
Alzheimer Disease/metabolism/pathology
Protein Aggregation, Pathological/metabolism
Tauopathies/metabolism/pathology
Recombinant Proteins/metabolism/isolation & purification/chemistry/genetics
Proteomics/methods
Mass Spectrometry/methods

@article {pmid42692760,
year = {2026},
author = {Qureshi, T and Balmik, AA and Chinnathambi, S},
title = {The extracellular Zinc-finger ubiquitin-binding domain of histone Deacetylase 6 enhances podosome formation in neuronal cells.},
journal = {Methods in enzymology},
volume = {734},
number = {},
pages = {301-326},
doi = {10.1016/bs.mie.2026.05.060},
pmid = {42692760},
issn = {1557-7988},
mesh = {*Histone Deacetylase 6/metabolism/chemistry/genetics ; Animals ; Humans ; *Neurons/metabolism/cytology ; *Podosomes/metabolism ; Zinc Fingers ; Protein Domains ; Ubiquitin/metabolism ; Histone Deacetylases/metabolism ; Protein Binding ; },
abstract = {Neurodegenerative disorders are characterized by progressive synaptic failure, neuronal loss, and the accumulation of pathological protein aggregates. A critical but often overlooked driver of this decline is cytoskeletal dysregulation, which compromises essential cellular functions ranging from intracellular transport to morphological stability. Histone Deacetylase 6 (HDAC6) is a central regulator of these dynamics, yet its role in neurodegeneration remains controversial: while its deacetylase activity is often linked to microtubule instability and toxicity, its ubiquitin-binding functions are essential for aggregate clearance. We have previously demonstrated that the ZnF-UBP domain acts as a direct modulator of cytoskeletal architecture, enhancing the formation of actin-rich migratory structures-such as podosomes and lamellipodia-and promoting neuritic outgrowth. It does this by inducing increased localization of actin remodelling proteins to the podosomes, ultimately conferring enhanced migration potential to cells. This chapter highlights the protocols essential for understanding the therapeutic potential of the HDAC6 Zinc Finger Ubiquitin-Binding Protein (ZnF-UBP) domain, in the context of actin remodelling through podosome structures.},
}

*Histone Deacetylase 6/metabolism/chemistry/genetics
Animals
Humans
*Neurons/metabolism/cytology
*Podosomes/metabolism
Zinc Fingers
Protein Domains
Ubiquitin/metabolism
Histone Deacetylases/metabolism
Protein Binding

@article {pmid42692766,
year = {2026},
author = {Balmik, AA and Sonawane, SK and Gorantla, NV and Chinnathambi, S},
title = {Mechanistic insights on HDAC6 ZnF UBP-Tau interaction through biophysical and computational approaches.},
journal = {Methods in enzymology},
volume = {734},
number = {},
pages = {79-103},
doi = {10.1016/bs.mie.2026.07.009},
pmid = {42692766},
issn = {1557-7988},
mesh = {*Histone Deacetylase 6/metabolism/chemistry ; *tau Proteins/metabolism/chemistry ; Humans ; Protein Binding ; Calorimetry/methods ; Protein Aggregates ; Magnetic Resonance Spectroscopy ; Nuclear Magnetic Resonance, Biomolecular ; },
abstract = {Histone deacetylase 6 is a unique cytoplasmic deacetylase implicated in cellular functions such as microtubule dynamics, protein quality control, ubiquitin-mediated degradation and neurodegenerative disorders. The ZnF UBP (zinc finger ubiquitin binding protein) domain of HDAC6 is known to be directly modulate several cellular processes linked to neurodegeneration such as sequestering polyubiquitinated aggregates and regulating protein aggregate clearance mechanisms in neurons. Microtubule associated protein Tau (MAP Tau) undergoes aggregation in neurodegenerative conditions like Alzheimer's disease (AD) and several other tauopathies. Tau is a natively disordered protein which is functionally regulated by wide array of post-translational modifications (PTMs) as well as by interacting with several proteins. This methodological study aims to understand the molecular interaction between HDAC6 ZnF UBP domain and Tau protein in order to elucidate the role of HDAC6 ZnF UBP domain in Tau aggregation and stability. We employed an integrated biochemical, biophysical and computational workflow to characterize the interaction between HDAC6 ZnF UBP and Tau. NMR spectroscopy, isothermal titration calorimetry and pull-down assay with purified HDAC6 ZnF UBP and Tau proteins demonstrated direct interaction between the two, with interaction associated structural perturbations and favourable binding kinetics as observed in NMR and ITC respectively. Computational analyses further suggest the formation of Tau-HDAC6 ZnF UBP complex and provided underlying molecular interactions involved in the binding of these two proteins. The findings in this study helps to advance the current understanding of regulatory role of HDAC6 specifically in Tau biology and further provides a useful framework for investigating the modulation of aggregation prone proteins via protein-protein interaction in neurodegenerative diseases.},
}

*Histone Deacetylase 6/metabolism/chemistry
*tau Proteins/metabolism/chemistry
Humans
Protein Binding
Calorimetry/methods
Protein Aggregates
Magnetic Resonance Spectroscopy
Nuclear Magnetic Resonance, Biomolecular

@article {pmid42693052,
year = {2026},
author = {Yu, YZ and Zhu, YH and Yang, XK and Wang, SS and Sun, JQ and Qiu, Y and Zhao, W and Yao, LM and Li, WR},
title = {[Danggui Shaoyao San promotes ketone body production and utilization to improve brain energy metabolism and prevent Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {15},
pages = {4377-4386},
doi = {10.19540/j.cnki.cjcmm.20260505.801},
pmid = {42693052},
issn = {1001-5302},
mesh = {Animals ; Male ; *Ketone Bodies/metabolism/biosynthesis ; *Alzheimer Disease/metabolism/prevention & control/genetics/drug therapy ; *Drugs, Chinese Herbal/administration & dosage ; *Energy Metabolism/drug effects ; *Brain/metabolism/drug effects ; Mice ; Mice, Inbred C57BL ; Humans ; },
abstract = {This study focuses on the mechanism by which Danggui Shaoyao San(DSS) regulates hepatic fatty acid metabolism to promote ketone body production, transport, and utilization, thereby alleviating brain energy metabolism disorders in APP/PS1 mice and enhancing their cognitive abilities. Six SPF-grade 3-month-old male C57BL/6J mice served as the control group. Thirty 3-month-old male APP/PS1 mice were randomly allocated into a model group, a low-dose DSS(DSS-L, 3.2 g·kg~(-1)) group, a medium-dose DSS(DSS-M, 6.4 g·kg~(-1)) group, a high-dose DSS(DSS-H, 12.8 g·kg~(-1)) group, and a ketogenic diet(KD) group. The control and model groups received 8 weeks of normal saline gavage, while the DSS-L, DSS-M, and DSS-H groups received corresponding concentrations of DSS via gavage for 8 weeks. The KD group was fed the ketogenic diet for 8 weeks. After 8 weeks of treatment, the Morris water maze test, novel object recognition test, Y-maze test, and open field test were carried out to evaluate the cognitive function, memory processing, spatial memory, and spontaneous activity and exploratory behavior, respectively. A Roche meter was used to measure the fasting blood glucose level. The β-hydroxybutyrate(BHB) and lactate levels in the liver and brain tissue were quantified by the microplate assay. The adenosine triphosphate(ATP) and adenosine diphosphate(ADP) levels were detected by chemiluminescence. ELISA was employed to measure the serum level of insulin and brain tissue levels of mitochondrial complexes Ⅰ-Ⅳ, citrate synthase(CS), isocitrate dehydrogenase(ICD), and α-ketoglutarate dehydrogenase(α-KG). Immunofluorescence assay was employed to detect the expression of monocarboxylate transporter 2(MCT2) in the hippocampus. Western blot was used to determine the expression levels of 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2(HMGCS2) in the liver, as well as 3-oxoglutarate-CoA transferase(OXCT1) and 3-hydroxybutyrate dehydrogenase(BDH1) in the brain. The results showed that compared with the control group, the model group exhibited reduced time and distance in the target quadrant in the Morris water maze, weakened novel object recognition, decreased Y-maze alternation percentage, and reduced distance and average speed in the open field(P<0.01, P<0.001). Furthermore, the model group exhibited raised levels of fasting blood glucose, insulin in the serum, and lactic acid in the brain, declined level of BHB in the liver(P<0.05, P<0.01), reduced levels of mitochondrial respiratory chain complexes Ⅰ-Ⅳ, CS, ICD, α-KG, ADP and ATP in the brain tissue(P<0.01, P<0.001), down-regulated expression of HMGCS2 in the liver, OXCT1 in the cortex and hippocampus, and BDH1 in the hippocampus(P<0.05, P<0.01). Compared with the model group, the DSS groups and the KD group showed increases in time in the target quadrant, levels of BHB in the liver and brain, mitochondrial complexes Ⅰ and Ⅳ, CS, α-KG, and ATP, and expression of BDH1 in the hippocampus and OXCT1 in the cortex, and reduced levels of fasting blood glucose, insulin in the serum, and lactate in the brain(P<0.05, P<0.01). All the DSS groups exhibited increased average speed in the open field test(P<0.05, P<0.01). The distance in the target quadrant, levels of mitochondrial complexes Ⅱ and Ⅲ, ICD, and ADP, and expression of BDH1 in the cortex increased in the DSS-M, DSS-H, and KD groups(P<0.05, P<0.01). The novel object recognition index and HMGCS2 expression in the liver raised in the DSS-L, DSS-H, and KD groups(P<0.05, P<0.01). The total distance traveled in the open field test increased in the DSS-L, DSS-M, and KD groups(P<0.05, P<0.01). The percentage of alternation in the Y-maze test and MCT2 expression level in the DG region increased in the KD group(P<0.05). In addition, the OXCT1 expression level in the hippocampus was up-regulated in the DSS-H and KD groups(P<0.05, P<0.01). DSS can promote the generation of ketone bodies in the liver and the transport and utilization of ketone bodies in the brain tissue, thereby alleviating the brain energy crisis and cognitive impairment of APP/PS1 mice.},
}

Animals
Male
*Ketone Bodies/metabolism/biosynthesis
*Alzheimer Disease/metabolism/prevention & control/genetics/drug therapy
*Drugs, Chinese Herbal/administration & dosage
*Energy Metabolism/drug effects
*Brain/metabolism/drug effects
Mice
Mice, Inbred C57BL
Humans

@article {pmid42693124,
year = {2026},
author = {Martino-Adami, PV and Coutinho de Alvarenga, J and Freccero, P and Huber, H and Fernandez, J and Bolaños Burgos, IC and Postillone, MB and Tomé Oliveira Engelmann, G and Mintz, I and Romano Silva, MA and Medel, N and de Oliveira Hansen, E and Lisso, J and Dias Silva, N and Teixeira Carvalho, A and Irureta, N and de Miranda, DM and Vallejo-Azar, M and Cunha de Marco, LA and Heilmann-Heimbach, S and de Paula, JJ and Kochen, S and Teixeira de Ávila, R and Solis, P and Schneider, A and Gonzalez, P and de Mattos Viana, B and Dalmasso, MC and Camargos Bicalho, MA and Ramírez, A},
title = {Diagnostic performance of plasma pTau217 in genetically admixed South American populations.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42693124},
issn = {2041-1723},
mesh = {Humans ; Brazil ; Biomarkers/blood/cerebrospinal fluid ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/diagnosis/genetics ; Argentina ; Female ; *tau Proteins/blood/cerebrospinal fluid ; Male ; Aged ; *Peptide Fragments/blood/cerebrospinal fluid ; Apolipoprotein E4/genetics ; Aged, 80 and over ; },
abstract = {Plasma pTau217 is a leading biomarker for Alzheimer's disease, but evidence from genetically admixed populations in low- and middle-income countries remains limited. We evaluated the diagnostic performance of pTau217 and pTau217/Aβ42 measured using Simoa technology in memory-clinic cohorts from Brazil (Cog-Aging-Study, n = 353) and Argentina (GeNED.ar, n = 134). Here we show that both biomarkers accurately identified cerebrospinal fluid (CSF)-defined amyloid pathology in Cog-Aging-Study-Brazil and showed high concordance with clinical diagnosis across both cohorts. Classification performance was improved using two-cut-off approaches that account for diagnostic uncertainty. We further show that APOE-ε4, lower body mass index, and reduced kidney function were associated with higher pTau217 in Cog-Aging-Study-Brazil, whereas education also influenced biomarker levels in GeNED.ar-Argentina. African ancestry modified APOE-ε4 effect on CSF but not plasma biomarkers. These findings support the use of plasma pTau217-based biomarkers in genetically admixed South American populations and in settings with limited access to CSF testing and brain imaging.},
}

Humans
Brazil
Biomarkers/blood/cerebrospinal fluid
*Amyloid beta-Peptides/blood/cerebrospinal fluid
*Alzheimer Disease/blood/diagnosis/genetics
Argentina
Female
*tau Proteins/blood/cerebrospinal fluid
Male
Aged
*Peptide Fragments/blood/cerebrospinal fluid
Apolipoprotein E4/genetics
Aged, 80 and over

@article {pmid42693182,
year = {2026},
author = {Ghallab, DS and Okda, TM},
title = {Melatonin seed priming reconfigures the metabolomic profile and functional attributes of brown mustard (Brassica juncea L.) sprouts.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42693182},
issn = {2045-2322},
mesh = {*Mustard Plant/metabolism/drug effects/growth & development ; *Melatonin/pharmacology/metabolism ; *Seeds/metabolism/drug effects ; Metabolomics/methods ; *Metabolome/drug effects ; Glucosinolates/metabolism ; Seedlings/metabolism/drug effects ; Tandem Mass Spectrometry ; Germination/drug effects ; },
abstract = {While mustard seeds offer a prime store of biologically active compounds, there is insufficient data regarding the impact of melatonin (MT) priming on remodelling the chemical patterns, metabolic pathways, and biological attributes of mustard sprouts. Accordingly, the current work is directed to investigate the metabolic shifts in mustard sprouts post MT-priming treatments using UPLC-MS/MS and chemometric analyses. Given this, MT-primed sprouted samples witnessed a significant elevation of phenolic acids, specifically hydroxybenzoic, ferulic, syringic, and chlorogenic acids, with approximately 2.5- to 6-fold increments compared to unprimed controls. In MT-primed mustard sprouts, some aliphatic glucosinolates, such as gluconapin, glucotropaeolin, and sinigrin, revealed a notable elevation with fold increments of 3.5, 2.9, and 2.6, respectively, compared to unprimed counterparts. Further, some flavonoids and stilbenes, primarily isorhamnetin, syringetin-O-glucoside, quercetin, and isorhapontigenin, exhibited a notable enrichment pattern in primed mustard sprouts relative to the others. KEGG pathway analysis revealed phenylpropanoid biosynthesis, flavonoid biosynthesis, glucosinolate biosynthesis, and stilbenoid, diarylheptanoid and gingerol biosynthesis pathways as the key metabolic pathways primarily govern these metabolic fluctuations. Regarding AChE and MAO-B inhibitory screening, MT-primed sprouted samples recorded the most leading observations with IC50 = 7.667 ± 0.306 mg/dl and 45.389 ± 0.953 mg/dl, respectively. OPLS-driven correlation analysis pinpointed syringic, ellagic, and chlorogenic acid, along with quercetin, pterostilbene, sinigrin, gluconapin, and eicosapentaenoic acid, majorly detected in MT-primed samples, as biologically active compounds beyond their AChE and MAO-B inhibitory activities. These findings support melatonin priming as a sustainable, effective technique for creating high-quality, nutritious, and health-promoting agricultural products to rectify chronic diseases.},
}

*Mustard Plant/metabolism/drug effects/growth & development
*Melatonin/pharmacology/metabolism
*Seeds/metabolism/drug effects
Metabolomics/methods
*Metabolome/drug effects
Glucosinolates/metabolism
Seedlings/metabolism/drug effects
Tandem Mass Spectrometry
Germination/drug effects

@article {pmid42693185,
year = {2026},
author = {Dalakas, MC and Lünemann, JD},
title = {Role of complement and complement-targeted therapeutics in neurological diseases.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42693185},
issn = {1759-4766},
abstract = {Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.},
}

@article {pmid42693199,
year = {2026},
author = {Hu, H and Lin, PB and Zeng, C and Li, Y and Bosch, ME and Emmerson, JT and Sharma, P and Ohara, RA and Dong, W and Wu, T and Du, S and Gao, W and Jiang, H and Yuan, L and Bao, X and Li, S and Vomund, AN and Erdmann-Gilmore, P and Gu, Y and Hu, M and Nulman, J and Miller, TM and Yokoyama, WM and Lichti, CF and Milbrandt, J and Perrin, RJ and Kipnis, J and Artyomov, MN and Murphy, KM and Ulrich, JD and Holtzman, DM},
title = {Priming of CD8[+] T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42693199},
issn = {1546-1726},
abstract = {Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8[+] T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8[+] T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8[+] T cell infiltration and glial activation. The remaining CD8[+] T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8[+] T cell accumulation in the brain and tau-mediated neurodegeneration.},
}

@article {pmid42693207,
year = {2026},
author = {Barnaghi, P and Fogel, A and Walsh, C and Nilforooshan, R and Ricotti, V and Voit, T},
title = {Applying a systemic approach that extends beyond the brain to Alzheimer's disease pathogenesis.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42693207},
issn = {2730-664X},
support = {UK DRI-7002//RCUK | Medical Research Council (MRC)/ ; RCSRF2324-18-69//Great Ormond Street Hospital for Children (GOSH)/ ; RCSRF2324-18-69//Royal Academy of Engineering/ ; },
}

@article {pmid42693285,
year = {2026},
author = {Oberhauser, J and Ding, B and Reid, MM and Xie, WH and Yang, AC},
title = {VINE-seq and MultiVINE-seq for single-nucleus and multiome profiling of the brain vasculature.},
journal = {Nature protocols},
volume = {},
number = {},
pages = {},
pmid = {42693285},
issn = {1750-2799},
abstract = {The human cerebrovasculature is a critical yet historically understudied component of neurological health. Dysfunction of the diverse endothelial, mural, and perivascular cells that comprise cerebral vessels is central to diseases ranging from stroke to Alzheimer's disease. However, characterizing these cell populations at a molecular level has proven exceptionally challenging. Encased within a robust basement membrane, vascular cells resist standard dissociation methods, leading to their systematic depletion and underrepresentation in existing single-nucleus genomic atlases. This has created a major blind spot in neuroscience. To overcome this barrier, we developed vessel isolation and nucleus extraction for sequencing (VINE-seq) and its advanced iteration, MultiVINE-seq. The protocol provides a robust, reproducible workflow for the enrichment and high-resolution profiling of vascular, perivascular, and immune cells from fresh or frozen human and mouse brain tissue. First, intact vessels (predominantly capillaries and small arterioles/venules, 100 µm in diameter) are isolated from homogenized brain tissue via dextran-based density-gradient centrifugation, separating the vascular pellet from myelin and the parenchymal fraction. Second, the collected vessels are rigorously washed over a cell strainer to remove trapped contaminants. A critical innovation lies in the third stage: the optimized extraction of nuclei from purified vessels using enzymatic digestion. After extraction, the protocol uses fluorescence-activated cell sorting (FACS) to ensure collection of high-purity nuclei suitable for widely used droplet-based sequencing platforms (e.g., 10x Genomics single cell 3' or multiome). This protocol requires 4-5 h to complete and can be carried out by researchers with single-cell and flow cytometry training.},
}

@article {pmid42693315,
year = {2026},
author = {Tran, TH and Tran, TS and Tran, TD},
title = {Computational discovery and dynamic profiling of dual acetylcholinesterase and monoacylglycerol lipase inhibitors for Alzheimer's disease.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42693315},
issn = {1573-501X},
abstract = {Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction and neuroinflammation. Dual inhibition of acetylcholinesterase and monoacylglycerol lipase has emerged as a promising therapeutic approach. This study employed an integrative in silico workflow to identify potential dual acetylcholinesterase/monoacylglycerol lipase inhibitors from a molecular library derived from known inhibitors (rivastigmine, JZL-184, ABX-1431). A total of 365 compounds were screened via molecular docking, interaction-based filtering, ADME/toxicity prediction, and molecular dynamics simulations. Among them, compound H34 demonstrated a comparatively favorable overall computational profile, supported by MM/GBSA binding-energy estimates (ΔGbind = - 30.96 and - 37.34 kcal/mol) and comparatively favorable structural stability metrics (RMSD, RMSF, Rg, and SASA) in the MD simulations. Further ProLIF interaction mapping and free energy landscape analysis supported the persistent interaction profile and conformational behavior of the H34-protein complexes. Additionally, H34 displayed favorable pharmacokinetic properties and low predicted acute toxicity. These results highlight H34 as a promising dual-target candidate for Alzheimer's disease therapy and illustrate the effectiveness of integrated computational strategies in early-stage drug discovery.},
}

@article {pmid42693331,
year = {2026},
author = {Kamalov, F and Ibrahim, A},
title = {From Volumetrics to 3D Tensors: A Multi-Cohort Evaluation of Machine Learning and Deep Learning for Alzheimer's Classification.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02240-3},
pmid = {42693331},
issn = {2948-2933},
support = {2024CANAD-KAM-060//Dubai Future Foundation/ ; },
abstract = {Automated Alzheimer's disease (AD) classification from structural MRI typically employs either feature-engineered machine learning (ML) or end-to-end 3D deep learning (DL). Addressing a lack of rigorous statistical comparison and multi-dataset validation in current literature, this study evaluates classical ML algorithms utilizing volumetric and voxel-based morphometry (VBM) features against 3D CNNs processing raw MRI tensors. Using the ADNI and OASIS datasets, models underwent internal 4-fold cross-validation and zero-shot cross-cohort testing to assess predictive performance, domain shift resilience, and clinical sensitivity. Welch's t-tests confirmed that 16 of 19 macro-regional brain aspects differed significantly between AD and cognitively normal subjects (p FDR < 0.05), led by the medial-temporal lobe. While DL architectures achieved marginal numerical superiority in peak accuracy on ADNI (DenseNet121: accuracy 0.92 ± 0.02 , F1 0.85 ± 0.04 , ROC-AUC 0.96 ± 0.02), they exhibited higher variance and lacked statistical significance compared to optimized ML baselines (XGBoost-VOL: F1 0.82 ± 0.03 ; p ≥ 0.28 for all 3D CNNs). On the highly imbalanced OASIS dataset, VBM-enhanced Logistic Regression matched top DL models in overall F1-score (0.68 ± 0.05) while delivering statistically superior AD recall (0.67 ± 0.04 ; p = 0.0026 versus baseline), exceeding every 3D CNN. Although both paradigms generalized robustly across cohorts (only a 2-4% zero-shot F1 reduction; ROC-AUC up to 0.9506), the findings highlight a crucial clinical trade-off: 3D CNNs autonomously extract complex spatial features, but simpler, interpretable ML models provide superior inferential stability and diagnostic sensitivity, making them highly viable for real-world deployment.},
}

@article {pmid42693456,
year = {2026},
author = {Tosi, G and Romano, D},
title = {Estimating and interpreting psychometric networks in neuropsychology: A tutorial with conceptual extensions.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70076},
pmid = {42693456},
issn = {1748-6653},
abstract = {Network psychometrics has emerged as a promising framework for modelling the structure of neuropsychological data, offering a complementary perspective to traditional latent variable approaches or single test approaches. In neuropsychology, test performance is rarely interpreted in isolation, but rather as reflecting interacting cognitive processes. Network models provide a formal framework to represent these interdependencies by estimating conditional associations among observed variables. The present article provides a comprehensive tutorial on the estimation and interpretation of psychometric networks in neuropsychology. First, we offer a step-by-step guide to estimating a cross-sectional Gaussian Graphical Model (GGM), including data preparation, model selection, regularization, visualization and stability assessment, using a neuropsychological dataset from patients with Alzheimer's disease. Particular emphasis is placed on best practices for ensuring reproducibility and robustness, including the use of bootstrap procedures and reporting standards. Second, we outline key methodological extensions, including Exploratory Graph Analysis for dimensionality assessment, joint graphical models and Network Comparison Test for group comparisons, mixed graphical models for heterogeneous data and longitudinal network approaches. These methods are presented conceptually to illustrate how network analysis can be extended beyond basic cross-sectional applications. Finally, we discuss the strengths and limitations of network psychometrics in neuropsychology. We emphasize that network models represent statistical associations among observed test scores rather than direct representations of cognitive architecture and that their interpretation requires theoretical caution. When applied with methodological rigour and conceptual restraint, network analysis provides a flexible and integrative framework for investigating the structure of cognitive systems.},
}

@article {pmid42693483,
year = {2026},
author = {Hatterer, E and Broyer, L and Pecoraro, S and Cusin, F and Simsek, N and Breve, JJ and Clavel, M and Batenburg, KL and Klein, B and Zuidweg, T and Piché, K and Bourguignon, J and Bonnet-Gamard, M and Malinge, P and Gueneau, F and Moine, V and Anceriz, N and Masternak, K and Fischer, N and Gjølberg, TT and Telstad, JS and Calamera, G and Mester, S and Scheper, W and Van de Berg, WDJ and Courade, JP},
title = {A third-generation, high-affinity biparatopic anti-tau antibody inhibits intracellular tau aggregation seeded by Alzheimer's brain extracts.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42693483},
issn = {1758-9193},
support = {N/A//discoveric bio alpha ag/ ; },
mesh = {*tau Proteins/metabolism/immunology ; Humans ; *Alzheimer Disease/metabolism/pathology ; *Brain/metabolism/pathology/drug effects ; Animals ; *Protein Aggregation, Pathological ; },
abstract = {BACKGROUND: Tau immunotherapy has recently shown clinical promise but required high dosing. We developed NIDB-3101, a novel third-generation, high-affinity anti-tau biparatopic antibody designed for superior tau binding, aggregation inhibition, and extended half-life.

METHODS: NIDB-3101 binds tau's microtubule-binding region and C-terminal domains. Various binding and cellular functional assays using recombinants, but more importantly human AD extracts were used to assess NIDB-3101 benefits. Half-life mutations impact was assessed via FcRn binding and cellular assays recycling.

RESULTS: NIDB-3101 exhibited sub-nanomolar affinity, binding a broad spectrum of pathological tau species in AD homogenates, inhibited AD extracts-induced cellular effect compared to benchmark antibodies. Mutations enhanced hFcRn-mediated cellular recycling.

CONCLUSIONS: NIDB-3101 captures a broad spectrum of pathological tau species leading to strong cellular efficacy using human AD extracts, supporting further clinical development as a potential disease-modifying therapy for AD and related tauopathies.},
}

*tau Proteins/metabolism/immunology
Humans
*Alzheimer Disease/metabolism/pathology
*Brain/metabolism/pathology/drug effects
Animals
*Protein Aggregation, Pathological

@article {pmid42693677,
year = {2026},
author = {Qi, L and Wang, W and Abdullah, R and Zhao, Y and Wang, Z and Tang, Y and Luo, B and Peng, G},
title = {Neurobiological mechanisms of 40-Hz stimulation in Alzheimer's disease: evidence, heterogeneity, and constraints.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71806},
doi = {10.1002/alz.71806},
pmid = {42693677},
issn = {1552-5279},
support = {2025C01120//Key R&D Program of Zhejiang/ ; 2025C02104//"Leading Goose + X" Science and Technology Program of Zhejiang Province of China/ ; 2022YFC3602604//Ministry of Science and Technology of the People's Republic of China/ ; },
mesh = {*Alzheimer Disease/therapy/physiopathology ; Humans ; *Gamma Rhythm/physiology ; *Brain/physiopathology ; Animals ; *Deep Brain Stimulation/methods ; },
abstract = {Early disruption of gamma oscillations is increasingly recognized as a contributor to neurodegeneration and cognitive decline in Alzheimer's disease (AD), positioning 40-Hz stimulation as a promising neuromodulatory strategy. However, its neurophysiological and cognitive effects remain highly variable across studies, underscoring the need for a more integrated mechanistic framework. This review synthesizes current evidence on the neurobiological mechanisms engaged by 40-Hz stimulation in AD, including circuit-, cellular-, and system-level processes underlying network dynamics, glial responses, and multi-target biological effects. We further highlight the conceptual distinction between "physiological resonance" and "artificial superimposition" as a potential determinant of deep-brain engagement and therapeutic outcomes. By integrating both supportive and conflicting findings, we highlight disease stage, biological sex, and behavioral state as important contributors to the heterogeneity of 40-Hz stimulation outcomes. Building on these observations, we propose that future research should move toward mechanistic stratification and precision neuromodulation to facilitate clinical translation.},
}

*Alzheimer Disease/therapy/physiopathology
Humans
*Gamma Rhythm/physiology
*Brain/physiopathology
Animals
*Deep Brain Stimulation/methods

@article {pmid42693696,
year = {2026},
author = {Catakli, D and Ozen-Basoglu, O and Tuncgovde, EB and Ozsarlak-Sozer, G},
title = {The Crosstalk Between Diabetes and Alzheimer's Disease: A Molecular Perspective.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {139},
number = {4},
pages = {e70294},
doi = {10.1111/bcpt.70294},
pmid = {42693696},
issn = {1742-7843},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology/epidemiology ; *Diabetes Mellitus, Type 2/drug therapy/metabolism/epidemiology/physiopathology/complications ; Animals ; Insulin Resistance ; Signal Transduction/drug effects ; Brain/metabolism/drug effects ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Hypoglycemic Agents/pharmacology/therapeutic use ; Insulin/metabolism ; },
abstract = {The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing significantly in an age-dependent manner. Growing evidence supports the conceptualization of AD as 'type 3 diabetes,' a term proposed to describe a metabolic disease primarily driven by impaired insulin signalling and insulin resistance within the brain. This review explores the shared molecular mechanisms underlying both T2DM and AD, including chronic neuroinflammation, oxidative stress, mitochondrial dysfunction and impaired glucose metabolism. Specifically, the crosstalk involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, where insulin resistance leads to increased glycogen synthase kinase 3β (GSK-3β) activity, promoting tau hyperphosphorylation and amyloid-β (Aβ) accumulation. Furthermore, the article examines the roles of the NOD-like receptor protein 3 (NLRP3) inflammasome, O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), and the gut-brain axis as critical mediators linking metabolic dysfunction to neurodegeneration. Unlike previous reviews that predominantly address individual pathways in isolation, this review provides an integrated molecular framework that connects insulin resistance to neurodegeneration through converging signalling cascades and highlights emerging therapeutic targets including the NLRP3 inflammasome and O-GlcNAcylation as potential mechanistic bridges between T2DM and AD. Finally, the therapeutic potential of various antidiabetic agents such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and thiazolidinediones is discussed, as these drugs offer promising opportunities for the treatment and prevention of AD by targeting these common molecular pathways.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/physiopathology/epidemiology
*Diabetes Mellitus, Type 2/drug therapy/metabolism/epidemiology/physiopathology/complications
Animals
Insulin Resistance
Signal Transduction/drug effects
Brain/metabolism/drug effects
Oxidative Stress
Amyloid beta-Peptides/metabolism
Hypoglycemic Agents/pharmacology/therapeutic use
Insulin/metabolism

@article {pmid42693831,
year = {2026},
author = {Lin, LY and Wu, JS and Jeng, WJ and Tsai, CH and Liu, SY and Huang, TW and Yuliani, FS and Lin, SH},
title = {Dementia Risk After Glaucoma Surgery and Medical Therapy: A Multicentre Real-World Cohort Study.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {9},
pages = {e70252},
doi = {10.1002/gps.70252},
pmid = {42693831},
issn = {1099-1166},
mesh = {Humans ; Female ; Aged ; *Dementia/epidemiology/etiology ; *Glaucoma/surgery/drug therapy/therapy ; Male ; Middle Aged ; Risk Factors ; Aged, 80 and over ; Vision Disorders/epidemiology ; Alzheimer Disease/epidemiology ; Cohort Studies ; },
abstract = {BACKGROUND AND PURPOSE: Glaucoma, a neurodegenerative optic neuropathy and leading cause of irreversible vision loss, shares vascular and neurodegenerative mechanisms with dementia. The 2024 Lancet Commission newly identified visual impairment as a modifiable dementia risk factor. As glaucoma management ranges from long-term medical therapy to laser/surgical intervention, it remains uncertain whether treatment modality influences long-term systemic outcomes such as dementia. This study compares dementia risk in patients receiving glaucoma surgery versus medical therapy.

METHODS: Glaucoma patients aged ≥ 40 years and diagnosed and managed before July 2021 were identified in the TriNetX database and followed from the first definitive treatment-surgery or initiation of medical therapy-until dementia diagnosis, death, or July 2026. The primary outcome was all-cause dementia; secondary outcomes included Alzheimer's disease, vascular dementia, and visual loss. Subgroup analyses examined surgical timing, modality, age, sex, and comorbidities.

RESULTS: After 1:1 propensity score matching, 51,923 patients were included in each cohort (mean age 64 years; 55.3% female). Glaucoma surgery was associated with reduced risks of all-cause dementia (HR 0.81) and vascular dementia (HR 0.53), a non-significant reduction in Alzheimer's disease (HR 0.87), and a higher risk of visual loss (HR 1.52), consistent with more advanced disease among surgical candidates. Associations were stronger with late surgery, traditional incisional procedures, younger age, and absence of comorbidities.

CONCLUSIONS: Patients who underwent glaucoma surgery were associated with a lower subsequent risk of all-cause dementia and vascular dementia, with a non-significant trend for Alzheimer's disease, compared with those receiving medical therapy. These findings suggest that surgical management is associated with more favourable long-term cognitive outcomes beyond ocular benefits, which may provide additional context for treatment-escalation decisions in suitable patients.},
}

Humans
Female
Aged
*Dementia/epidemiology/etiology
*Glaucoma/surgery/drug therapy/therapy
Male
Middle Aged
Risk Factors
Aged, 80 and over
Vision Disorders/epidemiology
Alzheimer Disease/epidemiology
Cohort Studies

@article {pmid42693839,
year = {2026},
author = {Aykora, D and Uzun, M},
title = {Plant-Derived Exosomes in Neurodegenerative Disorders and Age-Related Brain Dysfunction: From Isolation to Clinical Potential.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X456941260803062544},
pmid = {42693839},
issn = {1875-6190},
abstract = {INTRODUCTION: Plant-derived Exosome-like Nanovesicles (PELNs) have the potential to exhibit improved biological functions in multiple pathological disorders, particularly in neurodegenerative and age-related brain diseases. In this review, advanced isolation techniques, including Differential Ultracentrifugation (dUC), Size-Exclusion Chromatography (SEC), and Polyethylene Glycol (PEG) precipitation, were systematically evaluated to optimize the structural integrity, purity, and biological activity of PELNs.

METHODS: Novel studies on PELNs were the primary focus of this review. Evidence-based studies were compared and discussed in terms of chemical and functional characteristics, as well as optimized production strategies to enhance the therapeutic properties of PELNs.

RESULTS: According to the consensus of reviewed studies, PELNs demonstrate efficient cellular uptake due to their lipophilic chemical structures and modulate intracellular signaling pathways related to neurodegeneration. The main drawbacks of PELNs' utilization mostly depend on the extraction methods and limited delivery through the BBB. A combination of optimized methods, such as dUC and SEC, may exhibit maintained therapeutic strategies for neurological applications.

DISCUSSION: Due to the limited number of experimental studies in Parkinson's Disease (PD) and Alzheimer's Disease (AD), and brain aging, advances in PELNs extraction methods have been shown to enhance BBB delivery and therapeutic efficacy. Every study claims the superiority of its own method; however, none of these methods fully addresses the limitations inherent in producing optimal results.

CONCLUSION: PELNs represent a promising platform for neurological dysfunction and brain aging-related disorders. However, isolation and characterization methods must be carefully optimized and validated to ensure the production of therapeutically active PELNs suitable for BBB delivery.},
}

@article {pmid42693862,
year = {2026},
author = {Ardakani, RH and Dashtaki, M and Mohamadi-Zarch, SM and Bagheri, SM},
title = {Cortisol Dysregulation as a Major Factor in the Development of Neurodegenerative Diseases, Drug Targets and Therapeutic Prospects: A Comprehensive Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273466502260813092749},
pmid = {42693862},
issn = {1996-3181},
abstract = {Cortisol, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is critical for stress response, metabolism, and immune function. Its dysregulation is increasingly implicated in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). This review synthesizes evidence on cortisol's role in neurodegenerative disorders, exploring its mechanisms, clinical implications, and therapeutic potential. This study analyzed preclinical models, clinical studies, and biomarker data to elucidate cortisol's impact on neurodegeneration. Key mechanisms include glucocorticoid and mineralocorticoid receptor-mediated effects on synaptic plasticity, neuroinflammation, and oxidative stress. In AD, elevated cortisol accelerates cognitive decline, hippocampal atrophy, and amyloid-β accumulation. In PD, higher cortisol levels correlate with gait dysfunction and dopaminergic neuron loss. HD shows variable cortisol profiles, with early hypocortisolism shifting to hypercortisolism in later stages, linked to depression. In ALS, elevated cortisol hastens disease progression and neuroinflammation. In MS, HPA axis hyperactivity is associated with cognitive deficits and lesion activity, though it may support remyelination. Chronic stress exacerbates these effects across disorders, promoting neuronal vulnerability. Cortisol dysregulation is a significant contributor to neurodegenerative pathology, acting as both a biomarker and therapeutic target. Emerging interventions, including glucocorticoid receptor antagonists, cortisol synthesis inhibitors, and stress reduction strategies, show promise in mitigating neuronal damage. Personalized, stage-specific therapies and longitudinal studies are needed to optimize cortisol-targeted treatments for neurodegenerative diseases.},
}

@article {pmid42693863,
year = {2026},
author = {Chauhan, SB and Bhardwaj, A and Jain, C and Singh, I},
title = {Nano-Magnetism for Precision Neuroscience: Biohybrid Magnetoelectric Nanocarriers as Next-Generation Neural Drug Delivery Platforms.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273397455251030094458},
pmid = {42693863},
issn = {1996-3181},
abstract = {Neuroscience is making tremendous progress toward precision medicine, with nanotechnology playing a critical role in overcoming hurdles to successful brain medication delivery. Nano magnetism, namely biohybrid magnetoelectric nanocarriers (MENs), has emerged as a potential method for targeted and non-invasive medication delivery in neurological illnesses. These nanocarriers possess magnetoelectric properties, enabling stimulus-responsive drug release that is externally controlled. This allows for precise targeting across the blood-brain barrier (BBB), with exceptional spatial and temporal resolution. MENs can deliver neurotherapeutics deep into brain regions by combining magnetic guidance with electrical stimulation, thereby improving treatment outcomes for conditions such as Alzheimer's, Parkinson's, epilepsy, and glioblastoma. Furthermore, their biohybrid nature, which is accomplished by functionalizing nanocarriers with biocompatible coatings, peptides, or membranes produced from neural cells, increases biostability, decreases immune response, and improves neuron targeting. This review investigates the underlying concepts of magnetoelectric nanocarriers, production processes, and interactions with brain tissue. It dives deeper into recent advances in precision neural drug delivery, including the effect of external magnetic and electric fields on regulated drug release, neurostimulation, and neuromodulation. While MENs have tremendous promise, long-term biocompatibility, precise control systems, and regulatory restrictions continue to impede clinical translation. Future research should concentrate on enhancing nanocarrier design, increasing targeting efficiency, and undertaking large-scale preclinical and clinical trials. Magnetoelectric nanocarriers have the potential to transform non-invasive neurotherapeutics by bridging the gap between nano magnetism and neuroscience, resulting in safer and more successful treatment paradigms for complex brain illnesses.},
}

@article {pmid42693903,
year = {2026},
author = {Li, J and Liu, Q and Ma, Q and Shen, T and Xia, J and Yang, X and Liu, K and Li, N and Yan, B},
title = {Multilevel genomic, transcriptomic, and epidemiologic evidence linking diabetic retinopathy to Alzheimer disease.},
journal = {Journal of global health},
volume = {16},
number = {},
pages = {04311},
doi = {10.7189/jogh.16.04311},
pmid = {42693903},
issn = {2047-2986},
mesh = {Humans ; *Alzheimer Disease/epidemiology/genetics ; *Diabetic Retinopathy/genetics/epidemiology ; Mendelian Randomization Analysis ; Transcriptome ; Genetic Predisposition to Disease ; Genomics ; Multiomics ; Bayes Theorem ; },
abstract = {BACKGROUND: Diabetic retinopathy (DR) and Alzheimer disease (AD) share metabolic and vascular dysfunctions, but the extent to which they reflect overlapping genetic susceptibility and neurovascular-metabolic regulatory pathways remains unclear. We combined multi-omics analyses with population-based data to examine the genetic convergence, cellular pathways, and longitudinal association between DR and AD.

METHODS: We performed a two-sample Mendelian randomisation (MR) to estimate the association between genetically predicted DR liability and AD risk. We used Bayesian colocalisation analysis to identify shared genomic loci, and summary-data-based MR (SMR) to detect expression-mediated genes jointly associated with DR and AD. We analysed single-cell RNA sequencing data to characterise shared cellular features and related biological pathways. We also conducted an MR-based mediation analysis to explore whether lipid-related, metabolic, or inflammatory traits mediated the observed DR-AD association, and a longitudinal analysis of the UK Biobank cohort to assess the association between DR and incident AD.

RESULTS: With the MR analysis, we found that genetically predicted liability to DR was associated with a modest increase in AD risk. Colocalisation analysis supported a shared genetic signal. We identified three genes with shared expression-mediated associations across DR and AD through SMR. Functional enrichment analyses revealed partially overlapping neurovascular and metabolic pathways. Using MR-based mediation analysis, we found no significant intermediary traits linking DR and AD. Findings from the UK Biobank cohort were directionally consistent with the genetic analyses.

CONCLUSIONS: Genetic liability to DR is associated with an increased risk of AD and is accompanied by shared expression-mediated effects and convergent neurovascular-metabolic pathways. These findings support the possibility that DR may serve as a clinically accessible indicator of increased neurodegenerative vulnerability.},
}

Humans
*Alzheimer Disease/epidemiology/genetics
*Diabetic Retinopathy/genetics/epidemiology
Mendelian Randomization Analysis
Transcriptome
Genetic Predisposition to Disease
Genomics
Multiomics
Bayes Theorem

@article {pmid42694080,
year = {2026},
author = {Atri, TE and Denkinger, MN and Liu, J and Singh, A and Surdyn, M and Brown, VA and Martinez, G and Teran, M and Soza, V and Kuramoto, A and Marques, TM and Langbaum, JB and Atri, A and Ashton, NJ},
title = {Performance of upper-arm capillary blood collection for Alzheimer's disease and central nervous system biomarkers: comparison of Tasso+ and venous plasma.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.13.26360406},
pmid = {42694080},
abstract = {INTRODUCTION: Novel capillary-blood collection methods have not yet been evaluated for a wide range of central nervous system (CNS) and neurodegenerative disease-related proteins. Biomarkers of Alzheimer's disease (AD) and related disorders (ADRD) collected from devices like the Tasso+, a minimally invasive upper-arm capillary blood collection device, must be compared to traditional venipuncture to assess for validity.

METHODS: Participants underwent blood collection via traditional venipuncture and Tasso+ in a clinical research setting. The Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) CNS panel was used for biomarker quantification in venous and Tasso-derived plasma.

RESULTS: Eighty-three participants (age mean±SD 76.8±8.2 years, 79.5% cognitively unimpaired) completed blood collection. Little to no correlation was found between venous and Tasso+ plasma for p-tau217, but the correlation was improved by using a brain-derived (BD)-p-tau217/BD-p-tau181 ratio. Extremely strong correlations were found for neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Among the 131 biomarkers measured, 51 (38.9%) had a Pearson R ≥ 0.90; 27 (20.6%) had values between 0.70-0.90; 26 (19.9%) had values between 0.30-0.70; and 27 (20.6%) had values ≤0.30.

DISCUSSION: The Tasso+ accurately measures NfL and GFAP, but caution is warranted when measuring other AD/ADRD biomarkers, as agreement with venous plasma appears to be protein or ratio dependent. These results highlight that important biomarker-specific differences must be considered when translating capillary blood collection approaches. They also further support foundations for development of these methods, highlighting both the opportunities and remaining challenges for translating the promise of blood-based biomarkers beyond AD/ADRD specialty clinics and research settings.},
}

@article {pmid42694129,
year = {2026},
author = {Wear, D and Hussaini, SA and Yu, WH},
title = {Sleep and stress as modifiable drivers of Alzheimer's disease.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {84},
pmid = {42694129},
issn = {3005-1940},
abstract = {Proper sleep and stress maintenance are essential for health and may contribute to disease progression when dysregulated. This review highlights the intricate links between sleep, stress, and Alzheimer's disease, including underlying neural circuitry and mechanisms that contribute to disease. Sleep is essential for protein clearance pathways including autophagy and the glymphatic system, which are impaired in neurodegenerative diseases. Similarly, chronic stress incites neuroinflammatory responses known to be elevated in brains of patients with neurodegeneration. As a result, it is perhaps unsurprising that tau pathology and neurodegeneration affect sleep and stress circuitry in the brain, including the Locus Coeruleus and Lateral Hypothalamus, beginning in prodromal phases of Alzheimer's disease. Though the precise mechanisms underscoring these vulnerabilities are incompletely understood, this provides a unique therapeutic opportunity for targeting these pathways in early Alzheimer's disease patients with concomitant sleep impairments and/or chronic stress. In this review, we offer insights into these relationships including specific brain region involvements, the contribution of molecular mechanisms of disease, and these translational opportunities which may arise.},
}

@article {pmid42694243,
year = {2026},
author = {Akinyemi, T and Pola, I and Tan, K and Olalusi, O and Yaria, J and Ogunde, G and Traichel, W and Rahmouni, N and Oguntiloye, O and Fagbemi, A and Cadmus, E and Popoola, F and Therriault, J and Ogunronbi, M and Olujobi, D and Famuyiwa, O and Akinyemi, J and Pascoal, T and Owolabi, M and Rosa-Neto, P and Udeh-Momoh, CT and Ladokun, O and Romero-Ortuno, R and Ogunniyi, A and Lawlor, B and Kalaria, R and Zetterberg, H and Benedet, AL and Akinyemi, R},
title = {Blood-based biomarkers of Alzheimer's disease and neurodegeneration in an indigenous African cohort using both Simoa and NULISA platforms.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {80},
pmid = {42694243},
issn = {3005-1940},
abstract = {In low- and middle-income countries, Alzheimer's disease (AD) constitutes a growing public health burden. However, AD biomarkers research remains underrepresented in African populations. This study assesses core biomarkers of AD and their relevance in the African context as potential aid in clinical diagnosis. Nigerian older adults from VALIANT cohort (n = 967) underwent biomarker quantification in plasma (p-tau217, GFAP, NfL, Aβ42 and Aβ40) employing both the Single Molecule Assay (Simoa, Quanterix) and Nucleic acid-Linked Immuno-Sandwich Assay (NULISA, Alamar). Biomarkers were associated with disease severity in clinical-diagnostic and clinical-biological groups, with stepwise increases of p-tau217, NfL and GFAP from cognitively unimpaired to dementia (p < 0.05). Results were consistent across platforms. Comparison between sexes showed higher biomarker levels in male participants across diagnostic groups. A significant effect of apoE-E4 proteotype on p-tau217 levels, after adjusting for age and sex was identified. These findings support the application of plasma AD biomarkers in the African context and the relevance of further AD biomarker research in diverse populations.},
}

@article {pmid42694256,
year = {2026},
author = {Shukla, S and Kolmetzky, D and Goyani, S and Samantaray, K and Sinha, A and Kramer, PA and Tomar, D and Jadiya, P},
title = {Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {83},
pmid = {42694256},
issn = {3005-1940},
abstract = {Alzheimer's disease (AD) lacks effective therapies, partly due to an incomplete understanding of mitochondrial dysfunction, a key driver of neurodegeneration. Mitochondria activate the unfolded protein response (UPR[mt]) to maintain proteostasis, but the roles of matrix- and intermembrane space (IMS)-associated stress responses in AD remain unclear. Here, we used human microglial-like cells expressing mutant amyloid precursor protein together with compartment-targeted mitochondrial proteotoxic stressors to investigate matrix (UPR[mt-MM]) and IMS (UPR[mt-IMS]) stress responses. RNA-seq revealed activation of mitochondrial stress pathways and suppression of synaptic and lipid signaling in AD-like cells. UPR[mt-MM] promoted robust immune activation, severe oxidative phosphorylation defects, increased mitochondrial reactive oxygen species, and cell death. In contrast, UPR[mt-IMS] preferentially induced interferon signaling and suppressed antioxidant pathways. Notably, suppression of ATF5-dependent UPR[mt] signaling rescued mitochondrial dysfunction and reduced Aβ release. Together, these findings demonstrate that matrix- and IMS-targeted mitochondrial stress elicit distinct microglial responses and identify mitochondrial proteostasis as a potential therapeutic target in AD.},
}

@article {pmid42694370,
year = {2026},
author = {Song, J and Yuan, Y and Wang, M and Li, J and Ding, R and Jia, Y and Wang, Z and Xie, Z and Li, Z and Zhang, Z},
title = {Liuwei Dihuang pills attenuates cognitive dysfunction in APP/PS1 mice through restoring mitochondrial homeostasis and activating the IRS/AKT/GSK3β insulin signaling pathway.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1873606},
pmid = {42694370},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) features progressive cognitive decline, Aβ aggregation, neurofibrillary tangles, mitochondrial dysfunction and central insulin resistance, lacking effective disease-modifying treatments. Liuwei Dihuang Pills (LWDHP) exert neuroprotective effects, while its dual regulatory mechanisms targeting mitochondrial homeostasis and cerebral IRS/AKT/GSK3β insulin signaling remain unclear.

METHODS: APP/PS1 transgenic mice were used as AD models. Morris water maze assessed spatial cognition; immunofluorescence detected Aβ and MAP2; transmission electron microscopy observed neuronal/synaptic ultrastructure; western blot quantified synaptic proteins and insulin signaling cascade molecules.

RESULTS: LWDHP significantly rescued spatial learning and memory deficits, reduced cerebral Aβ plaques and tau hyperphosphorylation. LWDHP balanced mitochondrial fusion-fission via upregulating PGC-1α/MFN2 and downregulating FIS1, elevated synaptic structural proteins (MAP2, PSD-95, SYN), restored cerebral insulin sensitivity by elevating InsR, normalizing IRS-1/AKT/GSK3β phosphorylation, and suppressing tau hyperphosphorylation.

DISCUSSION: LWDHP alleviates AD cognitive impairment through dual regulation of mitochondrial homeostasis and IRS/AKT/GSK3β insulin signaling, providing solid preclinical evidence for its anti-AD application.},
}

@article {pmid42694457,
year = {2026},
author = {Ake, C and Cervantes, E and Garcia, C and Hammons, H and Obawole, L and Morton, I and Pham, L and Salas, B and Stacks, S and Villarreal, L and York, F and Biglari, S and Yeragi, E and Lillvis, E and Moulton, M and Keene, A},
title = {The effects of obesogenic diet on a Drosophila model of frontotemporal dementia.},
journal = {microPublication biology},
volume = {2026},
number = {},
pages = {},
pmid = {42694457},
issn = {2578-9430},
abstract = {Tau aggregation is a hallmark of neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. Here, we tested how an obesogenic diet affects a Drosophila tauopathy model across multiple behavioral assays. In group-housed flies, mutant tau shortened lifespan, and this effect was worsened by a high-sugar diet. We also examined sleep, motor behavior, and sensory responsiveness. Tau-expressing flies differed from controls in all assays, but these deficits were not further exacerbated by diet. These findings reveal assay-specific diet effects and highlight the value of using multiple behavioral measures to characterize tau mutant phenotypes.},
}

@article {pmid42694464,
year = {2026},
author = {Xu, L and Zhang, Y and Jiang, L and Xing, JF and Hu, J and Lan, T and Ta, G},
title = {Microglia-mediated neuroinflammation in Alzheimer's disease: mechanisms and emerging therapeutic targets.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1902577},
pmid = {42694464},
issn = {1662-5102},
abstract = {Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by amyloid-β deposition and pathological tau aggregation. Amyloid-β deposition typically occurs during the preclinical stage; however, amyloid burden does not exhibit a simple linear relationship with neurodegeneration or cognitive decline. In contrast, the spatial distribution of tau pathology is more closely associated with clinical progression. As the resident innate immune cells of the central nervous system, microglia participate in the recognition, uptake, and containment of amyloid-β and tau. Nevertheless, persistent exposure to damage-associated signals can lead to lysosomal dysfunction, dysregulated lipid metabolism, and mitochondrial impairment in microglia, thereby amplifying neuroinflammation, aberrant synaptic elimination, and neuronal injury. The traditional binary M1/M2 classification is inadequate to capture the continuous, overlapping, and context-dependent functional states of microglia, which vary across brain regions, genetic backgrounds, and disease stages. This review integrates recent evidence from genetic, single-cell/single-nucleus, and spatial transcriptomic studies and proposes a "cellular state-pathological network-therapeutic window" framework. We systematically discuss the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA-cGAS-STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia-tau feedback. On this basis, we critically evaluate the mechanistic rationale, stage dependence, and translational limitations of therapeutic axes involving TREM2/CD33, P2X7-NLRP3 and cGAS-STING, CSF1R/complement, and TNF-TNFR1-RIPK1. Current evidence suggests that the key to microglia-targeted therapy is not the broad activation or suppression of immune responses, but rather the biomarker-guided and disease-stage-specific modulation of pathogenic signaling while preserving homeostatic functions such as plaque containment, debris clearance, synaptic maintenance, and tissue repair.},
}

@article {pmid42694478,
year = {2026},
author = {Cui, Q and Zheng, K and Liu, Q and Wang, L and Liu, Y and Bai, R and Zhang, W and Guo, J and Chang, X and Wang, J},
title = {From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1921079},
pmid = {42694478},
issn = {1662-5099},
abstract = {Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.},
}

@article {pmid42694488,
year = {2026},
author = {Wang, M and Qian, Y and Huang, E and Chu, C and Gao, T and Chen, S and Zhao, N and Luo, C and Liu, Y and Zheng, X and Hu, H and Han, B and Chen, M and Mao, W and Li, W},
title = {Identification of interleukin-11 as a comorbid risk factor for prostate cancer and Alzheimer's disease using integrated bioinformatics and machine learning.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1911726},
pmid = {42694488},
issn = {1664-3224},
mesh = {Male ; *Interleukin-11/genetics/metabolism ; Humans ; *Alzheimer Disease/epidemiology/genetics/immunology/metabolism ; *Prostatic Neoplasms/epidemiology/genetics/metabolism/immunology ; *Machine Learning ; Animals ; Mice ; Risk Factors ; Computational Biology/methods ; Comorbidity ; Gene Expression Profiling ; Cell Line, Tumor ; Transcriptome ; Gene Expression Regulation, Neoplastic ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Prostate cancer (PCa) and Alzheimer's disease (AD) are age-related disorders with a complex epidemiological association and limited therapeutic options. Identifying shared molecular drivers may reveal new treatment targets.

OBJECTIVE: To identify common transcriptomic signatures between PCa and AD and validate the role of interleukin-11 (IL11) as a functional comorbidity factor.

METHODS: Multi-cohort transcriptomic datasets (GSE48350, GSE5281 and GSE28146 for AD; TCGA-PRAD, DKFZ2018 and MSKCC for PCa) were analyzed. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed, followed by a two-tier machine learning pipeline (Random Forest and LASSO Cox regression) to screen overlapping genes. Immune infiltration was evaluated by CIBERSORT and single-cell transcriptomics for PCa. The functional role of IL11 was assessed in RM-1 murine and DU145 human PCa cells using colony formation, wound healing, Transwell assays, and immunocompetent C57BL/6 orthotopic and subcutaneous xenograft models. The cognitive effects of IL11 were evaluated using Morris water maze (MWM) tests, and the neuropathological changes were assessed by detecting hippocampal amyloid-β (Aβ) deposition. Additionally, a cross-sectional analysis was performed in a population cohort (n=215) to investigate the associations between IL11 levels and AD pathological biomarkers.

RESULTS: A total of 455 shared candidate genes were identified, and a 10-gene signature (NDRG4, ISG15, IL11, ENO2, DYNC1I1, DNASE1, ATP6V1G2, ATCAY, ANLN, AGAP9) was established. The risk score effectively stratified PCa patients with poor progression-free interval (log-rank P < 0.001; AUC for 1-,3-,5-year = 0.78,0.73,0.70), validated in two external cohorts (DKFZ2018, MSKCC). IL11 was the top candidate and was significantly upregulated in both diseases. High IL11 expression correlated with an immunosuppressive microenvironment, characterized by increased M2 macrophages and regulatory T cells, and with higher tumor mutation burden. Single-cell analysis localized IL11 to a subset of cancer-associated fibroblasts. In vitro, IL11 treatment enhanced PCa cell proliferation, migration, and invasion. In vivo, intraperitoneal IL11 accelerated PCa tumor growth in mice. In the MWM test, IL11-treated mice exhibited significantly longer escape latencies and fewer platform crossings, which were accompanied by increased hippocampal Aβ deposition, suggesting that IL11 induced cognitive dysfunction. Cross-sectional cohort analyses further linked higher serum IL11 to reduced CSF Aβ42 and elevated p-tau181.

CONCLUSION: IL11 acts as a shared risk factor related to PCa progression and cognitive decline in AD, representing a convergent molecular pathway and a potential therapeutic target for both age-related diseases.},
}

Male
*Interleukin-11/genetics/metabolism
Humans
*Alzheimer Disease/epidemiology/genetics/immunology/metabolism
*Prostatic Neoplasms/epidemiology/genetics/metabolism/immunology
*Machine Learning
Animals
Mice
Risk Factors
Computational Biology/methods
Comorbidity
Gene Expression Profiling
Cell Line, Tumor
Transcriptome
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL

@article {pmid42694538,
year = {2026},
author = {Gavilan, J and Panes-Fernández, J and Araya, A and Pérez-Manríquez, C and Becerra, J and Varas, P and Moraga-Cid, G and Yévenes, GE and Fuentealba, J},
title = {Correction: Unraveling the neuroprotective mechanisms of elephant black garlic extract against beta amyloid peptide-induced neurotoxicity.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1960775},
doi = {10.3389/fnut.2026.1960775},
pmid = {42694538},
issn = {2296-861X},
abstract = {[This corrects the article DOI: 10.3389/fnut.2025.1725284.].},
}

@article {pmid42694561,
year = {2026},
author = {Shi, L and Zhou, C and Han, H and Lu, M and Li, M and Miao, J and Feng, S and Zhou, X and Chen, H and Ren, L},
title = {The APOE4-estrogen-microglia axis in perimenopausal cognitive changes: mechanisms and therapeutic implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1925850},
pmid = {42694561},
issn = {1664-3224},
mesh = {Humans ; *Microglia/metabolism/immunology ; *Estrogens/metabolism/deficiency ; Animals ; *Apolipoprotein E4/metabolism/genetics ; Female ; *Perimenopause/metabolism ; Alzheimer Disease/metabolism ; *Cognition ; },
abstract = {Alzheimer's disease (AD) exhibits marked sex differences, with women bearing a disproportionate burden of disease, particularly after midlife. Among the major factors contributing to this vulnerability, the apolipoprotein E ϵ4 allele (APOE4) and the abrupt endocrine transition of perimenopause have emerged as two critical and potentially synergistic drivers of neurodegeneration. Microglia, the resident immune cells of the central nervous system, lie at the center of this interaction because they integrate genetic, hormonal, metabolic, and inflammatory signals that shape amyloid clearance, synaptic remodeling, and neuroimmune homeostasis. Accumulating evidence indicates that APOE4 impairs microglial phagocytosis, disrupts lipid handling and lysosomal function, promotes pro-inflammatory activation, and compromises neurovascular integrity. In parallel, estrogen normally restrains microglial inflammatory signaling and supports phagocytic, metabolic, and reparative functions through estrogen receptor-dependent pathways. During perimenopause, fluctuating estrogen deficiency removes these protective constraints, thereby increasing the susceptibility of microglia to APOE4-driven dysfunction. This review synthesizes current evidence supporting an integrated pathogenic framework centered on the "APOE4-estrogen deficiency-microglia axis." We discuss how this axis promotes chronic neuroinflammation, synaptotoxicity, amyloid and tau pathology, mitochondrial dysfunction, blood-brain barrier disruption, and large-scale network disconnection, ultimately accelerating cognitive decline in women. We also summarize relevant experimental models, including APOE-targeted murine paradigms, ovariectomy and accelerated ovarian failure models, human induced pluripotent stem cell-derived microglia, and emerging single-cell and spatial omics approaches. Finally, we highlight translational opportunities, including precision hormone-based interventions, selective estrogen receptor modulation, TREM2-centered microglial therapies, APOE4-directed molecular and genetic strategies, and biomarker-guided multi-target interventions during the perimenopausal "window of opportunity." By integrating molecular mechanisms with translational perspectives, this review proposes a precision medicine framework for preventing or delaying neurodegenerative progression in high-risk perimenopausal women.},
}

Humans
*Microglia/metabolism/immunology
*Estrogens/metabolism/deficiency
Animals
*Apolipoprotein E4/metabolism/genetics
Female
*Perimenopause/metabolism
Alzheimer Disease/metabolism
*Cognition

@article {pmid42694564,
year = {2026},
author = {Lu, P and Liu, M and Zhang, L and Fan, JJ and Sun, Y},
title = {Synergistic Regulation of Alzheimer's Disease and Intestinal Microbiota Metabolism Mediated by the Gut-Brain Axis: A Comprehensive Analysis from a Multidisciplinary Perspective.},
journal = {International journal of medical sciences},
volume = {23},
number = {9},
pages = {2939-2962},
pmid = {42694564},
issn = {1449-1907},
mesh = {Humans ; *Alzheimer Disease/microbiology/metabolism/immunology/therapy ; *Gastrointestinal Microbiome/immunology/physiology ; *Brain/metabolism/immunology ; Animals ; Multiomics ; *Brain-Gut Axis/immunology/physiology ; *Dysbiosis/microbiology/immunology ; },
abstract = {Alzheimer's disease (AD), as a neurodegenerative disease with the interaction of multiple factors, has a close association between its pathological process and the metabolic imbalance of the gut microbiota mediated by the gut-brain axis. This review systematically summarizes the molecular mechanisms by which the gut microbiota regulates the functions of the central nervous system bidirectionally through molecular pathways such as metabolites (e.g., short-chain fatty acids, tryptophan-kynurenine metabolites), immunomodulatory mediators (e.g., cytokines, chemokines), and bioactive substances (e.g., γ-aminobutyric acid, 5-hydroxytryptophan) via the gut-brain axis. It synthesizes current evidence suggesting the imbalance of microbiota homeostasis may be closely associated with the core pathologies of AD (including β-amyloid deposition and tau protein hyperphosphorylation) through mechanisms such as the activation of the C/EBPβ-AEP signaling pathway, induction of chronic neuroinflammation, oxidative stress cascade reactions, and metabolic network remodeling. These findings, primarily derived from preclinical models and correlational human studies, indicate potential mechanisms but require further causal validation and rigorous clinical translation, including the downregulation of butyrate synthesis pathways and their associated epigenetic and immunomodulatory consequences (as mechanistically dissected in Section 5.2). Multi-omics integration (metagenomics, metabolomics, spatial transcriptomics) has delineated characteristic microbial and metabolic alterations in AD, while computational approaches are beginning to elucidate the complex networks underlying these associations (see Sections 6 and 7 for details).Intervention strategies based on microbiota regulation (such as microbiota-targeted dietary interventions and postbiotics) are emerging as promising approaches, although their clinical applications remain in early stages. Preliminary evidence suggests that fecal microbiota transplantation may improve cognitive outcomes in AD patients with comorbid conditions; however, rigorous randomized controlled trials are essential to validate its efficacy and safety. Critically, translating these mechanistic insights into clinical practice requires overcoming three translational bottlenecks: inferring causality from correlational multi-omics data, resolving species/strain-level functional heterogeneity masked by genus-level taxonomy, and establishing standardized safety protocols for live biotherapeutic products. Addressing these challenges defines the near-term roadmap for precision medicine in AD. However, current research still faces challenges such as the heterogeneity of cross-omics data, the lack of technical standardization, and insufficient interdisciplinary cooperation mechanisms. In the future, it is necessary to promote the early molecular diagnosis and personalized targeted treatment of AD through longitudinal multi-omics dynamic monitoring, modeling of the microbiota-host interaction network, and optimization of the ethical-translational medicine framework.},
}

Humans
*Alzheimer Disease/microbiology/metabolism/immunology/therapy
*Gastrointestinal Microbiome/immunology/physiology
*Brain/metabolism/immunology
Animals
Multiomics
*Brain-Gut Axis/immunology/physiology
*Dysbiosis/microbiology/immunology

@article {pmid42694579,
year = {2026},
author = {Morgans, W and Sharrocks, AD and Iqbal, M},
title = {Scalable joint non-negative matrix factorization for paired single cell gene expression and chromatin accessibility data.},
journal = {NAR genomics and bioinformatics},
volume = {8},
number = {3},
pages = {lqag104},
pmid = {42694579},
issn = {2631-9268},
mesh = {*Chromatin/metabolism/genetics ; Single-Cell Gene Expression Analysis ; Humans ; Algorithms ; *Single-Cell Analysis/methods ; *Computational Biology/methods ; Software ; Animals ; Gene Expression Profiling/methods ; },
abstract = {Single-cell multi-modal technologies provide powerful means to simultaneously profile cellular states. These are now being employed to study gene regulatory mechanisms in a variety of biological systems. Tailored computational methods for integration and analysis of these data are much needed, with desirable properties in terms of efficiency-to cope with high dimensionality of the data, interpretability-for downstream biological discovery and hypothesis generation, and flexibility-to easily incorporate future modalities. Existing methods cover some but not all of the desirable properties for effective integration and analysis of these data. Here, we present a highly efficient method, q-intNMF, for representation and integration of single-cell multi-modal data using joint non-negative matrix factorization, which can facilitate discovery of linked regulatory topics in each modality. We provide thorough benchmarking using large publicly available datasets against five popular existing methods. q-intNMF performs comparably against the current state-of-the-art methods across a range of metrics. Additionally, q-intNMF provides advantages in terms of computational efficiency and interpretability of discovered regulatory topics in the original feature space. We illustrate this enhanced interpretability in providing insights into cell state changes associated with Alzheimer's disease. q-intNMF is available as a Python package with extensive documentation and use cases at https://github.com/wmorgans/quick_intNMF.},
}

*Chromatin/metabolism/genetics
Single-Cell Gene Expression Analysis
Humans
Algorithms
*Single-Cell Analysis/methods
*Computational Biology/methods
Software
Animals
Gene Expression Profiling/methods

@article {pmid42694581,
year = {2026},
author = {Peng, Y and Jin, C and Sun, Y and Mu, W and Zheng, X},
title = {Roles of IL-34 in neurological diseases: neuroprotection, inflammatory regulation, and myeloid plasticity.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1898176},
pmid = {42694581},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Interleukins/metabolism/immunology ; *Neuroprotection ; *Nervous System Diseases/metabolism/immunology ; *Myeloid Cells/immunology/metabolism ; Inflammation/metabolism ; Cell Plasticity ; },
abstract = {Interleukin-34 (IL-34) is a brain-enriched cytokine and a tissue-restricted ligand of colony-stimulating factor-1 receptor (CSF-1R) that plays an important role in microglial development, survival, and functional specialization. A growing body of evidence indicates that IL-34 is dysregulated in both central and peripheral nervous system diseases and exerts pleiotropic effects not only through CSF-1R but also through non-canonical receptors, including TREM2, syndecan-1, and PTP-ζ. Under physiological conditions, IL-34 is constitutively produced predominantly by neurons across both the central and peripheral nervous systems. However, in pathological settings, its cellular sources expand dynamically: in CNS diseases, IL-34 is primarily derived from stressed neurons and reactive astrocytes, whereas in PNS disorders, it is robustly upregulated by injured sensory neurons, satellite glial cells, and reactive Schwann cells. IL-34 contributes to the regulation of resident glia in the CNS, while evidence from peripheral immune disorders suggests that it may also influence infiltrating myeloid-cell adaptation under pathological conditions. In this review, we highlight the multiple effects of IL-34 and its receptor network on CNS-resident, peripheral glial, and peripheral immune cells, with particular attention to the available data supporting its dual role in neuroprotection and inflammatory amplification. We synthesize recent findings regarding IL-34's role in myeloid reprogramming, particularly in orchestrating transcriptional and functional phenotypic shifts. While current literature provides evidence linking IL-34 to these transcriptional changes, its contribution to metabolic and epigenetic remodeling remains an emerging field. Furthermore, our findings summarized in this manuscript may help evaluate whether targeting IL-34-related pathways can be exploited for therapeutic intervention in neurodevelopmental, neurodegenerative, cerebrovascular, and peripheral nerve pathologies.},
}

Humans
Animals
*Interleukins/metabolism/immunology
*Neuroprotection
*Nervous System Diseases/metabolism/immunology
*Myeloid Cells/immunology/metabolism
Inflammation/metabolism
Cell Plasticity

@article {pmid42694654,
year = {2026},
author = {Wu, Y and Duan, L and Zhang, L and Wang, S and Yan, H and He, M and Wang, T and Li, L and Gao, Y},
title = {TREM2 as a central hub of neuroimmune-metabolic crosstalk in central nervous system disorders: from microglial biology to therapeutic targeting.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1912989},
pmid = {42694654},
issn = {1664-3224},
mesh = {Humans ; *Microglia/metabolism/immunology ; *Receptors, Immunologic/metabolism/genetics/immunology ; *Membrane Glycoproteins/metabolism/genetics/immunology ; Animals ; *Central Nervous System Diseases/metabolism/immunology/therapy ; Signal Transduction ; *Neuroimmunomodulation ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched immunoreceptor that functions as a central regulator of microglial adaptation by integrating immune surveillance, lipid sensing, metabolic reprogramming, and phagocytic responses in the central nervous system (CNS). Through association with the adaptor protein DAP12, TREM2 activates interconnected signaling networks involving the SYK pathway, PLCγ2-mediated Ca[2+] signaling, PI3K-AKT-mTOR signaling, NF-κB activation and inflammatory regulatory pathways, thereby shaping microglial survival, migration, clearance capacity, and interactions with surrounding neural and immune cells. Increasing evidence from genetic studies, single-cell transcriptomics, spatial analyses, and human-derived microglial models indicates that TREM2 dysfunction contributes to diverse CNS disorders; however, its biological consequences are highly dependent on disease stage, pathological substrate, cellular context, and microenvironmental cues. In Alzheimer's disease, TREM2 regulates amyloid-β-associated microglial responses, lipid metabolism, and synaptic remodeling, while its effects on tau-driven neurodegeneration remain controversial. In Parkinson's disease, stroke, epilepsy, and amyotrophic lateral sclerosis, TREM2 influences α-Syn clearance, inflammatory resolution, tissue repair, and microglial state transitions, but may exert beneficial or maladaptive effects depending on temporal dynamics and disease-specific stressors. Emerging clinical evidence, including TREM2 variants, soluble TREM2 (sTREM2) biomarkers, and human multi-omics studies, highlights both the translational potential and complexity of targeting this pathway. Herein, this review summarizes the molecular mechanisms, physiological functions, and disease-specific roles of TREM2 in CNS disorders, critically discusses unresolved controversies and species-specific challenges, and evaluates emerging therapeutic strategies toward biomarker-guided and stage-specific modulation of TREM2 signaling. Understanding how to restore appropriate microglial adaptability rather than simply enhance or suppress TREM2 activity may provide a foundation for precision therapies in CNS disorders.},
}

Humans
*Microglia/metabolism/immunology
*Receptors, Immunologic/metabolism/genetics/immunology
*Membrane Glycoproteins/metabolism/genetics/immunology
Animals
*Central Nervous System Diseases/metabolism/immunology/therapy
Signal Transduction
*Neuroimmunomodulation

@article {pmid42694660,
year = {2026},
author = {Hur, JY},
title = {Herpes simplex virus infection and Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858017},
pmid = {42694660},
issn = {1663-4365},
abstract = {Over 95% of Alzheimer's disease (AD) is caused by a complex mixture of genetic and environmental factors. This is called sporadic AD or late-onset AD, and much of its pathological mechanisms remain unclear. There is growing evidence indicating that the viral infection, such as herpes simplex virus type 1 (HSV-1), triggers and worsens the AD progression in combination with the APOE4 genotype in AD patients. The innate immunity of host cells produces proinflammatory cytokines, which further drive neuroinflammation in the brain. Concurrently, Aβ and phosphorylated tau could entrap foreign pathogens such as HSV-1 according to the "antimicrobial protection hypothesis of AD," and accelerate the progression of AD. In this review, growing evidence ranging from HSV-1 infection to the AD progression via the accumulation of Aβ and tau, and neuroinflammation is explored.},
}

@article {pmid42694676,
year = {2026},
author = {Chintalapally, S and Rajanala, K and Upadhyay, A},
title = {Retinoic acid-related orphan receptor alpha (RORα) as a candidate multi-pathway target in Alzheimer's disease: mechanisms and therapeutic prospects.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1912268},
pmid = {42694676},
issn = {1662-4548},
abstract = {The development of Alzheimer disease (AD) involves a cluster of pathogenic processes, including amyloid-beta (Aβ) deposition, tau-mediated neurodegeneration, chronic neuroinflammation, oxidative stress (OS), metabolic dysregulation, and disruption of circadian rhythms. Nuclear hormone receptor, Retinoic Acid-Related Orphan Receptor Alpha (RORα) was shown to regulate multiple neuroprotective pathways such as inflammatory signaling (NF-κB suppression), mitochondrial integrity and mitophagy, redox homeostasis [upregulation of glutathione peroxidase 1 (GPX1), and mitochondrial superoxide dismutase 2, (SOD2)], calcium-dependent synaptic architecture [inositol 1,4,5-trisphosphate receptor type 1 (ITPR1), Purkinje cell protein 4 (PCP4)], and circadian rhythm stability [period 2 (PER2), brain and muscle ARNT-like 1 (BMAL1)]. Multi-omics network analyses place RORα within regulatory networks that are co-associated with key AD-related genes and supports an associational, network-based relationship for RORA. Preclinical gene-augmentation studies using adeno-associated viral vectors report that RORα overexpression reduces APP levels, remodels the complement regulator CD59 glycoprotein (CD59), inhibits OS, and enhances neuronal survival, although these effects were established largely in retinal and other non-AD systems. These findings support the potential of RORA as a therapeutic target through genetic intervention, but direct demonstration of AD-modifying efficacy in-vivo is still lacking. Investigational RORA-focused gene therapy in retinal degenerative diseases provides proof-of-concept for, but does not yet establish, applicability within the central nervous system. Taken together, this evidence nominates RORA as a candidate system-level regulator that may help restore disrupted homeostatic transcriptional networks in AD, a hypothesis that remains to be tested. We propose that RORα functions as a transcriptional hub coupling three homeostatic axes that fail in AD; the circadian, mitochondrial-metabolic, and immune-inflammatory axes, and that its regional expression changes in AD (hippocampal up-regulation vs. suprachiasmatic down-regulation) represent a compensatory response that ultimately fails. Cell-type-specific expression profiling is required to determine in which regions augmentation may be therapeutically appropriate. Restoring RORα is therefore could be network-stabilizing rather than single-pathway intervention.},
}

@article {pmid42695218,
year = {2026},
author = {Nakajima, S and Watanabe, K and Sultanakhmetov, G and Fukuchi, A and Ito, K and Shimizu, S and Saito, T and Asada, A and Ando, K},
title = {MARK4 enhances stress granule formation under oxidative stress and increases tau accumulation.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70338},
pmid = {42695218},
issn = {2211-5463},
support = {//Takeda Foundation/ ; 24K02860//Japan Society for the Promotion of Science/ ; JP24wm0625509//Japan Agency for Medical Research and Development/ ; JP25wm0625509//Japan Agency for Medical Research and Development/ ; //Tokyo Metropolitan University/ ; },
abstract = {Overactivation of Microtubule affinity regulating kinase 4 (MARK4) is believed to contribute to Alzheimer's disease pathogenesis. MARK4 promotes the accumulation of the microtubule-binding protein tau, thereby enhancing tau-induced neurodegeneration. However, the underlying mechanisms by which MARK4 enhances tau accumulation are not fully understood. T-cell intracellular antigen 1 (TIA1), a critical regulator of stress granule (SG) formation, has been suggested to initiate tau abnormality. Here, we report that MARK4 and TIA1 synergistically induce stress granule (SG) formation. MARK4 is localized in SGs with TIA1 in mammalian cultured cells and primary neurons. MARK4 suppresses TIA1 dimerization and enhances SG formation under oxidative stress. Co-expression of MARK4 and TIA1 promotes tau accumulation, and knockdown of a fly ortholog of TIA1 suppressed tau toxicity in a Drosophila model. These results identify MARK4 as a novel regulator of SG formation and suggest a mechanistic link between oxidative stress and tau pathology.},
}

@article {pmid42695307,
year = {2026},
author = {Mohammadi, L and Baluchnejadmojarad, T and Roghani, M},
title = {Recent Updates on the Neuroprotective Effects of Nobiletin in Neurological Disorders: From Molecular Targets to Clinical Prospects.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673467257260821042739},
pmid = {42695307},
issn = {1875-533X},
abstract = {BACKGROUND: Neurological disorders are a significant and increasing public health concern due to their multifactorial pathogenesis, progressive clinical course, and limited long-term effectiveness of current therapeutic strategies. Recent experimental and clinical studies have increasingly focused on bioactive natural compounds as potential modulators of neuroinflammation, oxidative stress and neuronal apoptosis - processes that play a central role in neurodegeneration. Of these, nobiletin (a polymethoxylated flavonoid found in citrus peels) has attracted particular attention thanks to its reported antioxidant, anti-inflammatory and neuroprotective properties in preclinical models.

OBJECTIVE: We discuss the potential therapeutic role of nobiletin in neurological diseases, examining the relevant molecular mechanisms, preclinical findings, and emerging clinical data.

METHODS: We searched the electronic databases PubMed, Scopus, and Embase to identify studies examining the therapeutic effects of nobiletin on neurological disorders published up to October 2025.

RESULTS: This review discusses the neuroprotective actions of nobiletin, with particular attention to its anti-inflammatory, anti-apoptotic, and antioxidant activities and their involvement in major intracellular signaling pathways. In addition, available preclinical findings and emerging clinical data are examined to assess the therapeutic relevance of nobiletin in experimental and clinical models of neurological disorders.

DISCUSSION: Experimental evidence suggests that nobiletin has neuroprotective properties that could reduce pathological processes associated with neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. However, further well-designed studies are needed to clarify its mechanisms of action and determine whether these effects are beneficial in clinical practice, either as a standalone therapy or in combination with existing treatments.

CONCLUSION: Overall, the available evidence indicates that nobiletin may have beneficial effects on a wide range of neurological conditions, such as Parkinson's disease, Alzheimer's disease, stroke, epilepsy, depression, schizophrenia, multiple sclerosis, glioma, and sciatic nerve injury.},
}

@article {pmid42695325,
year = {2026},
author = {Tiwari, N and Kumar, V and Joshi, BC and Saeedan, AS and Rashid, S and Ansari, MN},
title = {A Systematic Review of the Vascular and Neuronal Role of L-Carnosine: Mechanistic and Pharmacological Perspectives.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X462604260803095102},
pmid = {42695325},
issn = {1875-6190},
abstract = {INTRODUCTION: L-carnosine is a powerful natural antioxidant found in the brain, muscles, and digestive systems of all vertebrates, including humans, that helps fight Reactive Oxygen Species (ROS) and other harmful byproducts of oxidative stress. L-carnosine has antioxidant properties as well as the ability to bind with metal ions and prevent glycation, a process that can damage cells. This review article highlights the protective effects of L-carnosine against a variety of pathological conditions, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), ischemia‒reperfusion injury, Huntington's disease, stroke, depression, traumatic brain injury, cancer, diabetes, ageing, etc. Among these conditions, mitochondrial dysfunction and increased oxidative stress are common. Moreover, methylglyoxal (MG), another metabolic product, and Advanced Glycation End products (AGEs) damage cells through interactions with proteins. Through receptor-mediated endocytosis, macrophages absorb them and release proinflammatory chemicals that induce severe inflammation and lead to cell death.

METHODS: Search engines, including PubMed, ScienceDirect, ProQuest, Scopus, ResearchGate, MDPI, journals, websites, and databases such as Google Scholar, were thoroughly searched and reviewed. The search strategy for articles published between 2000 and 2025 used various combinations of key Medical Subject Headings (MeSH) terms and phrases, including L-carnosine, alanine, histidine, Randomized Controlled Trial (RCT), aging, cancer, cardiovascular disease, diabetes, and neurodegenerative disorders, and various non-MeSH terms.

RESULTS: L-carnosine exhibits protective effects on models of neurological, ischemic, metabolic, and malignant diseases because of its antioxidant, anti-inflammatory, and neuroprotective properties. In Alzheimer's disease, carnosine specifically increases the production of heat shock proteins (Hsps). In Parkinson's disease, it increases dopamine levels and stops alpha-synuclein protein accumulation. In ischemia‒reperfusion injury, L-carnosine inhibits the release of inflammatory mediators such as cytokines and TNF-alpha. In cancer, it inhibits the Mitogen-Activated Protein Kinase (MAPK)/ Extracellular Signal-Related Kinase (ERK) signaling pathway. It mitigates aging-related damage to proteins. Additionally, L-carnosine inhibits the formation of MG and AGEs, suggesting its potential therapeutic efficacy in a range of diseases.

DISCUSSION: L-carnosine shows multitarget therapeutic potential through antioxidant, anti-inflammatory, and antiglycation actions, as well as mitochondrial protection. It influences key pathways involved in neurodegeneration, including protein aggregation and oxidative stress. Evidence from preclinical and early clinical studies suggests benefits in neurological and metabolic disorders. Despite promising outcomes, challenges such as rapid degradation and limited bioavailability affect clinical translation. Further studies are needed to define the optimal dosing and therapeutic use.

CONCLUSION: L-carnosine acts as a cytoprotective molecule in multiple ways, including mitigating oxidative stress, protein glycation, mitochondrial dysfunction, and inflammation, thereby modulating pathways characteristic of chronic illnesses. By altering these interconnected pathways, L-carnosine has the potential for several therapeutic applications as an adjuvant for a range of neurological, metabolic, ischemic, cancer, and aging-related illnesses.},
}

@article {pmid42683795,
year = {2026},
author = {Moon, Y and Jeon, HJ and Kim, HJ and Noh, MY and Kim, SH and Han, SH and Kim, H and Moon, WJ},
title = {Education Moderates the Biomarker-Cortical-Thickness Relationship in Females With Cognitive Decline: A Descriptive Study With Sex Comparisons.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {5},
pages = {552-559},
doi = {10.3988/jcn.2025.0686},
pmid = {42683795},
issn = {1738-6586},
support = {/KU/Konkuk University/Korea ; },
abstract = {BACKGROUND AND PURPOSE: Education is a well-established proxy for cognitive reserve and hence may influence the relationship between Alzheimer's disease pathology and brain structure. This is particularly relevant in South Korea, where historical sex disparities in educational level among current elderly populations create unique cohort characteristics. This study examined how educational level moderates the biomarker-cortical-thickness relationship in females with cognitive decline, with descriptive sex comparisons used to contextualize these findings within a cohort reflecting disparities in the history of educational opportunities in South Korea.

METHODS: In 80 patients (58 females, 22 males) with cognitive decline, we assessed plasma amyloid-β 42 (Aβ42), phosphorylated tau 181 (p-tau), and total tau levels, p-tau/Aβ42 ratio, regional cortical thickness, and scores on the Mini-Mental State Examination. Given the substantial confounding between sex and educational level in this cohort, moderated mediation analyses examining the biomarker-cortical-thickness-cognition pathway were restricted to females (n=53 with complete data).

RESULTS: Females had a higher p-tau/Aβ42 ratio (p=0.026) and thicker frontal cortex (p=0.049) despite the absence of a significant difference in age-adjusted cognition. No significant sex× educational level interaction was observed for the biomarkers or cognition. In females, educational level moderated the relationship between the p-tau/Aβ42 ratio and cortical thickness (p<0.05 in all five brain regions), with high-educational level females showing the expected cortical thinning with pathology, while low-educational level females exhibited preserved thickness, which did not mediate the cognitive performance.

CONCLUSIONS: Descriptive sex comparisons revealed a higher biomarker burden yet greater cortical thickness in females. Importantly, educational level significantly moderated the biomarker-cortical thickness relationship specifically in females, with lower-educated individuals showing structural preservation despite the presence of pathology. These findings suggest that measurements of the cortical thickness can underestimate the disease burden in lower-educated females, which highlights the need for educational level-stratified interpretations of structural biomarkers.},
}

@article {pmid42683796,
year = {2026},
author = {Yoon, B and Lee, HJ and Hong, YJ and Park, KH and Kim, S and Wang, MJ and Choi, SH and Kang, S and Jeong, JH and Yang, DW},
title = {Comparative Prognostic Performance of Hippocampal Volume and Plasma Biomarkers in Amyloid-Negative Subjective Cognitive Decline: A Four-Year Follow-up.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {5},
pages = {560-572},
doi = {10.3988/jcn.2025.0659},
pmid = {42683796},
issn = {1738-6586},
support = {P0018061/KIAT/Korea Institute for Advancement of Technology/Korea ; HI18C0530/MOHW/Ministry of Health and Welfare/Korea ; },
abstract = {BACKGROUND AND PURPOSE: Subjective cognitive decline (SCD) may precede mild cognitive impairment (MCI) and dementia. However, the prognosis of patients with amyloid-negative (A-) SCD remains unclear. We investigated whether baseline plasma and imaging biomarkers predict four-year clinical progression in A-SCD.

METHODS: Sixty-five individuals with A-SCD were followed for four years. Baseline plasma biomarkers-phosphorylated tau 181 (pTau181), glial fibrillary acidic protein, neurofilament light chain (NfL), and pTau181/Aβ42 ratio-and MRI markers (hippocampal volume and white matter hyperintensity [WMH] grade) were assessed. Outcomes included MCI conversion and cognitive progression defined as ≥1-point (Prog-1) or ≥2-point (Prog-2) decline in Korean Mini-Mental State Examination. Predictive performance was evaluated using multivariable logistic regression and bootstrap-validated receiver operating characteristic analyses.

RESULTS: Fourteen participants (21.5%) converted to MCI, and 24 (36.9%) were classified as Prog-1. Plasma biomarkers did not show consistent predictive performance across predefined endpoints (all p>0.05), although NfL demonstrated modest discrimination for MCI conversion (area under the curve [AUC] 0.686, p=0.008). Hippocampal volume demonstrated significant discriminative performance for MCI conversion (AUC 0.765, p=0.016) and Prog-1 (AUC 0.933, p<0.001). For Prog-2, hippocampal volume showed high discrimination (AUC 0.952, p<0.001). WMH grade also demonstrated significant discrimination for MCI conversion (AUC 0.835, p<0.001) and Prog-1 (AUC 0.857, p<0.001). Bootstrap analyses (1,000 iterations) tended to show higher AUC estimates for imaging markers compared with plasma biomarkers.

CONCLUSIONS: In this A-SCD cohort, hippocampal atrophy demonstrated more consistent prognostic performance than Alzheimer's disease-focused plasma biomarkers for predicting four-year conversion to MCI and cognitive decline, suggesting a potential role for MRI-based neurodegeneration markers in clinical risk stratification.},
}

@article {pmid42683825,
year = {2026},
author = {El-Shiekh, RA and Mandour, AA and Abdel-Sattar, E and Ali, NB},
title = {Phytochemical profiling of Olea europaea subsp. cuspidata aerial parts using LC-DAD-QToF: cholinesterase inhibition and molecular docking insights into potential Alzheimer's disease targets.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/14786419.2026.2727544},
pmid = {42683825},
issn = {1478-6427},
abstract = {Olea europaea subsp. cuspidata is traditionally used in African medicine, but its phytochemical composition and cholinesterase inhibitory activity have not been comprehensively investigated. This study evaluated the cholinesterase inhibitory activity and phytochemical profile of the methanolic extract of O. europaea aerial parts, integrating in vitro assays with LC-DAD-QToF-MS characterisation and molecular modelling. We used the Ellman assay to measure cholinesterase inhibition and LC-DAD-QToF-MS for metabolite profiling, while molecular docking and dynamics simulations helped us understand how specific metabolites interact with human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extract inhibited AChE (IC50 = 15.99 ± 1.62 μg/mL) to a greater extent than BChE (IC50 = 22.62 ± 2.20 μg/mL). LC-DAD-QToF-MS allowed the tentative identification of 65 metabolites, comprising iridoids, phenylethanoids, flavonoids, phenolic acids, terpenoids, fatty acids, and one alkaloid. Computational predictions support potential interactions only between constituents within the enzyme active sites but do not establish biological activity. These results offer the first detailed phytochemical profile of the aerial parts of O. europaea and confirm its in vitro cholinesterase inhibitory activity. Bioactivity-guided isolation and in vivo studies are required to pinpoint the metabolites responsible for the observed effects and to establish their therapeutic relevance.},
}

@article {pmid42683892,
year = {2026},
author = {Han, P and Dong, P and Zhou, Y and Zhang, L and Mahomed, O},
title = {Stage-Dependent Cognitive Effects of a Multinutrient Intervention in Alzheimer's Disease: A Stage-Stratified Meta-Analysis.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {235},
pages = {},
doi = {10.3791/72385},
pmid = {42683892},
issn = {1940-087X},
mesh = {*Alzheimer Disease/therapy/psychology ; Humans ; Randomized Controlled Trials as Topic ; Cognition ; },
abstract = {A specific multinutrient intervention provides precursors and cofactors for synaptic membrane synthesis. Randomized trials across the Alzheimer's disease (AD) continuum have reported mixed findings. We conducted a systematic review and stage-stratified meta-analysis of randomized, placebo-controlled trials. MEDLINE, Embase, CENTRAL, Web of Science, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform were searched through February 28, 2026. Disease stage was prespecified as an effect modifier. Standardized mean differences (SMDs; Hedges' g) were synthesized using restricted maximum likelihood random-effects models. Four trials met the inclusion criteria; three contributed to the quantitative synthesis (analyzed n = 906). Souvenir I was retained for qualitative synthesis because its distinct co-primary outcomes and reporting did not permit a compatible SMD for the prespecified pooled analysis. The exploratory pooled cognitive effect was small and not significant (SMD = 0.08; 95% CI, -0.09 to 0.26; p = 0.35; I[2] = 41.8%). For biomarker-confirmed prodromal AD, the 24-month primary neuropsychological test battery (NTB) 5-item composite endpoint showed a small, nonsignificant effect (SMD = 0.16; 95% CI, -0.08 to 0.41; original trial p = 0.166). The primary NTB memory endpoint in mild, drug-naive AD showed a small effect (SMD = 0.21; 95% CI, -0.06 to 0.49; original longitudinal-model p = 0.023), whereas the primary Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) endpoint in treated mild-to-moderate AD showed no benefit (SMD = -0.06; 95% CI, -0.25 to 0.13; p = 0.513). At 36 months, the LipiDiDiet extension reported significant differences in the NTB 5-item composite, clinical dementia rating - sum of boxes (CDR-SB), memory, and brain-volume outcomes. The intervention was well tolerated. The evidence is compatible with a potential early-stage signal, but the small evidence base, lack of replication across stages, and manufacturer sponsorship warrant cautious interpretation.},
}

*Alzheimer Disease/therapy/psychology
Humans
Randomized Controlled Trials as Topic
Cognition

@article {pmid42683894,
year = {2026},
author = {Agnello, L and Pilotto, A and Gaetani, L and Bellomo, G and Bessi, V and Bozzali, M and Cagnin, A and Labate, A and Massa, F and Moda, F and Monastero, R and Musso, G and Piccoli, T and Sancesario, G and Parnetti, L and Padovani, A and Ciaccio, M},
title = {Toward harmonized reporting of Alzheimer's disease biomarkers in clinical practice.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42683894},
issn = {1437-4331},
abstract = {Cerebrospinal fluid biomarkers, and more recently blood-based biomarkers, are playing a pivotal role in reshaping the clinical management of neurodegenerative diseases, supporting early detection, biological diagnosis, patient stratification, prognostic assessment, therapeutic decision-making, and longitudinal disease monitoring. To effectively support clinical decision-making, biomarker measurements must be communicated in a standardized, transparent, and clinically interpretable manner. Despite international quality standards, considerable heterogeneity persists in reporting practices, including differences in terminology, units of measurement, analytical descriptions, reference frameworks, and interpretative comments, limiting comparability across laboratories and potentially affecting clinical decision-making. In this article, we discuss the principles of harmonized reporting for Alzheimer's disease biomarkers and propose a structured framework for standardized clinical neurochemistry reports. We describe the essential components of a harmonized report, including report identification, analytical information, specification of analytical method and platform, standardized units of measurement, appropriate use of reference intervals and clinical decision thresholds, documentation of pre-analytical and quality-related factors, and evidence-based interpretative comments. We further discuss the importance of structured multimarker interpretation and the need to contextualize biomarker findings within the clinical scenario. Finally, we examine the role of harmonized reporting in promoting interoperability across healthcare systems, facilitating longitudinal patient monitoring, supporting electronic health records and standardized terminologies, and enabling artificial intelligence-driven clinical decision support. As neurodegenerative disease diagnostics continue to evolve and novel biomarkers and technologies emerge, harmonized reporting should be regarded as a critical component of laboratory quality, ensuring that analytical advances translate into consistent, clinically meaningful, and interoperable information that ultimately improves patient care.},
}

@article {pmid42683906,
year = {2026},
author = {Luca, A and Luca, M and Olgiati, P and Ferri, R and Perry, G and Serretti, A},
title = {Neuropsychiatric characteristics of capgras syndrome in Alzheimer's disease in the CATIE-AD.},
journal = {International journal of psychiatry in clinical practice},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/13651501.2026.2724972},
pmid = {42683906},
issn = {1471-1788},
abstract = {INTRODUCTION: Capgras syndrome (CS) is a recurrent and transient delusional misidentification disorder in which an individual is firmly convinced that a familiar person has been replaced by an identical impostor. The aim of the study was to evaluate neuropsychiatric characteristics of CS in a cohort of patients with Alzheimer's disease (AD).

METHODS: 150 participants [84 (56.0%) women, mean age 77.4 ± 7.5 years)] were collected within the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer disease (CATIE-AD). According to the Neuropsychiatric Inventory, patients were classified into Capgras[+] and Capgras[-].

RESULTS: Fifty-five (36.7%) AD patients were Capgras[+]. CS was strongly associated with other misidentification syndromes including phantom boarder (p < 0.001) and misidentification of places (p < 0.001). Moreover, Capgras[+] were presented more frequently with agitation (p = 0.036), depressive (p = 0.018) and anxious (p = 0.004) symptoms, and aberrant motor behaviours (p = 0.020).

CONCLUSIONS: According to our findings, CS was not an 'isolated' phenomenon but rather a complex neuropsychiatric syndrome frequently associated with other misidentification syndromes and specific behavioural disturbances.},
}

@article {pmid42684699,
year = {2026},
author = {Aaronson, A and Nosek, SB and Abdolmohammadi, B and Hadley, J and Labonte, J and Uretsky, M and Mosaheb, S and Nowinski, CJ and Altaras, C and Asken, BM and Banks, SJ and Barr, WB and Dams-O'Connor, K and Hromas, G and Ly, MT and Wethe, JV and Martin, BM and Palmisano, JN and Stern, RA and Tripodis, Y and Stein, TD and McKee, AC and Mez, J and Alosco, ML},
title = {Neuropsychological Profile of Autopsy-Confirmed Chronic Traumatic Encephalopathy.},
journal = {JAMA network open},
volume = {9},
number = {9},
pages = {e2631754},
pmid = {42684699},
issn = {2574-3805},
mesh = {Humans ; *Chronic Traumatic Encephalopathy/diagnosis/pathology/psychology/physiopathology ; Male ; Retrospective Studies ; *Neuropsychological Tests ; Autopsy ; Middle Aged ; Aged ; *Football/injuries ; Female ; Brain/pathology ; tau Proteins/metabolism ; },
abstract = {IMPORTANCE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact exposure. CTE can only be diagnosed post mortem, and the antemortem neuropsychological profile is poorly understood, hindering accurate diagnosis before death.

OBJECTIVE: To characterize antemortem neuropsychological test performance of former National Football League (NFL) players with autopsy-confirmed CTE.

This retrospective case series included former NFL players who completed an antemortem neuropsychological evaluation and had autopsy-confirmed CTE. Data were collected between January 1, 2017, and April 30, 2025. Statistical analysis was performed from September 2025 to June 2026.

EXPOSURE: CTE neuropathology, defined by the National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus panel.

MAIN OUTCOMES AND MEASURES: Neuropsychological test performance, neuropathologic diagnoses, and semiquantitative phosphorylated tau (p-tau) pathology across 11 brain regions were examined. Raw scores were converted to z scores using age, sex, and/or education level-based normative data. Test results with z scores of -1.5 or less were categorized as impaired; domains with 2 or more impaired test results were considered impaired.

RESULTS: The primary analytic sample included 33 men (mean [SD] age at death, 65.4 [13.3] years; mean [SD] time between testing and death, 2.4 [1.6] years), 25 with high- and 8 with low-stage CTE. Learning and memory was most impaired (17 of 27 [63.0%]), followed by executive function (15 of 29 [51.7%]) and language (12 of 29 [41.4%]). High-stage CTE participants generally had worse scores than low-stage CTE participants. Greater global p-tau burden was associated with worse learning and memory performance (B = -0.40; 95% CI, -0.70 to -0.09; P = .01). Findings were similar after excluding 9 participants with co-occurring Alzheimer disease or frontotemporal lobar degeneration tau.

CONCLUSIONS AND RELEVANCE: In this retrospective case series of NFL players with autopsy-confirmed CTE, memory, executive function, and language impairments were common, and p-tau burden was associated with worse memory performance. Findings provide insight into the expected CTE neuropsychological profile and may help advance diagnosis before death.},
}

Humans
*Chronic Traumatic Encephalopathy/diagnosis/pathology/psychology/physiopathology
Male
Retrospective Studies
*Neuropsychological Tests
Autopsy
Middle Aged
Aged
*Football/injuries
Female
Brain/pathology
tau Proteins/metabolism

@article {pmid42684813,
year = {2026},
author = {Unger, RH and Rohatgi, S and Ferraciolli, SF and Kako, B and Omid-Fard, N and Imbett, REM and Dowling, T and Zhu, S and Romero, JM and Ford, JN},
title = {Real-World Challenges in the MRI Detection and Classification of Amyloid-Related Imaging Abnormalities.},
journal = {AJR. American journal of roentgenology},
volume = {},
number = {},
pages = {},
doi = {10.2214/AJR.26.35478},
pmid = {42684813},
issn = {1546-3141},
abstract = {Anti-amyloid monoclonal antibody therapies (AATs) are increasingly used for the treatment of early symptomatic Alzheimer disease. Safe implementation of AATs relies on accurate assessment for exclusionary findings on baseline brain MRI and reliable longitudinal detection of amyloid-related imaging abnormalities (ARIA), including ARIA-H (hemosiderin or hemorrhage) and ARIA-E (edema or effusion). In routine clinical practice, MRI findings encountered during baseline screening and ARIA surveillance sometimes fall into borderline or ambiguous categories that do not clearly conform to trial-defined criteria. For example, subtle or artifactual FLAIR signal abnormality, equivocal microhemorrhage counts, and overlapping features of ARIA-E and ARIA-H can create uncertainty with direct implications for treatment management. Given limited practical guidance addressing these and other gray zones, this imaging-focused review synthesizes common interpretive challenges encountered in a high-volume AAT program and offers practical management-oriented recommendations. Key issues addressed include recognizing technical factors that affect interpretation of susceptibility-weighted and FLAIR images, managing variability in lesion detection across serial examinations, and accurately reporting the temporal evolution of ARIA-related findings. As AAT use expands, recognition of the presented pitfalls can improve diagnostic confidence and help avoid misclassification of findings that may influence therapeutic decisions.},
}

@article {pmid42684942,
year = {2026},
author = {Huang, D and Zhang, Z and Gong, X},
title = {Context-dependent roles of osteopontin in aging-related neurological disorders.},
journal = {The Journal of international medical research},
volume = {54},
number = {9},
pages = {3000605261476190},
pmid = {42684942},
issn = {1473-2300},
mesh = {Humans ; *Osteopontin/metabolism ; *Aging/pathology/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Brain/pathology/metabolism ; Alzheimer Disease ; Microglia/metabolism ; },
abstract = {Osteopontin (encoded by secreted phosphoprotein 1) is a multifunctional matricellular phosphoglycoprotein that has emerged as an important mediator in the aging nervous system. During aging, osteopontin interacts with microglial priming, vascular remodeling, myelin repair, and innate immune responses and is consistently implicated in major late-life neurological disorders. However, its biological effects are highly context dependent. Depending on its cellular source, proteolytic processing, receptor interactions, anatomical distribution, and disease stage, osteopontin may either exacerbate chronic neuroinflammation and tissue injury or promote phagocytic clearance, neuronal survival, remyelination, neuroplasticity, and tissue repair. This review critically synthesizes studies indexed in PubMed and Google Scholar through 3 April 2026 on the role of osteopontin in brain aging, Alzheimer's disease and related dementias, Parkinson's disease and Lewy body disorders, cerebrovascular disease, vascular cognitive impairment, cerebral small vessel disease, and amyotrophic lateral sclerosis. In Alzheimer's disease, cerebrospinal fluid and plasma osteopontin concentrations increase from the prodromal to symptomatic stages, whereas microglial or perivascular secreted phosphoprotein 1 expression correlates with amyloid pathology, synaptic remodeling, and cognitive decline. However, under specific conditions, osteopontin also enhances macrophage-mediated amyloid-beta clearance. In stroke, elevated circulating osteopontin predicts poor clinical outcomes, whereas experimental studies demonstrate that appropriately timed exogenous osteopontin, regulatory T cell-derived osteopontin, and osteopontin-mediated autophagic and reparative pathways promote white-matter repair, peri-infarct plasticity, and blood-brain barrier integrity. Evidence from Parkinson's disease, Lewy body disease, frontotemporal dementia, and amyotrophic lateral sclerosis further supports the role of osteopontin as both a candidate biomarker and a regulator of selective neuronal vulnerability. Rather than being uniformly detrimental or protective, osteopontin should be regarded as a context-dependent regulator of age-related neuroimmune remodeling. This perspective reconciles seemingly conflicting findings and supports the development of therapeutic strategies that are tailored to disease stage, protein fragment, and cell type rather than broadly targeting osteopontin.},
}

Humans
*Osteopontin/metabolism
*Aging/pathology/metabolism
Animals
*Nervous System Diseases/metabolism/pathology
Brain/pathology/metabolism
Alzheimer Disease
Microglia/metabolism

@article {pmid42684969,
year = {2026},
author = {Chen, L and Xiao, L and Li, Y},
title = {Multi-trajectories of activity participation and risk of mild cognitive impairment in China: A national longitudinal cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483186},
doi = {10.1177/13872877261483186},
pmid = {42684969},
issn = {1875-8908},
abstract = {BackgroundEngagement in physical, social, and intellectual activities is associated with cognitive health in later life, but how their long-term combinations relate to mild cognitive impairment (MCI), a key preclinical stage of Alzheimer's disease, remains unclear.ObjectiveTo identify multi-activity trajectories and examine their associations with MCI.MethodsData were from the China Health and Retirement Longitudinal Study (CHARLS), a nationally representative biennial survey collecting demographic, socioeconomic, health, cognitive, and activity-related information. We included 1884 participants aged ≥60 years in 2020. Group-based multi-trajectory modeling identified physical, social, and intellectual activity patterns using the 2011, 2013, 2015, and 2018 waves. Multivariable logistic regression examined associations with MCI in 2020, with subgroup analyses by sex, baseline age, education, and residence.ResultsFour distinct trajectory groups were identified: Moderate PA-low SI (social and intellectual activity), High PA-low SI, Moderate PA-higher SI, and High PA-moderate SI. The Moderate PA-higher SI group had the lowest MCI prevalence (9.47%) and served as the reference. In the fully adjusted model, MCI odds were highest in the High PA-low SI group (OR = 2.05, 95% CI: 1.34-3.15), followed by the Moderate PA-low SI group (OR = 1.57, 95% CI: 1.08-2.30). The High PA-moderate SI group was not significantly associated with MCI (OR = 1.38, 95% CI: 0.72-2.58).ConclusionsModerate physical activity combined with higher social and intellectual engagement was associated with more favorable cognitive outcomes, supporting integrated, pattern-based lifestyle strategies for early prevention of MCI and Alzheimer's disease.},
}