@article {pmid42973348,
year = {2026},
author = {Aziz, N and Sachan, K and Singh, A and Srivastava, S and Wal, P and Gupta, R and Sharma, KK and Gasmi, A},
title = {AI-integrated Approaches in Alzheimer's Disease: Linking Molecular Pathways, Biomarkers, and Emerging Therapies.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501504715261014100550},
pmid = {42973348},
issn = {1873-5592},
abstract = {OBJECTIVE: Alzheimer's disease (AD) continues to be the leading cause of dementia worldwide, due to its complicated, multifactorial pathophysiology. To shift the AD paradigm from reactive to proactive, from a specific time to a precision medicine intervention strategy, this study examines the role of artificial intelligence (AI) as a potential linking point for multi-omics data, new fluid biomarkers, and developing medicines.

METHODS: A thorough search was conducted in clinical trial registries (ClinicalTrials.gov) and peerreviewed literature (PubMed, Scopus). Without going too far into detail, this study discussed novel anti-amyloid/anti-tau monoclonal antibody treatments, blood biomarkers (p-tau217, p-tau181), and machine learning approaches for early diagnostic classification and for prediction modelling.

RESULTS: Recent breakthroughs in understanding that different disease-modifying treatments, such as lecanemab and donanemab, can stop cognitive decline by targeting specific types of disease-causing aggregates have greatly shortened diagnostic time through blood-based diagnostic markers. Importantly, AI systems (e.g., structural MRI and multi-omics-based panels analyzed using Deep Learning architectures) can predict conversion from Mild Cognitive Impairment (MCI) to overt AD more than a year before the onset of clinical symptoms, with accuracy exceeding 90%. Sensitivity of real-world trials is significantly enhanced by the use of Digital Biomarkers and remote cognitive monitoring.

DISCUSSION: As a tool, AI is not discrete but serves as a coherent framework that can progressively connect data from different biological systems (e.g., upstream molecular events such as amyloid cascades, tauopathy, neuroinflammation) with downstream clinical events (phenotypes). The lack of standardized datasets across different ethnic groups, algorithm interpretability (the "black box" problem), and possible regulatory validation, however, is now preventing the full clinical translation.

CONCLUSION: With insulin injections, or even just the excitement of a new drug, the world of AD research is transformed. The multimodal AI frameworks provide clinicians with ways to treat patients with highly personalized, multi-targeted treatment strategies to capture AD pathology at its asymptomatic early stage, by simultaneously computing genetic risk, neuroimaging features, and plasma biomarker levels.},
}

@article {pmid42973365,
year = {2026},
author = {Chao, C and Lihua, G and Yan, C and Yujian, Z and Chunying, Z and Yazhen, S},
title = {Bioinformatics-Guided Scutellaria Flavonoids Ameliorate Memory Impairment Induced by Ovariectomy and D-Galactose in Rats.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073490811261002051328},
pmid = {42973365},
issn = {1875-5402},
abstract = {INTRODUCTION: This study aimed to explore the protective effects of flavonoids extracted from the stems and leaves of Scutellaria baicalensis (SSFs) against memory deficits in rats induced by combined ovariectomy and D-galactose treatment, as well as the underlying regulatory mechanisms linked to apoptosis-related molecules, estrogen receptors, and Paired Helical Filaments (PHFs).

METHODS: Comprehensive bioinformatic analysis was performed to screen Alzheimer's Disease (AD)- related Differentially Expressed Genes (DEGs) and conduct functional pathway enrichment analysis. An estrogen-deficient menopausal-like rat model-associated memory impairment was established via ovariectomy combined with D-galactose administration, and the Morris Water Maze (MWM) assay was used to verify model establishment. Rats with successful model induction were randomly divided into a model group and three SSF treatment groups with distinct doses. The learning and memory capacities of rats were assessed using the MWM. Immunohistochemistry was used to detect the protein expression of 5- Bromo-2'-deoxyuridine (BrdU). Quantitative real-time Polymerase Chain Reaction (qPCR) was used to quantify the mRNA level of BCLAF1. Western Blotting (WB) was applied to measure the protein levels of Estrogen Receptor α (ERα), Estrogen Receptor β (ERβ), the anti-apoptotic protein Bcl-2, BCLAF1, non-phosphorylated tau, and PHFs in the cerebral cortex and hippocampus.

RESULTS: Bioinformatic analysis identified 13 AD‑related DEGs along with their enriched functional pathways. Combined ovariectomy and D‑galactose treatment induced severe memory impairment in rats (P < 0.01), accompanied by a prominent decrease in BrdU‑positive cells in the hippocampal dentate gyrus (P < 0.01). In the cerebral cortex and hippocampus of model rats, the mRNA and protein expression of BCLAF1, as well as protein levels of ERα and PHFs, were significantly upregulated (P < 0.05, P < 0.01). By contrast, the expression of ERβ, Bcl‑2 and non- phosphorylated tau was markedly downregulated (P < 0.05, P < 0.01). SSFs dose- dependently ameliorated the above behavioral and molecular abnormalities triggered by ovariectomy plus D- galactose.

DISCUSSION: Our bioinformatic analysis identified 13 Alzheimer's disease-related differentially expressed genes, mainly enriched in ion-channel- and GABA-receptor-associated pathways, providing potential molecular clues for postmenopausal cognitive impairment. The ovariectomy-combined-Dgalactose rat model partially recapitulates postmenopausal AD‑like neuropathological changes and serves as a practical in vivo tool for evaluating natural phytoestrogen‑like candidates. SSFs exerted multi‑target neuroprotection by modulating neuronal proliferation, estrogen receptor balance, neuronal apoptosis and tau‑related pathology. Nevertheless, this animal model cannot fully recapitulate complete Alzheimer's‑disease hallmarks such as mature senile plaques. Moreover, the direct molecular targets of SSFs remain uncharacterized, warranting further mechanistic exploration. Collectively, our findings support that SSFs is a promising natural agent against postmenopausal memory decline.

CONCLUSION: SSFs effectively ameliorate memory impairment in rats induced by ovariectomy combined with D-galactose. The therapeutic mechanism may involve the regulation of SSFs on BrdU, ERα/ERβ, Bcl-2/BCLAF1, and non-phosphorylated tau levels, and PHFs formation. These results suggested that SSFs ameliorate memory impairment through neuronal proliferation, estrogen signaling, neuronal apoptosis, and tau pathology, supporting its use for postmenopausal cognitive decline.},
}

@article {pmid42973818,
year = {2026},
author = {Fernández-Romero, L and Delgado-Alonso, C and Grasso, SM and Cabrera-Martín, MN and Balugo, P and Fraile-Pereda, A and Suárez-Coalla, P and Barroso, Y and Oliver-Mas, S and Matias-Guiu, J and Olazarán, J and Díez-Cirarda, M and Matias-Guiu, JA},
title = {Predictors of 6-month clinical change in primary progressive aphasia following language therapy and transcranial magnetic stimulation.},
journal = {Brain communications},
volume = {8},
number = {6},
pages = {fcag398},
pmid = {42973818},
issn = {2632-1297},
abstract = {Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by progressive language impairment. Available treatments and information on factors associated with clinical change and treatment response remain limited. This study is a post hoc analysis of a randomized controlled trial and aimed to identify baseline demographic, cognitive and neuroimaging factors associated with clinical change in a subanalysis of a double-blind, randomized, parallel clinical trial of transcranial magnetic stimulation (TMS) and language therapy in PPA. Fifty-seven patients diagnosed with PPA received 6 months of lexical retrieval treatment, 40 with active TMS and 17 with sham TMS. All participants underwent comprehensive cognitive and language assessments before treatment and were evaluated using the Mini Linguistic State Examination (MLSE), naming task, words per minute, the Interview for Deterioration in Daily Living Activities in Dementia (IDDD), the Neuropsychiatric Inventory (NPI) and fluorodeoxyglucose-PET scans before and after treatment. Predictors of clinical change were analysed using least absolute shrinkage and selection operator (LASSO) and Elastic Net regression models, and unsupervised k-means clustering was applied to identify response profiles. Models for MLSE (LASSO: R2 = 0.52; Elastic Net: R [2] = 0.57), naming (LASSO: R [2] = 0.42; Elastic Net: R [2] = 0.41), IDDD (LASSO: R [2] = 0.46; Elastic Net: R [2] = 0.58) and NPI (LASSO: R [2] = 0.81; Elastic Net: R [2] = 0.77) demonstrated good predictive accuracy. TMS treatment consistently emerged as the strongest predictor of clinical improvement across all outcomes. Higher metabolism in several brain regions (left hippocampus, posterior cingulate and orbitofrontal cortex) predicted greater clinical improvement. Cluster analysis identified two subgroups: responders and non-responders, with 77.5% of patients receiving active TMS in the responder cluster and 82.4% of the sham group in the non-responder cluster. Among patients receiving active TMS, a positive effect was associated with the non-fluent and semantic variants and with better cognitive performance in non-language domains. In conclusion, TMS treatment emerged as the main factor associated with clinical improvement on cognitive-linguistic and functional measures. Better cognitive performance and preserved brain metabolism in key regions were linked to more favourable clinical outcomes. These findings underscore the potential of TMS in combination with language therapy and pave the way for precision medicine approaches in PPA, emphasizing the need to identify individual profiles that predict optimal treatment response.},
}

@article {pmid42973868,
year = {2026},
author = {Tong, W},
title = {Physical exercise: a multi-target strategy for the prevention and treatment of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1876075},
pmid = {42973868},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease characterized by irreversible cognitive dysfunction and neuronal loss. The complex pathogenesis of AD involves core proteinopathies of amyloid-β (Aβ) and tau, chronic neuroinflammation, and extensive cerebral metabolic disorders, which collectively drive progressive neuronal damage and disease deterioration. Currently, effective disease-modifying drugs for AD are still lacking, and physical exercise has been recognized as a safe and effective non-pharmacological intervention to prevent and alleviate AD pathological progression. Specifically, exercise inhibits abnormal Aβ deposition and tau hyperphosphorylation, suppresses microglial overactivation and sustained neuroinflammatory responses, and remodels cerebral metabolic homeostasis by improving glucose utilization, balancing lactate metabolism, restoring mitochondrial function, and correcting dysregulated lipid metabolism. Additionally, exercise-mediated upregulation of brain-derived neurotrophic factor (BDNF) enhances neuronal survival and synaptic plasticity to block AD pathological progression. This review innovatively combines core AD pathological markers and multi-dimensional metabolic mechanisms, providing a theoretical reference for further exploring the molecular mechanism of exercise intervention in AD.},
}

@article {pmid42974248,
year = {2026},
author = {Zhang, Y and Wang, L and Wei, J and Shuzan, N and Zheng, J},
title = {Cancer-Alzheimer inverse comorbidity from epidemiology to protein self-assembly.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1992522},
pmid = {42974248},
issn = {1664-2392},
mesh = {Humans ; *Alzheimer Disease/epidemiology/metabolism ; *Neoplasms/epidemiology/metabolism ; Comorbidity ; Animals ; },
abstract = {Cancer and Alzheimer's disease (AD) are common age-associated disorders characterized by contrasting cellular outcomes, yet epidemiological studies repeatedly report an apparent, modest bidirectional inverse association between cancer and dementia, including AD. This Mini Review examines the extent to which this pattern reflects biological antagonism versus competing mortality, diagnostic bias, survivor selection, and treatment exposure. Breast and prostate cancers are considered as endocrine models because estrogen- and androgen-receptor signaling supports tumor growth while also regulating neuronal metabolism, mitochondrial function, vascular homeostasis, and inflammation. Population studies show heterogeneous neurological associations for breast cancer hormone-modulating therapy and prostate cancer androgen-deprivation therapy, emphasizing the need to distinguish tumor biology from systemic endocrine treatment. Mechanistically, cancer and AD engage overlapping metabolic pathways, including insulin/IGF-PI3K-AKT, mTOR, and AMPK; cell-fate programs involving cell-cycle control and senescence; and proteostatic systems involving molecular chaperones and autophagy-lysosomal function. These networks produce divergent outcomes: proliferative and proteotoxic adaptation in tumors versus energetic failure, impaired proteostasis, and neuronal degeneration in AD. Protein self-assembly provides an additional, context-dependent connection: amyloidogenic proteins can modify cancer-cell fitness, while recent preclinical evidence identifies a tumor-derived cystatin C-TREM2 pathway that enhances cerebral Aβ clearance. Whether these mechanisms contribute to human cancer-AD inverse comorbidity remains unproven. The observed cancer-AD inverse comorbidity therefore likely reflects interacting epidemiological, endocrine, metabolic, proteostatic, and protein-assembly mechanisms rather than a single causal pathway. Treatment-aware longitudinal studies incorporating AD biomarkers and physiologically relevant models are needed to distinguish genuine biological antagonism from observational bias.},
}

Humans
*Alzheimer Disease/epidemiology/metabolism
*Neoplasms/epidemiology/metabolism
Comorbidity
Animals

@article {pmid42975704,
year = {2026},
author = {Gauttier, V and Coupet, CA and Trilleaud, C and Girault, I and Morello, A},
title = {Emerging GPCR Agonist-Based Therapies to Trigger the Resolution of Inflammation.},
journal = {Current topics in microbiology and immunology},
volume = {},
number = {},
pages = {},
doi = {10.1007/82_2026_352},
pmid = {42975704},
issn = {0070-217X},
abstract = {The long-lasting paradigm that inflammation resolves through a passive decline of pro-inflammatory signals has been fundamentally revised by extensive research demonstrating that the resolution of inflammation is an active, programmed, and tightly regulated process driven by a temporally coordinated sequence of molecular and cellular events for restoring tissue homeostasis. Under physiological conditions, specialized lipid pro-resolving mediators (SPMs), as well as some pro-resolving proteins and peptides, initiate the resolution of inflammation process by halting pro-inflammatory immune cell recruitment, clearance of effector cells and cellular inflammatory debris, tissue repair, and restoration of local immunity. Clinical and experimental observations indicate that failure to activate this endogenous pro-resolving program or alteration of SPM synthesis leads to persistent inflammatory activity, contributing to chronic diseases such as arthritis, Alzheimer's disease, cancer, and inflammatory bowel disorders through excessive neutrophil infiltration, impaired efferocytosis, and unresolved tissue damage. Advances in the understanding of SPMs, their biology, and their mechanisms have driven the development of new therapeutic molecules mimicking the activity of endogenous pro-resolving lipids or pro-resolutive proteins and derivatives. Multiple classes of molecules, including stabilized lipid analogs, peptides, and agonist antibodies, have shown promising preclinical activity, particularly through ChemR23 (gene CMKLR1) and formyl peptide receptor 2 (FPR2) targeting. Ongoing and completed phase I/II clinical trials report encouraging results in conditions such as eczema and ocular diseases, with favorable safety profiles. Unlike traditional anti-inflammatory strategies, these approaches engage a natural physiological program rather than inhibiting or depleting inflammatory pathways, aiming to establish long-term tissue homeostasis without compromising the immune system. Emerging pro-resolutive G protein-coupled receptor (GPCR) therapies are designed for enhanced target specificity, biodistribution, and specific pro-resolutive signaling for sustained efficacy. Targeting pro-resolving GPCRs holds strong potential to redefine the treatment of inflammatory diseases by promoting the active reinstatement of immune balance and homeostasis.},
}

@article {pmid42976263,
year = {2026},
author = {Kverno, K},
title = {Dextromethorphan as a Potentially Safer Treatment for Agitation Associated With Dementia Due to Alzheimer's Disease.},
journal = {Journal of psychosocial nursing and mental health services},
volume = {64},
number = {11},
pages = {6-8},
doi = {10.3928/02793695-20260921-01},
pmid = {42976263},
issn = {0279-3695},
mesh = {Humans ; *Dextromethorphan/therapeutic use ; *Alzheimer Disease/complications/drug therapy ; *Psychomotor Agitation/drug therapy/etiology ; Aged ; },
abstract = {Agitation associated with dementia due to Alzheimer's disease can present safety issues for older adults, potentially leading to dangerous or harmful behaviors and escalating emotional distress. The burden of persistent or severe agitation on caregivers is one of the primary reasons for hospitalization or institutionalization of persons living with dementia. Treating agitation with sedatives or antipsychotics can further reduce cognitive functioning, safety, and quality of life. The combination antidepressant drug dextromethorphan-bupropion (Auvelity) was repurposed by the U.S. Food and Drug Administration in 2026 for treatment of agitation in dementia due to Alzheimer's disease, and appears to be a safe and effective alternative.},
}

Humans
*Dextromethorphan/therapeutic use
*Alzheimer Disease/complications/drug therapy
*Psychomotor Agitation/drug therapy/etiology
Aged

@article {pmid42976683,
year = {2026},
author = {Maher, A and England, A and McEntee, M and O'Donovan, T and Devine, A and Albeshan, SM and Elhaie, M},
title = {Assessing the perspectives of radiation therapists on managing dementia in radiotherapy: An international qualitative study.},
journal = {Journal of medical imaging and radiation sciences},
volume = {58},
number = {1},
pages = {102611},
doi = {10.1016/j.jmir.2026.102611},
pmid = {42976683},
issn = {1876-7982},
abstract = {BACKGROUND: The incidence of dementia and cancer increases with age, creating additional challenges for cancer services as populations age and life expectancy rises. Radiotherapy is a cornerstone of cancer treatment and should remain accessible through patient-centred care. Understanding registered radiation therapists' (RRTs) knowledge, attitudes, and perceptions regarding patients with dementia is therefore important for equitable service provision.

AIM: To evaluate dementia-related knowledge, attitudes, and perceptions among registered radiation therapists (RRTs) working in radiotherapy departments and to explore factors influencing their confidence and preparedness in caring for patients with dementia.

METHODS: A cross-sectional online survey was conducted among RRTs working in radiotherapy practice. The questionnaire collected demographic information and included the validated Alzheimer's Disease Knowledge Scale (ADKS), the Dementia Attitude Scale (DAS), and supplementary open-ended questions. Closed-ended responses were summarised using descriptive statistics, and open-ended responses were reviewed descriptively to contextualise participants' experiences and perceived challenges.

RESULTS: Of 54 responses received, 40 questionnaires were complete. Prior clinical or personal exposure to dementia was reported by 55.0% (n = 22). Only three respondents (7.5%) reported that their departments had dementia-management guidelines, while 90.0% (n = 36) identified opportunities to improve radiotherapy care for patients with dementia. Across the 30 ADKS items, 76.7% of responses were correct. DAS item responses varied, and only 4.8% (n = 2) strongly agreed that they felt confident around people with dementia.

CONCLUSION: RRTs showed generally positive attitudes toward caring for patients with dementia, but limited confidence and the scarcity of departmental guidance may hinder consistent care. Targeted education and radiotherapy-specific protocols are warranted.

PLAIN LANGUAGE SUMMARY: More people are living with both cancer and dementia, which can create challenges during radiation therapy treatment. This study surveyed radiation therapists about their knowledge, confidence, and experiences of caring for people living with dementia. This study found that therapists had generally positive attitudes but often lacked confidence and reported limited guidance for managing dementia-related needs. This matters because better training and clear care guidelines can help improve the treatment experience for people living with dementia.},
}

@article {pmid42977753,
year = {2026},
author = {Tuunanen, J and Hautamäki, K and Väyrynen, T and Järvelä, M and Korhonen, V and Huotari, N and Kaakinen, M and Kananen, J and Helakari, H and Raitamaa, L and Jukkola, J and Herukka, SK and Laurén, K and Salmi, U and Eklund, L and Nikkinen, J and Nedergaard, M and Kiviniemi, V},
title = {Vasomechanic treatment is associated with increased efflux of human brain proteins.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42977753},
issn = {2041-1723},
support = {360508//Academy of Finland (Suomen Akatemia)/ ; TERVA grants 1-2//Academy of Finland (Suomen Akatemia)/ ; 275342//Academy of Finland (Suomen Akatemia)/ ; 338599//Academy of Finland (Suomen Akatemia)/ ; 314497//Academy of Finland (Suomen Akatemia)/ ; 335720//Academy of Finland (Suomen Akatemia)/ ; R01AT012312//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AT011439//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U19NS128613//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 00018024//Simons Foundation/ ; NNF20OC0066419//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; R386-2021-165//Lundbeckfonden (Lundbeck Foundation)/ ; R523-2025-1486//Lundbeckfonden (Lundbeck Foundation)/ ; R523-2025-1486//Lundbeckfonden (Lundbeck Foundation)/ ; 2022-120//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; 1//Jane ja Aatos Erkon Säätiö (Jane and Aatos Erkko Foundation)/ ; 210043//Jane ja Aatos Erkon Säätiö (Jane and Aatos Erkko Foundation)/ ; },
mesh = {Humans ; Female ; *Brain/metabolism/diagnostic imaging/blood supply ; Male ; Adult ; *Nitric Oxide/administration & dosage/metabolism ; Amyloid beta-Peptides/metabolism/blood ; Middle Aged ; Glial Fibrillary Acidic Protein/blood/metabolism ; Aged ; Biomarkers/blood ; Young Adult ; Alzheimer Disease/metabolism/therapy ; Vasoconstriction/physiology ; Vasodilation ; Ion Channels/metabolism ; Peptide Fragments ; },
abstract = {An age-related neurovascular impairment in nitric oxide (NO)-mediated vasodilation and reciprocal Piezo1-dependent vascular vasoconstriction may precede the accumulation of soluble brain proteins such as amyloid-β (Aβ) and disruption of brain fluid homeostasis in Alzheimer's disease (AD). Preclinical studies suggest that restoring these pathways can enhance neurofluid transport and improve cognitive outcomes. In this study (EudraCT 2021-000625-27), we investigated the effects of sublingual NO and Piezo1-targeted whole-body vibrations (WBVp) in healthy adults (n = 29) using multimodal neuroimaging and blood biomarker analysis. The combined intervention (NO+WBVp) was associated with correlating changes in brain fluid dynamics and increased blood levels of soluble brain-derived proteins (Aβ40&42, GFAP). These effects increased with age and the magnitude of NO-induced hypotension. The interventions were well tolerated under controlled experimental conditions. Overall, the findings are consistent with transient redistribution of brain-derived proteins toward circulation, suggesting a potential non-invasive approach to increase neurofluidic solute efflux in humans. Pre-specified primary endpoints, changes in circulating brain-derived protein concentrations, brain fluid imaging and brain pulsation measures, were met. Secondary outcomes included physiological analyses.},
}

Humans
Female
*Brain/metabolism/diagnostic imaging/blood supply
Male
Adult
*Nitric Oxide/administration & dosage/metabolism
Amyloid beta-Peptides/metabolism/blood
Middle Aged
Glial Fibrillary Acidic Protein/blood/metabolism
Aged
Biomarkers/blood
Young Adult
Alzheimer Disease/metabolism/therapy
Vasoconstriction/physiology
Vasodilation
Ion Channels/metabolism
Peptide Fragments

@article {pmid42978226,
year = {2026},
author = {Pitz, ME and Mickol, RL and Pyles, CG and Brown, SM and Fidler, AP and Fears, KP and Beasley, MA},
title = {Methods for Identification and Structural Characterization of Tau Polymorphs in Neurodegenerative Disease.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.10.034},
pmid = {42978226},
issn = {1542-0086},
abstract = {Tauopathies are neurodegenerative diseases associated with the misfolding and aggregation of the tau protein in the brain, including Alzheimer's Disease (AD) and Chronic Traumatic Encephalopathy (CTE). Current medical technology is only able to definitively diagnose tauopathies post-mortem, which limits patient treatment options and reduces quality of life. Structural differences related to specific tauopathies ultimately result in unique disease progression and require unique treatments. In particular, CTE-related tauopathies are relatively understudied compared to AD. To improve diagnosis and treatment options for patients with CTE, it is essential to understand the role of tau in disease onset and progression. Experimental methods such as atomic force microscopy (AFM) and computational methods such as molecular dynamics simulations have been used to gain an understanding of pathological tau structure and mechanics. Spectroscopy and molecular probes have also been effective in revealing mechanisms of tau aggregation. State-of-the-art methods such as cryogenic electron microscopy and two-dimensional infrared spectroscopy (2DIR) are now being used to further explore tau at atomic resolution. In this review, we discuss the current state of both experimental and computational strategies in the assessment of tauopathies, specifically related to structural characterization. We highlight technological advances in relevant methods, such as AFM and 2DIR, that are pivotal to our understanding of structural amyloid formation and progression ante-mortem.},
}

@article {pmid42979005,
year = {2026},
author = {Shukla, R and Bhattacharya, S and Singh, TR},
title = {Identification of potential inhibitors against monoamine oxidase (MAO-B) using an integrative chemoinformatics approach: a lead against neurodegenerative disorder.},
journal = {In silico pharmacology},
volume = {14},
number = {3},
pages = {278},
pmid = {42979005},
issn = {2193-9616},
abstract = {UNLABELLED: The Monoamine Oxidase-B (MAO-B) is a flavin adenine dinucleotides enzyme found in the brain, intestine liver, and placenta. Recently MAO-B has drawn important attention for neurodegenerative disease treatment. Firstly, the Smina-A fork of AutoDock Vina and idock tools were used for the screening of 98,072 compounds. Based on a binding cut-off of >= - 11.5 Kcal/mol, the potential inhibitors were selected and evaluated through the ADMET filters. The ADMET analysis revealed that 18 compounds were best in the pharmacokinetics descriptors evaluation hence we have used the cross-docking approach to confirm the virtual screening result for these 18 compounds. Cross-docking results revealed that four compounds showed a higher binding affinity and interaction with the key catalytic residues. Hence, we have taken these four hits and employed them for the MDS analysis. The MAO-B-RGZ, MAO-B-ZINC2147610, MAO-B-ZINC4237106, MAO-B-ZINC4701203 and MAO-B-ZINC5818772 showed - 67.45, - 103.75, - 88.39, - 96.27 and - 104.11 kJ/mol binding free energy. The overall result of docking, MDS, and binding free energy showed that all the predicted leads are favorable towards the MAO-B binding site. Therefore, we have proposed that ZINC2147610, ZINC4237106, ZINC4701203, and ZINC5818772 as potential hit compounds against MAO-B to open a new gate for the neurodegenerative disease treatment. However, experimental validation is necessary to confirm their biological activity, binding affinity, and therapeutic potential before they can be advanced as putative hits.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00783-5.},
}

@article {pmid42979024,
year = {2026},
author = {Shiao, YJ},
title = {A comprehensive review of the two most commonly studied traditional Chinese medicines for treating Alzheimer's disease.},
journal = {Journal of traditional and complementary medicine},
volume = {16},
number = {6},
pages = {573-583},
pmid = {42979024},
issn = {2225-4110},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder primarily characterized by progressive cognitive decline. Its pathological hallmarks include senile plaques, neurofibrillary tangles, chronic neuroinflammation, and widespread neuronal loss. Beyond aging, several major hypotheses have been proposed to explain AD pathology, including amyloid cascade hypothesis, tau hyperphosphorylation hypothesis, mitochondrial dysfunction hypothesis, neuroinflammation hypothesis, and microbiota-gut-brain axis hypothesis. These mechanisms often interact with one another, further complicating the disease process. While genetic factors contribute significantly to AD susceptibility, other modifiable risk factors-such as traumatic brain injury, hyperlipidemia, diabetes, hypertension, and obesity-also play critical roles. Despite decades of intensive research, current drug development for AD remains largely inadequate. Traditional Chinese medicine, with its multi-component and multi-target approach, holds promise as a potential therapeutic strategy for this multifactorial disease. Comparing the biomedical hypothesis with traditional Chinese medicine theory, both frameworks recognize the multifactorial, systemic, and progressive nature of dementia. However, their theories are complementary, with concepts such as "Phlegm and dampness" in traditional Chinese medicine aligning well with amyloid plaques and lipid/protein aggregates. "Qi and essence deficiency" correspond to mitochondrial and metabolic dysfunction. This article reviews recent progress in the therapeutic mechanisms of Huanglian Jiedu Decoction and Liuwei Dihuang Decoction in AD, aiming to provide a reference for future research on AD and the development of traditional Chinese medicine treatment. Future traditional Chinese medicine studies should integrate syndrome-based therapeutic principles with modern systems biology approaches to establish mechanism-based, personalized, and clinically translatable strategies for AD management.},
}

@article {pmid42979037,
year = {2026},
author = {Rinne, JO and Cummings, JL and Breznoscakova, D and Hakulinen, P and Hänninen, J and Goetghebeur, P and Miller, DS and Rouru, J},
title = {Efficacy of ORM-12741 on agitation/aggression symptoms in participants with Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70332},
pmid = {42979037},
issn = {2352-8737},
abstract = {INTRODUCTION: ORM-12741 is a potent and selective alpha-2C adrenoceptor antagonist. The primary objective of this study was to evaluate the efficacy of ORM-12741 in treating agitation/aggression symptoms in patients with Alzheimer's disease (AD).

METHODS: This was a phase II, double-blind, placebo-controlled study of 308 community-dwelling participants with mild to moderate AD (Mini-Mental State Examination [MMSE] scores 10 to 24) and Neuropsychiatric Inventory agitation/aggression scores of ≥4. Participants were randomized to 60 or 120 mg of ORM-12741 or placebo twice daily for 12 weeks. Efficacy was assessed primarily with the sum of Neuropsychiatric Inventory Clinician Rating (NPI-C) Agitation and Aggression domain scores. In addition, effects on cognition, psychotic, depressive, and overall neuropsychiatric symptoms were assessed.

RESULTS: No relevant treatment effects as compared to placebo group were detected on either the primary or secondary efficacy measures. ORM-12741 was generally well tolerated.

DISCUSSION: The study does not support the efficacy of ORM-12741 on agitation/aggression symptoms in patients with AD.},
}

@article {pmid42979167,
year = {2026},
author = {Decourt, B and Azarfar, K and Reyna, EM and Kennedy, JM and Sabbagh, MN},
title = {Emerging and Repurposed Immune System Modulators for Alzheimer's Disease.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {559284},
pmid = {42979167},
issn = {1177-8881},
support = {R01 AG059008/AG/NIA NIH HHS/United States ; R01 AG073212/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; Animals ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors/immunology ; *Immunologic Factors/therapeutic use/pharmacology ; Adaptive Immunity/drug effects ; Immunity, Innate/drug effects ; },
abstract = {Alzheimer's disease (AD) remains an incurable neurodegenerative condition to date. Pathologically, the hallmarks of AD are (i) extracellular senile plaques mainly composed of amyloid beta peptides (Aβ), (ii) intracellular neurofibrillary tangles comprised of abnormally folded and hyperphosphorylated tau proteins, and (iii) neuroinflammation. In the past two decades, the investigation of these brain pathologies has led to the identification of novel diagnostic biomarkers and putative therapeutic targets, ultimately resulting in the first two commercial disease-modifying anti-Aβ immunotherapies. More recently, modulation of the overactivated central immune system has emerged as a unique putative approach to slow down the progression of AD. In the present narrative review, we summarize the main findings on modulators of inflammation tested in Phase 2 and 3 trials in AD patients. After a deep literature review, we ended up selecting 19 agents spanning immune primers, monoclonal antibodies, recombinant proteins, synthetic peptides, immunomodulatory drugs, ion channel blockers, tyrosine kinase inhibitors, senolytics, antivirals, and herbal formulations. For each agent, we briefly explain the preclinical findings that led to translation into clinical trials and provide details about each trial design, and, when available, the main findings from the trials. Overall, it appears that Aβ and abnormal tau activate both the innate and adaptive immune systems, which in turn galvanize the production of Aβ and abnormal tau, thereby forming a viscous cycle that inflates AD neuropathology and is difficult to interrupt. Based on the successes and failures of the 19 agents reported here, we postulate that immune system modulators with the strongest potential for AD treatment are those displaying pleiotropic actions on both innate and adaptive immune responses rather than those exhibiting very targeted mechanisms. We conclude that modulators of inflammation need to be studied further, both as stand-alone AD therapies and in combination with anti-amyloid and anti-tau approaches.},
}

Humans
*Alzheimer Disease/drug therapy/immunology
Animals
Amyloid beta-Peptides/metabolism/antagonists & inhibitors/immunology
*Immunologic Factors/therapeutic use/pharmacology
Adaptive Immunity/drug effects
Immunity, Innate/drug effects

@article {pmid42979863,
year = {2026},
author = {Choudhury, AK and Rani, P and Gupta, R and Gulati, M and Kapoor, B},
title = {Liposomal Delivery of a Riluzole-Butyric Acid Mutual Prodrug Enhances Neuroprotection and Cognitive Recovery in Experimental Alzheimer's Disease.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/1061186X.2026.2759730},
pmid = {42979863},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, impaired synaptic signaling, and persistent neuroinflammation. Current therapies primarily provide symptomatic relief and have limited effects on disease progression. Riluzole, approved for amyotrophic lateral sclerosis, exhibits neuroprotective effects through modulation of glutamatergic signaling, but its poor oral bioavailability limits its therapeutic potential. Butyric acid, a short-chain fatty acid postbiotic produced by gut microbial fermentation, possesses well-established anti-inflammatory and neuroprotective properties. In this study, a mutual prodrug of riluzole and butyric acid was synthesized and encapsulated into liposomes to investigate its effects on drug distribution and preclinical efficacy. The prodrug-loaded liposomes exhibited an average particle size of 322 nm, zeta potential of -7.95 mV, and entrapment efficiency of 43.49%. Oral administration significantly improved cognitive performance and attenuated neuroinflammation and oxidative stress in an AlCl3-induced AD-like rat model. Administration of prodrug-loaded liposomes led to the highest concentrations of riluzole in brain homogenates among the relevant treatment groups. Overall, the prodrug-loaded liposomes demonstrated better therapeutic efficacy than the prodrug suspension, individual drug-loaded liposomes, and their respective conventional formulations. The enhanced therapeutic performance is attributed to the complementary pharmacological actions of riluzole and butyric acid, combined with the ability of the liposomal system to improve drug bioavailability and facilitate cerebral delivery.},
}

@article {pmid42967168,
year = {2026},
author = {Cao, S and Liu, T and Cheng, X and Tian, X and Wei, J},
title = {The "Invisible Killer" of Neurodegeneration: Mitochondrial Dysfunction in Neurodegenerative Disorders, Mechanisms, Emerging Pathways and Therapeutic Strategies.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {653025},
pmid = {42967168},
issn = {1178-7031},
abstract = {Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) place substantial burden on global public health. Mounting evidence identifies mitochondrial dysfunction as a central contributor to neuronal damage and progressive brain functional decline. As a narrative review, this work aims to dissect mitochondrial‑associated pathological features across these major neurodegenerative disorders, summarize under‑recognized emerging mechanisms, and highlight translational bottlenecks for mitochondrial‑targeted therapies. Mitochondria sustain neuronal survival by mediating oxidative‑phosphorylation‑driven energy production, biomolecule biosynthesis, calcium homeostasis, reactive oxygen species (ROS) metabolism, and apoptotic regulation. In PD, aggregated α‑synuclein (α‑syn) damages respiratory‑chain complex I, perturbs mitochondrial dynamics and blocks PINK1/Parkin‑dependent mitophagy. In AD, amyloid‑β together with hyper‑phosphorylated tau (p-Tau) impairs respiratory complex activity, axonal mitochondrial trafficking and mitophagic clearance. Mutant huntingtin induces multiple mitochondrial lesions in HD, while inflammation‑triggered oxidative stress secondarily compromises mitochondrial function in MS. Pathogenic mutations in ALS disrupt respiratory‑chain assembly, mitochondrial dynamics and mitophagy. Beyond classic mitochondrial defects including respiratory‑chain impairment, dynamic imbalance and defective mitophagy, emerging mechanisms such as mitocytosis, mitochondrial aminoacyl‑tRNA synthetase (mt‑aaRS) dysfunction and mitochondria‑associated membrane (MAM) disruption are discussed. Mitochondrial dysfunction drives neurodegeneration via energy exhaustion, aggravated oxidative stress, pathological protein aggregation and excessive neuronal apoptosis. We further recapitulate mitochondrial‑oriented therapeutic approaches including small‑molecule regulators, mitophagy activators, mitochondrial biogenesis promoters, gene‑editing strategies and mitochondrial transplantation. Notable translational obstacles remain, including limited blood‑brain‑barrier penetration of candidate drugs, narrow therapeutic time‑window post‑symptom onset, and prominent disease heterogeneity. By synthesizing basic experimental findings and pre‑clinical and clinical trial progress, this review provides updated insights into the pathogenesis of neurodegenerative diseases and facilitates the development of precise mitochondrial‑targeted therapeutic regimens.},
}

@article {pmid42968533,
year = {2026},
author = {Mohammadi, Y and Salehi, MS and Heidari, E and Ebrahimi, M and Ashjazadeh, N},
title = {Development, Optimization, and Physicochemical Characterization of Fluorescent Carbon Dot-Ginkgo biloba Extract Co-Loaded Niosomes for Future Neurological Disease-Relevant Evaluation.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {11},
pages = {},
pmid = {42968533},
issn = {1755-5949},
mesh = {*Liposomes/chemistry ; Ginkgo biloba ; *Plant Extracts/chemistry/administration & dosage ; *Carbon Quantum Dots/chemistry ; Humans ; Animals ; Ginkgo Extract ; Cell Survival/drug effects ; Particle Size ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the major neurodegenerative diseases that affect the human brain and lead to memory loss. The present approaches to disease management have been relatively poor; the therapies provided do not arrest the disease process. This study aimed to develop and optimize dual-loaded niosomes containing Ginkgo biloba extract and CDOTs and to evaluate their physicochemical properties, formulation-level fluorescence, in vitro release, and preliminary cytocompatibility. The study did not assess blood-brain barrier transport, neuronal effects, Alzheimer's disease-specific mechanisms, or in vivo therapeutic efficacy.

RESULTS: Niosomes were prepared based on non-ionic surfactants and cholesterol for the encapsulation of Ginkgo and CDOTs. The response surface methodology (RSM) was used to optimize niosomal formulations through a Box-Behnken design. The formulations were evaluated for vesicle size, entrapment efficiency, and release profile. Field Emission Scanning Electron Microscopy (FESEM) research indicated that the average diameters of the free niosomes and CDOT@Ginkgo@Niosomes were 69.56 nm and 72.19 nm, respectively. HFF cell viability remained high at lower concentrations, whereas significant reductions in viability were observed at 10 and 50 μg/mL after 48 h, indicating concentration-dependent cytocompatibility. The formulation exhibited acceptable preliminary cytocompatibility at lower concentrations, whereas reduced viability was observed at higher concentrations. For both CDOT and Ginkgo, CDOT@Ginkgo@Niosomes showed a delayed release profile over 72 h, with near-complete release observed at the final time point.

CONCLUSIONS: CDOT@Ginkgo@Niosomes showed successful co-loading, preserved formulation-level fluorescence, delayed release, and acceptable cytocompatibility at lower concentrations in HFF cells. These findings support further formulation optimization and subsequent evaluation in disease-relevant neuronal, blood-brain barrier, and in vivo models. The present results do not demonstrate neuroprotection, diagnostic performance, blood-brain barrier transport, or the prevention or treatment of neurodegenerative disease.},
}

*Liposomes/chemistry
Ginkgo biloba
*Plant Extracts/chemistry/administration & dosage
*Carbon Quantum Dots/chemistry
Humans
Animals
Ginkgo Extract
Cell Survival/drug effects
Particle Size

@article {pmid42968820,
year = {2026},
author = {Klimova, B},
title = {Language Impairment in Alzheimer's Disease: An Updated Narrative Review of Digital Assessment, Social Interventions, and Medical Treatment, 2016-2026.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {633855},
pmid = {42968820},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/complications/therapy ; *Language Disorders/therapy/etiology ; Biomarkers ; },
abstract = {Language impairment is a core clinical manifestation of Alzheimer's disease (AD) that profoundly affects autonomy, decision-making, and social participation. Building upon the 2015 review by Kuca et al., this narrative review synthesizes empirical evidence from 2016 through 2026. A structured Web of Science Core Collection search retrieved 154 records. Following screening, 66 records were excluded and 88 full-text reports were appraised, of which 13 were consolidated, yielding 75 cited core empirical studies alongside foundational diagnostic, neuropathological, and trial benchmarks. Four main areas are synthesized. First, progressive linguistic decline across clinical stages is characterized, delineating typical amnestic AD dementia, mild cognitive impairment due to AD, and the logopenic variant of primary progressive aphasia (lvPPA), highlighting the necessity of biological amyloid and tau biomarker confirmation. Second, automated speech and natural language processing biomarkers have emerged as scalable tools predicting progression to dementia and detecting biological amyloid-beta positivity; however, real-world translation remains constrained by demographic bias, cross-linguistic variations, acoustic sensitivity, and privacy issues. Third, non-pharmacological interventions, including structured language stimulation and naming therapy, demonstrate measurable task-specific improvements; nevertheless, gains are largely restricted to trained items with minimal transfer to everyday discourse. Caregiver communication training programs reliably improve dyadic interactions and mitigate caregiver distress. Fourth, approved symptomatic drugs do not directly reverse language decline, and add-on memantine in the randomized ROMEO-AD trial produced no statistically significant language benefit over donepezil alone. Disease-modifying anti-amyloid antibodies offer biological intervention for biomarker-positive lvPPA, but pivotal trials lacked primary speech endpoints, establishing eligibility rather than demonstrated language recovery. Non-invasive neuromodulation remains preliminary and requires sham-controlled trials. Communication should be recognized as a distinct clinical outcome in trial designs, prioritizing standardized speech endpoints to assess disease-modifying therapies.},
}

Humans
*Alzheimer Disease/complications/therapy
*Language Disorders/therapy/etiology
Biomarkers

@article {pmid42969459,
year = {2026},
author = {François, G and Michalon, R and Tannou, T and Damier, P and Desmoulin, S and Lebouvier, T},
title = {Navigating the Challenges of Shared Decision-Making in Amyloid Immunotherapy for Alzheimer's Disease.},
journal = {European journal of neurology},
volume = {33},
number = {11},
pages = {},
pmid = {42969459},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/therapy/drug therapy ; *Decision Making, Shared ; *Immunotherapy/methods ; Informed Consent ; *Patient Participation ; },
abstract = {BACKGROUND: Anti-amyloid therapies (AATs), such as lecanemab and donanemab, represent a major therapeutic development for early Alzheimer's disease (AD). However, safety risks and uncertainties regarding long-term effects make treatment decisions complex. These decisions arise when patients remain legally capable of providing informed consent but may experience cognitive vulnerabilities affecting their ability to engage in complex decisions. Shared decision-making (SDM) is therefore particularly relevant, yet its implementation raises ethical and practical challenges.

METHODS: This position paper draws on a multidisciplinary reflection on decision-making, informed consent, and cognitive vulnerability in early AD and AATs. The authors, with expertise in neurology, geriatrics, law, and history, examined challenges to patient participation and developed a relational framework integrating SDM and supported decision-making.

RESULTS: Impairments in memory, insight, and executive function, together with cognitive biases, stigma, and the complexity of AAT-related information, may compromise patient participation despite preserved legal capacity. Formal capacity assessments and improved information delivery may address some difficulties but are unlikely to provide comprehensive support. We propose a relational framework involving assessment of patients' cognitive vulnerabilities, values, preferences, and informational needs; tailored information; and involvement of a patient-designated care partner to support information exchange, deliberation, and expression of preferences. Consent should be iterative, with safeguards to preserve autonomy and confidentiality, prevent coercion, and avoid excluding socially isolated individuals.

CONCLUSION: Combining SDM with supported decision-making may provide an ethical and practical framework for autonomous treatment decisions regarding AATs in early AD.},
}

Humans
*Alzheimer Disease/therapy/drug therapy
*Decision Making, Shared
*Immunotherapy/methods
Informed Consent
*Patient Participation

@article {pmid42969693,
year = {2026},
author = {Chen, Z and Chen, D and Zhang, J and Wang, C and Liu, J and Liang, Y and He, Q and Du, X},
title = {Iron Boride Nanostructures as Oral Acid-Responsive Hydrogen Donors for Alzheimer's Disease Therapy.},
journal = {Molecular pharmaceutics},
volume = {23},
number = {11},
pages = {5288-5304},
doi = {10.1021/acs.molpharmaceut.6c00223},
pmid = {42969693},
issn = {1543-8392},
support = {RCJC20210706092010008//Shenzhen Science and Technology Program/ ; 2025A1515011129//Natural Science Foundation of Guangdong Province/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; 82550005//National Natural Science Foundation of China (NSFC)/ ; W2512066//National Natural Science Foundation of China (NSFC)/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Hydrogen/chemistry/metabolism/administration & dosage ; Mice ; Male ; *Nanostructures/chemistry/administration & dosage ; Administration, Oral ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Brain/metabolism/drug effects/pathology ; Humans ; *Iron Compounds/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition with complex causes. Despite extensive research, effective disease-modifying treatment options remain limited. Recent studies have indicated that hydrogen molecule (H2) possesses therapeutic potential for AD, and it is of vital importance to enhance the bioavailability of H2 in the gastrointestinal tract based on the gut-brain axis. In this work, we develop iron boride nanostructures (FBN) as a novel acid-responsive hydrogen-releasing material with a high hydrogen release capacity to enhance the H2 delivery efficacy towards the gastrointestinal tract for AD treatment. In male 5×FAD and 3×Tg-AD mice, oral FBN administration generated H2 under gastric conditions and was associated with AD-like behavioral and pathological improvements, including improved learning and memory and attenuation of neuronal and synaptic damage. FBN treatment was associated with increased synaptophysin (SYP) expression and dendritic spine density. Additionally, FBN treatment was associated with reduced amyloid-beta (Aβ) accumulation and attenuated tau pathology, two key pathological features of AD. FBN treatment was also associated with increased expression of mitochondrial fusion-related proteins and improved mitochondrial morphology. Furthermore, FBN treatment increased antioxidant defense-related proteins and reduced apoptosis-related markers, suggesting a possible enhancement of neuroprotective responses. In addition, FBN treatment induced changes in gut microbiota-related metabolites, suggesting a possible contribution of the gut-brain axis. These findings provide valuable insight into the mechanisms underlying the protective effects of hydrogen against AD and support the development of hydrogen-based therapies for slowing or preventing disease progression.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Hydrogen/chemistry/metabolism/administration & dosage
Mice
Male
*Nanostructures/chemistry/administration & dosage
Administration, Oral
Amyloid beta-Peptides/metabolism
Mice, Transgenic
Disease Models, Animal
Brain/metabolism/drug effects/pathology
Humans
*Iron Compounds/chemistry

@article {pmid42969705,
year = {2026},
author = {Hyvärinen, J and Todorovska, R and Palacios, MDP and Gynther, M and Afonin, A and Lehtonen, M and Auriola, S and Saveleva, L and Kanninen, KM and Fricker, G and Puris, E},
title = {Proteomics Reveals Blood-Brain Barrier Membrane Protein Remodeling in Amyloid-β Pathology.},
journal = {Molecular pharmaceutics},
volume = {23},
number = {11},
pages = {5848-5862},
doi = {10.1021/acs.molpharmaceut.6c00935},
pmid = {42969705},
issn = {1543-8392},
support = {//Alexander von Humboldt-Stiftung/ ; //Biocenter Finland/ ; //Alzheimer Forschung Initiative/ ; 362227//Research Council of Finland/ ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Proteomics/methods ; Mice ; *Alzheimer Disease/metabolism/pathology ; Humans ; Mice, Transgenic ; Endothelial Cells/metabolism ; Brain/metabolism/blood supply ; *Membrane Proteins/metabolism ; Disease Models, Animal ; Tandem Mass Spectrometry/methods ; Microvessels/metabolism ; Chromatography, Liquid ; },
abstract = {The protective function of the blood-brain barrier (BBB) is achieved by membrane proteins expressed in the endothelial cells of brain microvessels, such as tight junction proteins, receptors, and transporters, which regulate the passage of solutes, including nutrients, drugs, and metabolites. In Alzheimer's disease (AD), characterized by the accumulation of amyloid-β (Aβ) plaques, BBB dysfunction has been widely reported. However, quantitative information on Aβ-associated changes in the membrane proteome in the brain microvasculature remains limited. Here, we investigated the changes in abundances of membrane proteins playing roles in BBB function in the isolated brain microvessels of a mouse model mimicking human Aβ pathology, 5xFAD mice, versus corresponding wild-type (WT) mice using a state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS)-based data-independent acquisition (DIA) quantitative proteomics. In addition, we applied quantitative targeted absolute proteomics to evaluate the impact of Aβ1-42 on the absolute protein abundance of multiple transporters in an in vitro model of brain endothelial cells, hCMEC/D3. We identified changes in the protein abundance of numerous proteins involved in BBB integrity, including tight junction-associated proteins and proteins implicated in Aβ transport and clearance, in the brain microvasculature of 5xFAD mice. Furthermore, Aβ1-42 treatment altered GLUT1 protein abundance and the gene expression of SLC27A1 and SLC22A2 in hCMEC/D3 cells, which play roles in nutrient transport and drug disposition at the BBB. The present study provides novel insights into Aβ-associated molecular alterations in brain microvascular membrane proteins and advances our understanding of BBB changes in AD. The results may support the development of BBB-targeted therapeutic approaches and strategies for optimizing brain drug delivery in AD.},
}

Animals
*Blood-Brain Barrier/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*Proteomics/methods
Mice
*Alzheimer Disease/metabolism/pathology
Humans
Mice, Transgenic
Endothelial Cells/metabolism
Brain/metabolism/blood supply
*Membrane Proteins/metabolism
Disease Models, Animal
Tandem Mass Spectrometry/methods
Microvessels/metabolism
Chromatography, Liquid

@article {pmid42970319,
year = {2026},
author = {Shin, J and Park, YJ and Lee, S and Kang, J and Lee, S and Lee, ES and Jung, HN and Ryoo, I and Chung, SJ and Eo, JS and Suh, SI and Oh, K and Koh, SB and Kang, SH},
title = {Baseline Physical Frailty Predicts Clinical Outcomes During Lecanemab Therapy in Early Alzheimer's Disease: A Prospective Real-World Cohort Study.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0978},
pmid = {42970319},
issn = {2152-5250},
abstract = {BACKGROUND: Physical frailty and sarcopenia are recognized as determinants of Alzheimer's disease (AD) progression, but their implications during anti-amyloid therapy remain unclear. We investigated their associations with longitudinal cognitive outcomes, treatment safety, tolerability, and plasma p-tau217 trajectories in patients with early AD receiving lecanemab.

METHODS: This prospective cohort included 187 patients with amyloid-positive early AD who initiated lecanemab at a tertiary memory clinic. Physical frailty was defined using the Short Physical Performance Battery (SPPB), and sarcopenia according to the 2019 Asian Working Group for Sarcopenia criteria. Logistic regression was used for infusion-related reactions (IRRs) and treatment discontinuation, whereas amyloid-related imaging abnormalities (ARIA) outcomes were evaluated using Firth penalized logistic regression because of the limited number of events. Longitudinal cognitive outcomes and plasma p-tau217 trajectories were analyzed using linear mixed-effects models.

RESULTS: SPPB-defined physical frailty and sarcopenia were associated with faster CDR-SB worsening (β = 1.52 and 1.40 points/year, respectively; both nominal p<0.001; both q<0.001). A greater decline in SNSB-D was observed in participants with SPPB-defined physical frailty (β=-11.36 points/year; 95% CI, -22.38 to -0.34; nominal p=0.044), although this association did not remain statistically significant after FDR correction (q=0.065). Neither exposure was associated with MMSE change. SPPB-defined physical frailty was associated with a higher risk of IRRs (adjusted odds ratio, 4.75; 95% confidence interval, 2.03-11.66; p<0.001), but was not associated with ARIA or treatment discontinuation. No differential plasma p-tau217 trajectories were detected according to baseline SPPB-defined physical frailty or sarcopenia status.

CONCLUSIONS: Baseline SPPB-defined physical frailty was associated with longitudinal clinical progression and IRRs during lecanemab treatment. These findings suggest that SPPB-defined physical frailty may represent a candidate prognostic marker of clinical outcomes during lecanemab therapy and warrant further validation in larger cohorts.},
}

@article {pmid42971333,
year = {2026},
author = {El-Far, SS and Abo-Saif, M and El-Sherbeni, SA and Ragab, AE and Ibrahim, SM},
title = {Phytochemical investigation and neuroprotective effect of Encephalartos kisambo Faden & Beentje: Regulation of SIRT1, lnc-MALAT1, and vimentin in mice.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107545},
doi = {10.1016/j.fitote.2026.107545},
pmid = {42971333},
issn = {1873-6971},
abstract = {The aim of this study is to conduct research about the phytochemical composition and neuroprotective potential of Encephalartos kisambo leaves. LC-ESI-MS/MS profiling of the methanolic extract putatively annotated 56 different compounds. Six compounds, namely β-sitosterol, 7,4',7'',4'''-tetra-O-methyl amentoflavone, kayaflavone, isoginkgetin, bilobetin, and amentoflavone were isolated and characterized by spectroscopical investigations using UV, 1D- and 2D-NMR, HPLC-ESI-MS, and HR-ESI-MS. The neuroprotective efficacy of the ethyl acetate and n-butanol fractions was evaluated in vivo using an aluminum chloride-induced neurodegeneration model. The ethyl acetate and n-butanol fractions exihibted significant cognitive improvement in the Morris water maze test. These fractions also enhanced catalase activity while markedly reducing malondialdehyde levels, indicating their ability to alleviate oxidative stress associated with dementia. Furthermore, treatment with the n-butanol fraction downregulated the expression of lnc-MALAT1 and vimentin while upregulating SIRT1, suggesting modulation of neuroinflammatory and apoptotic pathways. Histopathological examination revealed that co-administration of the n-butanol fraction with AlCl3 preserved the neuronal architecture in the cerebral cortex and CA2 region of the hippocampus. These findings highlighted E. kisambo as a promising source of neuroprotective agents with potential therapeutic relevance to help prevent Alzheimer's disease and manage its development.},
}

@article {pmid42971381,
year = {2026},
author = {Hosseini, F and Ashengroph, M and Alaei, L},
title = {Molecular descriptor-based QSAR modeling of carbamate derivatives for predicting acetylcholinesterase inhibitory activity.},
journal = {Chemico-biological interactions},
volume = {441},
number = {},
pages = {112412},
doi = {10.1016/j.cbi.2026.112412},
pmid = {42971381},
issn = {1872-7786},
abstract = {BACKGROUND: Acetylcholinesterase (AChE) inhibition remains an important therapeutic strategy for symptomatic treatment of Alzheimer's disease. Quantitative structure-activity relationship (QSAR) modeling may help identify molecular features associated with AChE inhibitory activity.

METHODS: Forty-one carbamate derivatives with reported AChE inhibitory activities were analyzed using 1420 DRAGON molecular descriptors. An 11-descriptor multiple linear regression model was developed using forward stepwise selection and evaluated through leave-one-out cross-validation, Y-randomization, applicability-domain analysis, nested cross-validation, and external validation.

RESULTS: The model showed good fit to the training data (R[2] = 0.9207), adjusted (R[2] = 0.8907), (RMSE = 0.0766) and leave-one-out performance (Q[2]LOO = 0.8382), RMSECV = 0.1094). Y-randomization yielded an empirical probability of 0.0190 for obtaining a training (R[2]) at least as high as the observed value. However, supplementary nested cross-validation produced a mean out-of-fold (R[2]) of 0.178, while external validation yielded (R[2]ext = -0.0548), indicating limited generalizability. The selected descriptors represented electronic, topological, geometrical, and molecular-property characteristics.

CONCLUSIONS: The model identifies descriptor-activity associations within the studied carbamate series but has limited demonstrated external predictive capability. It should therefore be considered an exploratory QSAR model requiring further validation on larger, independent datasets before application to the design or prioritization of new AChE inhibitors.},
}

@article {pmid42971925,
year = {2026},
author = {Xiao, J and Yang, Z and Li, J and Xiong, Q and Xia, X and Hao, L and Ling, Z and Pang, K and Zhou, C and Wu, H},
title = {Nanobody-Modified Outer Membrane Vesicles Attenuate Alzheimer's Disease-Like Neurodegeneration by Modulating Mitophagy-Associated Phenotypes and cGAS-STING-Related Inflammatory Signaling.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {},
doi = {10.1002/adhm.71891},
pmid = {42971925},
issn = {2192-2659},
support = {2025ZDXM003//Chongqing Science-Health Joint Medical Research Project/ ; },
abstract = {This study examined anti-transferrin receptor (TfR) nanobody-functionalized bacterial outer membrane vesicles (OMVs) as an engineered platform for improving Alzheimer's disease (AD)-like neuronal injury. Escherichia coli-derived OMVs were characterized for morphology, size distribution, surface charge, protein features, nanobody loading, residual endotoxin levels, endotoxin-associated inflammatory responses, and repeated-exposure immune-safety readouts, and were evaluated in neuronal-related cells and APP/PS1 mice. Engineered OMVs showed receptor-associated uptake and preferential brain-delivery signals, increased HT-22 cell viability, reduced apoptosis, and elevated mitophagy-associated markers including LC3-II, PINK1, and Parkin. OMV treatment also reduced cytosolic mtDNA abundance, DNA/cGAS colocalization, phosphorylation of STING/TBK1/IRF3, and inflammatory-marker expression. PINK1 or Parkin knockdown partially weakened OMV-associated mitochondrial and inflammatory readouts, whereas pharmacological autophagy modulation supported a contribution of autophagy-related processes without establishing selective PINK1/Parkin-dependent mitophagy in vivo. In APP/PS1 mice, OMV administration improved Morris water maze and rotarod performance and alleviated neuroinflammatory and histological injury-related changes. Overall, anti-TfR nanobody-modified OMVs were associated with enhanced receptor-related delivery, mitophagy-linked phenotypes, reduced cytosolic mtDNA/cGAS-STING-related inflammatory signaling, and improved AD-like outcomes, supporting further delivery-system optimization and mechanistic validation.},
}

@article {pmid42972106,
year = {2026},
author = {Walton, C and Oleinik, N and Kassir, MF and Lee, HG and Bhat, NR and Sambamurti, K and Albayram, O and Angel, P and Wang, GY and Bose, RJC and Ha, K and McCarthy, JR and Ogretmen, B},
title = {Amyloid beta governs mitochondrial lipid metabolism defects and neurodegenerative lysosomal stress.},
journal = {EMBO reports},
volume = {},
number = {},
pages = {},
pmid = {42972106},
issn = {1469-3178},
support = {CA214461//Foundation for the National Institutes of Health (FNIH)/ ; DE016572//Foundation for the National Institutes of Health (FNIH)/ ; CA285926//Foundation for the National Institutes of Health (FNIH)/ ; CA203628//Foundation for the National Institutes of Health (FNIH)/ ; AG069769//Foundation for the National Institutes of Health (FNIH)/ ; CA275631//Foundation for the National Institutes of Health (FNIH)/ ; C06 RR015455//Foundation for the National Institutes of Health (FNIH)/ ; P30 CA138313//Foundation for the National Institutes of Health (FNIH)/ ; P30 GM103339//Foundation for the National Institutes of Health (FNIH)/ ; },
abstract = {Mechanisms linking amyloid peptides to mitochondrial dysfunction and impaired mitophagy in Alzheimer's disease (AD) remain poorly defined. Here, we report that, in healthy aging neurons, mitochondrial ceramide synthase 1 (CerS1) localization accompanies increased mitochondrial C18-ceramide and mitophagy in damaged mitochondria. In neuronal, mouse, and human AD tissues, amyloid precursor protein (APP) or Aβ40, but not Aβ42, shows increased proximity or co-association with TOM20/TOM40 alongside reduced mitochondrial CerS1/C18-ceramide accumulation and mitophagy. Mitochondria-excluded mutant APP does not reproduce these responses in neuronal cells. WT-APP expression is associated with reduced p17/PERMIT-ICT1 proximity, which does not establish direct APP-ICT1 binding or disruption of complex formation. Reduced mitophagy also accompanies lysosomal Aβ42 accumulation and secretion from neurons. Aged CerS1top/top mice, expressing catalytically inactive CerS1, exhibit mitochondrial dysfunction, behavioral deficits, and amyloid-positive plaque accumulation. Treatment with the peptide-targeted nanoparticle Pen-Cera-LCL768, which accumulates in the brain after intranasal administration, increases mitophagy-related readouts, reduces plaque burden, and improves behavioral performance in aged 3xTg and CerS1top/top mice. Mdivi-1 attenuates treatment effects in 3xTg mice, but its lack of specificity limits conclusions about mitophagy dependence.},
}

@article {pmid42973315,
year = {2026},
author = {Mishra, R and Gupta, JK},
title = {Neuroprotective Effects of Neolamarckia cadamba against β-amyloid-induced Cognitive Dysfunction via Antioxidant and Anti-inflammatory Mechanisms in Rats.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026492928260911072747},
pmid = {42973315},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease is a progressive neurodegenerative disorder characterised by oxidative stress, amyloid-beta accumulation, and neuroinflammation, leading to cognitive decline. Current treatments offer only limited symptomatic relief. This study evaluates the neuroprotective potential of the ethanolic leaf extract of Neolamarckia cadamba in an Aβ1-42-induced rat model of Alzheimer's disease.

METHODS: Adult Wistar rats were divided into seven groups (n=6), and Alzheimer's disease was induced by intracerebroventricular Aβ1-42 injection. Neolamarckia cadamba extract was administered orally for 21 days at doses of 100, 200, and 400 mg/kg. Cognitive and behavioural functions were evaluated using standard tests, while biochemical assays and ELISA assessed oxidative stress markers, antioxidant enzymes, and pro-inflammatory cytokines.

RESULTS: Aβ1-42 induction significantly impaired learning and memory and increased oxidative stress and inflammatory markers (p < 0.05). Treatment with Neolamarckia cadamba produced dose-dependent improvements, including reduced escape latency (up to 42% at 400 mg/kg, p < 0.01), improved behavioural performance, restoration of antioxidant enzymes (SOD, CAT, GSH), and reduced lipid peroxidation, nitric oxide, TNF-α, and IL-1β levels (p < 0.05), with the 400 mg/kg dose showing the greatest effect.

DISCUSSION: The observed effects of Neolamarckia cadamba may be attributed to its antioxidant, anti-inflammatory, and cholinergic modulatory properties, which contribute to the preservation of neuronal function and cognitive performance. Overall, the findings indicate dose-dependent improvements in both behavioural and biochemical parameters, supporting its potential neuroprotective role in the experimental model.

CONCLUSION: The ethanolic extract of Neolamarckia cadamba demonstrated potential in attenuating Aβ1-42-induced cognitive impairments, possibly through antioxidant and anti-inflammatory mechanisms. These findings support its promise for further investigation in Alzheimer's disease, with additional mechanistic and clinical studies required to establish its therapeutic applicability.},
}

@article {pmid42965774,
year = {2026},
author = {Takahashi, R and Ikegami, S and Iseki, C and Nakajima, M and Oishi, K and Ishii, K},
title = {Anatomical VOI-based assessment of the three DESH components in probable idiopathic normal pressure hydrocephalus.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42965774},
issn = {1867-108X},
abstract = {PURPOSE: To evaluate whether anatomical volume-of-interest (VOI) thresholds derived from a SINPHONI-2 reference cohort could provide standardized component-wise quantification of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in a separate clinical cohort.

MATERIALS AND METHODS: Thresholds were derived from 61 SINPHONI-2 cases using a prespecified mildest-case rule and applied without re-optimization to 33 participants with probable idiopathic normal pressure hydrocephalus (iNPH), 26 with Alzheimer disease, 18 with progressive supranuclear palsy, and 20 normal controls. DESH metric-S summed binary positivity for ventriculomegaly, Sylvian fissure enlargement, and tight high-convexity and medial sulci; DESH metric-I was defined as (Sylvian fissure volume + lateral ventricular volume)/high-convexity and medial sulcal volume. Evans index and callosal angle were evaluated as conventional imaging measures.

RESULTS: For iNPH versus pooled non-iNPH, DESH metric-S had an area under the curve (AUC) of 0.958 (95% CI, 0.921-0.990), sensitivity of 97.0% (84.7-99.5%), and specificity of 92.2% (83.0-96.6%). DESH metric-I had an AUC of 0.995 (95% CI, 0.983-1.000), sensitivity of 100.0% (89.6-100.0%), and specificity of 93.8% (85.0-97.5%).

CONCLUSION: Anatomical VOI-based measures provided standardized component-wise quantification of DESH morphology. DESH metric-S retained the status of each component, whereas DESH metric-I provided a continuous summary. Because DESH contributed to probable-iNPH classification, the observed discrimination reflects concordance with a DESH-supported classification rather than independent diagnostic accuracy for iNPH. External validation, including cohorts spanning incomplete/non-DESH morphology and treatment-response outcomes, is required before clinical or prognostic use.},
}

@article {pmid42966047,
year = {2026},
author = {Devi, B and Jangid, K and Temgire, P and Kumar, N and Thareja, S and Kumar, P and Kumar, V},
title = {Computationally driven design and validation of piperazine-bridged phthalimide derivatives as multifunctional agents against Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {321},
number = {Pt 3},
pages = {119417},
doi = {10.1016/j.ejmech.2026.119417},
pmid = {42966047},
issn = {1768-3254},
abstract = {A multi-target-directed ligand (MTDL) strategy has been proposed as an effective approach for treating complex multifactorial neurological disorders like Alzheimer's Disease. A 3D-QSAR pharmacophore model of piperazine derivatives against AChE was developed and validated (R[2] = 0.99 and Q[2] = 0.91). The best pharmacophore hypothesis model (AHR_1) was used to screen an in-house generated library of 188 phthalimide-piperazine derivatives, followed by structure-based virtual screening against the targeted enzymes. The docking scores of the identified eleven hit molecules were found to be better than the standard inhibitors, and MD simulations confirmed the stability of the compound-target complexes. As a proof of concept, the top hits were synthesized in the laboratory and evaluated for their inhibitory potential. Compound VPT-2 displayed IC50 values of 0.897 μM against AChE and 0.519 μM against MAO-B, while VPT-5 showed IC50 values of 3.45 μM against AChE and 1.074 μM against MAO-B, respectively. VPT-2 and VPT-5 inhibited Aβ1-42 self-aggregation significantly by 43.27 % and 43.28 %, respectively at a concentration of 20 μM, after 48 h. Additionally, an MTT assay using SH-SY5Y cells confirmed the safety of both the lead compounds up to 20 μM. Both compounds exhibited neuroprotective effects against 6-OHDA-induced neurotoxicity and significantly reduced intracellular ROS levels by 80-90 % at 5 μM. Thus, in this drug design strategy, CADD is integrated with in vitro experimental validation for the identification of phthalimide-piperazine derivatives as promising multi-target drug candidates for the treatment of Alzheimer's disease.},
}

@article {pmid42966893,
year = {2026},
author = {Gao, W and Gao, J and Su, X and Kong, X and Wei, X and Ding, T and Guo, T and Gao, S and Zhou, Y and Zhou, J and Zhao, H},
title = {Cross-Organ Multi-Omics Profiling of Systemic Alterations in 5xFAD Mice and Changes Associated with Huanglian Jiedu Decoction Treatment.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {},
pmid = {42966893},
issn = {2198-3844},
support = {CI2023C020YL//Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences/ ; CI2023E001TS09//Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences/ ; CI2026A04509//Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences/ ; 81974523//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a systemic disorder involving metabolic abnormalities beyond the brain, but links between hepatic alterations and neuroinflammation remain unclear. We integrated behavioral, histopathological, transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses in male mice assigned to WT (n = 15), AD (n = 16), high-dose HLJDD (n = 16), low-dose HLJDD (n = 11), and donepezil (n = 10) groups and treated for 10 weeks. Longitudinal behavioral data were analyzed using repeated-measures models, and omics p-values were adjusted using the Benjamini-Hochberg FDR procedure. Cognitive impairment, glial activation, and neuroinflammation were accompanied by hepatic metabolic disturbances and alterations in insulin signaling and energy metabolism, implicating PPAR and PI3K/Akt-related processes. HLJDD, particularly at the high dose, improved behavioral and neuropathological outcomes and shifted abnormalities in TCA-cycle metabolites, amino acid neurotransmitters, and oxidative balance toward WT levels. To assess hepatocyte contributions to microglial inflammation, we established an AML12-BV2 conditioned-medium model with hepatocyte PPAR-γ knockdown. Conditioned medium from LPS/HLJDD-cotreated AML12 cells elicited lower inflammatory responses in BV2 cells than medium from LPS-treated hepatocytes. PPAR-γ knockdown attenuated this effect, supporting a hepatocyte PPAR-γ-dependent contribution to microglial regulation and further investigation of hepatic involvement in HLJDD-associated neuroprotection.},
}

@article {pmid42966930,
year = {2026},
author = {Paladino, J and Echols, H and Thacker, A and Gale, SA and Ramirez Gomez, L and Weizenbaum, E and Pu, CT and Ritchie, C and Shah, SJ and Lindenberger, E},
title = {Communication and shared decision-making for anti-amyloid therapy in early Alzheimer's disease: An exploratory qualitative study of real-world audio-recorded clinical encounters.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70343},
pmid = {42966930},
issn = {2352-8737},
abstract = {INTRODUCTION: Anti-amyloid therapies (AATs) for Alzheimer's disease (AD) offer modest slowing of cognitive decline but involve meaningful risks, burdens, and uncertainty. Decisions about AAT are preference sensitive and optimally guided by shared decision making (SDM), yet little is known about how these conversations unfold in real-world clinical practice.

METHODS: We conducted an exploratory qualitative content analysis of audio-recorded AAT counseling encounters in neurology clinics at two academic medical centers. Participants included neurology clinicians, patients with mild cognitive impairment or mild dementia due to AD, and care partners. We examined how clinicians presented options, benefits, risks, and burdens; elicited patient values and preferences; assessed understanding; and engaged patients and care partners.

RESULTS: We analyzed 10 encounters involving 9 patients and 5 clinicians; 8 patients had a care partner present. Encounters occurred at different stages of decision making, including pre-decision visits and visits in which a treatment decision was made. Clinicians consistently explained AAT mechanisms using action-oriented language, emphasized modest benefits, and discussed amyloid-related imaging abnormalities, magnetic resonance imaging monitoring as a safety net, and treatment logistics. However, communication framing varied. Some clinicians used optimistic framing that may have shaped treatment perceptions, while explicit discussion of not pursuing AAT as a valid option was rare. Open-ended exploration of values and goals varied and occurred more often in pre-decision encounters, whereas visits closer to treatment decisions focused on treatment selection and logistics. Assessment of treatment understanding ranged from open-ended teach-back, which revealed misunderstandings in some cases, to closed-ended checks. Clinicians also varied in how they balanced patient and care partner participation.

DISCUSSION: Although clinicians consistently addressed core medical information about AAT, variation in framing, values elicitation, teach-back, presentation of alternatives, and patient-care partner engagement may shape AAT decision making. Communication strategies that explicitly present options, connect potential outcomes to patient priorities, and reinforce understanding may support balanced, values-aligned SDM.},
}

@article {pmid42966961,
year = {2026},
author = {Alwithanani, NA},
title = {Bidirectional Interplay Between Periodontitis and Alzheimer's Disease: Mechanisms, Clinical Management, and Preventive Strategies.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e117264},
pmid = {42966961},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder, whereas periodontitis is a highly prevalent chronic inflammatory disease that may have important systemic consequences. Increasing evidence suggests a bidirectional relationship between periodontitis and AD, with periodontal inflammation potentially contributing to cognitive decline and neurodegeneration, while cognitive and motor impairment may simultaneously worsen oral hygiene and periodontal health. This narrative review synthesizes current evidence regarding the epidemiological association, potential biological mechanisms, clinical implications, and emerging preventive and therapeutic strategies linking the two conditions. Evidence indicates that periodontitis is associated with an increased risk of cognitive impairment and AD, although causality remains unproven. Proposed mechanisms include translocation of periodontal pathogens, particularly Porphyromonas gingivalis, systemic inflammation and neuroinflammation, blood-brain barrier disruption, oxidative stress, microbiome alterations, and effects on amyloid-β and tau pathology. In patients with AD, progressive cognitive impairment can compromise oral self-care and increase dependence on caregivers, contributing to periodontal deterioration. Early periodontal assessment, individualized treatment, caregiver-supported oral hygiene, regular maintenance, and interdisciplinary care may therefore be clinically beneficial. Emerging approaches targeting periodontal pathogens, gingipains, and the oral microbiome are promising but require stronger clinical validation. Overall, maintaining periodontal health represents a potentially modifiable component of comprehensive strategies for reducing the oral and systemic burden associated with AD.},
}

@article {pmid42966975,
year = {2026},
author = {Kujuro, Y and Saito, M and Maruko, M and Qian, E and Koh, H and Katai, H and Hattori, H},
title = {Spatial patterns of amyloid clearance after donanemab: A preliminary 12-month real-world amyloid PET study in Japanese patients with early Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70539},
pmid = {42966975},
issn = {2352-8729},
abstract = {INTRODUCTION: The regional pattern of amyloid clearance during donanemab treatment in routine practice is poorly characterized.

METHODS: We analyzed amyloid positron emission tomography (Centiloid, regional standardized uptake value ratio, visual reads) at baseline and 12 months in 18 donanemab-treated patients with early Alzheimer's disease.

RESULTS: Clearance was near-complete (removal 96%; 72% visually negative, i.e., full treatment-related amyloid clearance), although lower in the 2 early-onset (78%) than the 16 late-onset patients (98%). Higher baseline burden and older age predicted greater clearance (r = 0.88, P < .001; r = 0.60, P = .009, respectively). This held regionally (r = 0.82-0.91, all P < .001), with the posterior cingulate and precuneus clearing first. Clearance was independent of medial temporal atrophy and unrelated to 12-month cognitive change.

DISCUSSION: Donanemab cleared regional amyloid in proportion to its baseline distribution, with deposition-heavy regions clearing first and the temporal cortex retaining residual signal, independent of neurodegenerative stage and unrelated to short-term cognition.},
}

@article {pmid42967021,
year = {2026},
author = {Bao, X and García Pascual, B and Blakstad, E and Norgren, J and Abzhandadze, T and Zhu, N and Hoang, MT and Chatterjee, S and Scolamiero, M and Eriksdotter, M and Xu, H and Ptacek, SG},
title = {Mini-Mental State Examination trajectories across dementia subtypes in the Swedish Registry for Cognitive/Dementia Disorders and U.S. National Alzheimer's Coordinating Center.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70531},
pmid = {42967021},
issn = {2352-8729},
support = {P30 AG086403/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG092752/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Mini-Mental State Examination (MMSE) trajectories are widely used to describe cognitive decline in dementia, but estimates may be sensitive to cohort structure, follow-up density, and modeling assumptions. We compared subtype-specific MMSE trajectories across two complementary longitudinal data resources.

METHODS: The analyzed data were from the Swedish Registry for Cognitive/Dementia Disorders (SveDem) and the U.S. National Alzheimer's Coordinating Center (NACC). Participants were included with at least two valid cognitive assessments separated by ≥ 90 days. The final cohorts included 30,115 SveDem participants and 33,429 NACC participants. Subtype-stratified regression-spline generalized additive mixed models and linear mixed-effects models were fitted with adjustment for demographic and clinical covariates.

RESULTS: Compared with NACC, SveDem participants were older (median age 79 vs. 72 years), had lower baseline MMSE scores (22.3 ± 4.2 vs. 26.5 ± 4.6), and had shorter follow-up (median 1.9 vs. 3.2 years; mean cognitive assessments 2.9 vs. 4.5). Shared dementia subtypes showed broadly similar relative decline patterns across cohorts. In regression-spline models, Alzheimer's disease showed faster estimated annualized decline than vascular dementia in both SveDem (-0.79 vs. -0.49 MMSE points/year) and NACC (-1.22 vs. -0.24 points/year). Lewy body dementias and frontotemporal dementia showed intermediate but less consistent patterns. Absolute decline estimates varied by model specification, particularly where later follow-up was sparse.

DISCUSSION: Relative subtype-specific MMSE decline patterns were broadly reproducible, whereas absolute long-horizon estimates required cautious interpretation. These cross-cohort reference patterns may support future dementia epidemiology studies using MMSE trajectories to compare subtypes, examine clinical factors or evaluate treatment-related associations.},
}

@article {pmid42961657,
year = {2026},
author = {Rezapour, R and Jaberi-Asl, A and Vasheghani Farahani, A and Bahramirad, A and Farhadi, M and Jameie, SB},
title = {Resveratrol partially restores the expression of the clock genes Per1 and Bmal1 in the suprachiasmatic nucleus of scopolamine-induced Alzheimer's rat model.},
journal = {Experimental brain research},
volume = {244},
number = {12},
pages = {},
pmid = {42961657},
issn = {1432-1106},
mesh = {Animals ; *Resveratrol/pharmacology ; *Alzheimer Disease/metabolism/chemically induced/drug therapy/pathology ; Male ; *Period Circadian Proteins/metabolism/genetics/drug effects ; *ARNTL Transcription Factors/metabolism/drug effects/genetics ; Rats, Wistar ; Disease Models, Animal ; *Suprachiasmatic Nucleus/drug effects/metabolism ; Rats ; Scopolamine/toxicity ; *Antioxidants/pharmacology ; Stilbenes/pharmacology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia and is associated with disruptions in biological rhythms regulated by clock genes within the suprachiasmatic nucleus (SCN). Altered expression of these genes may contribute to disease progression and symptom severity. Resveratrol (Res), a polyphenolic compound with antioxidant and neuroprotective properties, has been reported to alleviate AD-related impairments. This study aimed to examine the effects of Res on the expression of the clock genes Bmal1, Per1, and p53 in the SCN of a scopolamine-induced AD rat model. Thirty-six male Wistar rats were randomly assigned to four groups: control (Cont), AD, AD+ethanol (AD + Eth), and AD+Resveratrol (AD + Res). AD was induced by intraperitoneal injection of scopolamine, and histopathological confirmation was performed using Congo red staining. The mRNA expression levels of Bmal1, Per1, and p53 in the SCN were quantified by qRT-PCR, and neuronal density was assessed using Nissl staining. The expression of Bmal1 and Per1 was significantly decreased in the AD and the AD + Eth groups compared with the control group. Resveratrol treatment significantly upregulated these genes relative to both the AD and the AD + Eth groups. In contrast, p53 expression was markedly elevated in all AD-related groups, while Res significantly reduced its expression in the AD + Res group. Nissl staining showed a reduction in neuronal density in the SCN of AD rats, which was partially restored by Res. Res improved spatial learning and memory and partially restored Per1 and Bmal1 expression in the SCN, but a causal relationship was not tested.},
}

Animals
*Resveratrol/pharmacology
*Alzheimer Disease/metabolism/chemically induced/drug therapy/pathology
Male
*Period Circadian Proteins/metabolism/genetics/drug effects
*ARNTL Transcription Factors/metabolism/drug effects/genetics
Rats, Wistar
Disease Models, Animal
*Suprachiasmatic Nucleus/drug effects/metabolism
Rats
Scopolamine/toxicity
*Antioxidants/pharmacology
Stilbenes/pharmacology
Tumor Suppressor Protein p53/metabolism

@article {pmid42961718,
year = {2026},
author = {Li, D and Ding, G and Sun, Z and Qian, Y and Zhang, W and Wang, G and Zhang, F},
title = {Heat-Killed Lactobacillus murinus Attenuates Aβ25-35-Induced Neurotoxicity and Alters Hippocampal 6-Phosphogluconate Metabolism.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42961718},
issn = {1867-1314},
support = {F-1055//Doctor Start Fund of Zunyi Medical University/ ; MS[2025]382, ZK[2024]259//Guizhou Provincial Basic Research Program (Natural Science)/ ; GMULH (2025) 020//Guizhou Science and Technology Department/ ; No. 82460711//the National Natural Science Foundation of China/ ; Nos. ZYD[2025]022, ZD[2026]163 and KJLYRC-[2026]038//the Science and Technology Foundation of Guizhou Province/ ; },
abstract = {The gut microbiota is increasingly recognized as an important contributor to Alzheimer's disease (AD), potentially influencing disease progression through the gut-brain axis. Lactobacillus murinus (L. murinus) is a Gram-positive bacterium with established anti-inflammatory and antibacterial properties; however, the neuroprotective potential of heat-killed L. murinus (H-K L. murinus) in AD models remains unclear. In the present study, we investigated the effects of H-K L. murinus in an Aβ25-35-induced rat model. H-K L. murinus treatment significantly improved behavioral and cognitive performance while attenuating neuronal damage in the hippocampus and cerebral cortex. Untargeted metabolomic analysis identified 6-phosphogluconic acid (6-PGA) as a markedly elevated hippocampal metabolite following H-K L. murinus administration. Exogenous 6-PGA supplementation largely recapitulated the protective effects of H-K L. murinus, improving cognitive performance and preserving neuronal integrity. Mechanistically, both H-K L. murinus and 6-PGA increased NADPH and glutathione (GSH) levels, suppressed reactive oxygen species (ROS) accumulation, down-regulated Bax expression, up-regulated Bcl-2 expression, and ultimately attenuated neuronal apoptosis in Aβ25-35-treated rats. Collectively, these findings demonstrate that H-K L. murinus mitigates Aβ25-35-induced neurotoxicity and highlight hippocampal 6-PGA-associated metabolism as a potential candidate contributor to its neuroprotective effects.},
}

@article {pmid42963328,
year = {2026},
author = {Kim, D and Ho, BC and van Voorst, H and Liu, Y and Benzinger, TLS and Sha, S and Mormino, E and Henderson, VW and Zaharchuk, G},
title = {Deep learning-based prediction of regional brain Tau PET burden from MRI.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42963328},
issn = {1552-5279},
support = {P30 AG066515/AG/NIA NIH HHS/United States ; P30AG066515/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Magnetic Resonance Imaging/methods ; *tau Proteins/metabolism ; *Deep Learning ; *Brain/diagnostic imaging/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; Male ; Aged ; Predictive Learning Models ; Prediction Algorithms ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Regional tau is strongly associated with Alzheimer's disease (AD) symptoms, but tau positron emission tomography (PET) is not routinely available, limiting early risk stratification.

METHODS: We trained a deep learning model to predict regional tau PET standardized uptake value ratios (SUVRs) from magnetic resonance imaging (MRI) with and without basic demographics using public cohorts (Alzheimer's Disease Neuroimaging Initiative [ADNI], Open Access Series of Imaging Studies 3 [OASIS3-tau], Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study [A4], Harvard Aging Brain Study [HABS]). Mean absolute error (MAE), Pearson r, area-under-the-receiver-operating-curve (AUC), and comparison with cognitive testing were assessed in external test sets (SCAN, Stanford University).

RESULTS: The model achieved an MAE of 0.14 (95% confidence interval [CI]: 0.12-0.16) and r = 0.72 for an early uptake region (Braak I-IV), and an MAE of 0.14 (95% CI: 0.12-0.17) and r = 0.71 for a late uptake region (Braak V-VI). AUCs for binary tau positivity in these regions were 0.87 (95% CI: 0.83-0.90) and 0.88 (95% CI: 0.84-0.91), respectively.

DISCUSSION: Predicting regional tau burden from magnetic resonance imaging (MRI) is feasible and may enable scalable tau-informed clinical AD care.},
}

Humans
*Positron-Emission Tomography/methods
*Magnetic Resonance Imaging/methods
*tau Proteins/metabolism
*Deep Learning
*Brain/diagnostic imaging/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Female
Male
Aged
Predictive Learning Models
Prediction Algorithms
Aged, 80 and over

@article {pmid42963333,
year = {2026},
author = {Tariot, PN and Dickson, SP and Dwyer, J and Granda, C and Hughes, L and Karlawish, J and Linz, N and Nair, KV and Paulsen, R and Pawson, D and Perneczky, R and Schindler, SE and Scholler, E and Taylor, J and Tiede, B and Vradenburg, G},
title = {Expert perspectives on the design and communication of endpoints in Alzheimer's disease clinical trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42963333},
issn = {1552-5279},
support = {//Bristol Myers Squibb/ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; *Clinical Trials as Topic ; *Endpoint Determination ; *Communication ; *Research Design ; },
abstract = {Disease-targeted therapies (DTTs) for Alzheimer's disease (AD) represent a major advance, yet challenges remain on how best to interpret and communicate their benefits. As clinical development increasingly targets the earliest stages of AD (before symptoms emerge and early symptomatic AD), there is a need for novel, complementary endpoints and improved communication of treatment benefits. The Global CEO Initiative on Alzheimer's Disease convened a multi-stakeholder working group to develop recommendations for improving the design and communication of endpoints in AD clinical trials. In the near term, communication can be improved by contextualizing treatment effects at the individual level, including framing benefits in terms of responder analyses and "time saved" over defined timeframes. In parallel, continued development of complementary endpoints is needed to enable more sensitive, scalable, and patient-centered measurements aligned with early intervention. These recommendations aim to support stakeholders in evaluating and communicating the meaningful benefits of current and emerging therapies.},
}

*Alzheimer Disease/therapy/drug therapy
Humans
*Clinical Trials as Topic
*Endpoint Determination
*Communication
*Research Design

@article {pmid42963367,
year = {2026},
author = {Tian, J and Jia, K and Chen, Y and Wang, T and Guo, L and Swerdlow, RH and Du, H},
title = {Mitochondrial complex IV disruption is a detrimental pathology conferring ssusceptibility to alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42963367},
issn = {1476-5578},
support = {R01AG075108//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01AG059753//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; P30 AG072973//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; P30 AG035982//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; A20201159S//BrightFocus Foundation (BrightFocus)/ ; A2022036S//BrightFocus Foundation (BrightFocus)/ ; },
abstract = {Mitochondrial complex IV (CIV) is an integral part of the mitochondrial electron transport chain (ETC) and plays a pivotal role in maintaining mitochondrial function. In contrast to the long-standing recognition of its dysfunction in Alzheimer's disease (AD), the exact role of CIV deficit in the pathogenesis of this neurodegenerative disorder remains poorly defined. In this study, by incorporating clinical resources, mouse- and human-based models of AD risk, and a genetic approach to bypass defective CIV via the ectopic expression of alternative oxidase (AOX), we examined whether CIV deficits are a pathogenic driver of or a beneficial adaptation to AD-associated pathologies. Our results showed a clinicopathological association between neuronal CIV dysfunction and pathological characteristics of AD. Further experiments linked defective CIV to the development of mitochondrial dysfunction and synaptic loss in the tested mouse- and human-based models of AD risk. In addition, a reciprocal relationship between CIV dysfunction and amyloid pathology was determined. Lastly, a proteome-wide association study (PWAS) using genetic data from large-scale AD cohorts identified that downregulation of COX11, a crucial CIV assembly factor, confers susceptibility to AD risk. Collectively, our findings suggest that CIV dysfunction is a detrimental pathology contributing to AD-associated mitochondrial and neuronal damage. The dual role of CIV dysfunction, both as a consequence of and a contributor to amyloid toxicity in AD pathogenesis, further justifies the therapeutic potential of strategies targeting CIV deficits to diversify the tools for prevention and treatment of this neurodegenerative disorder.},
}

@article {pmid42964735,
year = {2026},
author = {Ghiasvand, K and Meftahi, GH},
title = {Black Myrobalan (Terminalia chebula) as a potential multitarget neuroprotective agent: Translational insights and future directions in neurodegenerative diseases.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102850},
pmid = {42964735},
issn = {2405-5808},
abstract = {Myrobalan or Haritaki (Terminalia chebula Retz.) has been integrated into Ayurvedic, Unani, and even Tibetan medicine systems for over 2000 years. The "King of Medicines" has traditionally been used for diverse ailments such as digestive issues, wound healing, and general body strengthening. Now, modern medicine is focusing on the myrobalan's potential neuroprotective properties and its use in Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS) neurodegenerative disorders. These ailments are characterized by some combination of enduring oxidative damage, mitochondrial dysfunction, neuroinflammation, irregular protein aggregation, and progressive neuron cell death. Most of the current treatment options revolve around addressing the symptoms of the diseases, which is insufficient as the underlying disease continues to progress. There is an urgent need to devise therapies that work simultaneously on multiple disease pathways. Some of the noted secondary metabolites in T. chebula include hydrolyzable tannins like chebulinic and chebulagic acid as well as corilagin. Others occur as phenolic acids such as gallic and ellagic acid and flavonoids quercetin and kaempferol. Moreover, glycosides, sterols, and a wide range of alkaloids are also present. A number of these compounds are known to possess multifunctional biological properties like scavenging ROS, activating Nrf2/ARE signaling, downregulating pro-inflammatory mediators through blockade of NF-κB, and exerting protective effects on the mitochondria, as well as modulating apoptosis via Bcl-2 and caspases. T. chebula extracts and some isolated compounds have also been shown to improve cognitive function, reduce neuroinflammation, and protect dopaminergic neurons, and ameliorate neurotoxic effects of amyloid-β or α-synuclein through in vitro and in vivo animal studies. A review of the contributions from the phytochemistry, mechanism of action, preclinical, translational, and adjunctive applications of Terminalia chebula in neurodegenerative disease therapy is presented here.},
}

@article {pmid42964797,
year = {2026},
author = {Gaggi, NL and Hurwitz, B and Bernal, J and O'Brien, C and Ren-Fielding, C and Lofton, H and Chen, J and Saperstein, A and Lee, SH and Chang, YJ and Yates, KF and Fieremans, E and Osorio, R and Convit, A},
title = {Brain and Cardiometabolic Effects of Major Weight Loss in People With Obesity: Preliminary Cohort Findings.},
journal = {Obesity science & practice},
volume = {12},
number = {6},
pages = {e70191},
pmid = {42964797},
issn = {2055-2238},
support = {RF1 AG080609/AG/NIA NIH HHS/United States ; R01 AG080609/AG/NIA NIH HHS/United States ; R01 AG056031/AG/NIA NIH HHS/United States ; R01 AG055624/AG/NIA NIH HHS/United States ; R01 AG070821/AG/NIA NIH HHS/United States ; R01 AG056682/AG/NIA NIH HHS/United States ; R01 AG056531/AG/NIA NIH HHS/United States ; R01 AG068248/AG/NIA NIH HHS/United States ; R01 AG079282/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: Given the overlap between obesity-related metabolic and vascular abnormalities and Alzheimer's disease (AD) risk factors, it is critical to determine whether weight loss improves brain and cardiovascular health. This study examined whether ≥ 40% excess-weight loss is associated with improvements in cardiometabolic risk, brain structure, and cognition.

METHODS: The study was a longitudinal study of individuals with obesity undergoing metabolic and bariatric surgery or medical/behavioral weight-loss treatment. Participants were classified at follow-up as weight-loss (WL; ≥ 40% excess-weight loss) or non-weight-loss (nWL; < 40%). All completed medical evaluations, structural MRI, and cognitive testing at baseline and 1 year.

RESULTS: At 1 year, the WL group exhibited improvements in BMI, HbA1C, inflammatory, metabolic, and lipid profiles. MRI-based volumetrics revealed increases in subcortical gray-matter volume and preservation of AD-vulnerable regions. Cognitive performance remained unchanged.

CONCLUSIONS: Achieving ≥ 40% excess-weight loss was associated with improvements in metabolic health and brain structure, including favorable subcortical volume increases. These findings underscore the potential of sustained weight reduction to mitigate risks linked to metabolic syndromes and neurodegeneration. Longer-term follow-up is warranted to determine whether continued metabolic improvements lead to detectable cognitive gains and additional brain-health benefits beyond 1 year.},
}

@article {pmid42964993,
year = {2026},
author = {Blivet, G and Bertrand, C and Brauge, D and Delrieu, J and Touchon, J},
title = {Photobiomodulation as a regulator of neuroinflammation: mechanistic insights and therapeutic potential in brain disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1902491},
pmid = {42964993},
issn = {1664-2295},
mesh = {Humans ; *Low-Level Light Therapy/methods ; *Neuroinflammatory Diseases/radiotherapy/metabolism ; Animals ; *Brain Diseases/radiotherapy/therapy/metabolism ; },
abstract = {Brain disorders, including neurodegenerative, neuropsychiatric, and cerebrovascular diseases, represent a growing global health challenge contributing to disability and mortality worldwide. Although these conditions differ in etiology and clinical presentation, accumulating evidence identifies neuroinflammation as a shared pathological mechanism. Involving microglial activation, astrocytic reactivity, cytokine dysregulation, oxidative stress, mitochondrial dysfunction, and blood-brain barrier disruption, it contributes to synaptic dysfunction, neuronal loss, and disease progression, yet therapeutic strategies targeting these processes remain limited. Photobiomodulation (PBM), the therapeutic application of low-intensity red to near-infrared light, has emerged as a neurotechnology capable of modulating biological pathways relevant to neuroinflammation. Preclinical studies suggest that PBM may influence mitochondrial activity through cytochrome c oxidase-mediated mechanisms, enhancing cellular metabolism while regulating reactive oxygen species, inflammatory signaling pathways, and tissue homeostasis. Through these effects, PBM may attenuate neuroinflammatory responses, regulate glial activation, and support neuroprotective processes across multiple neurological models. This narrative review examines evidence supporting neuroinflammation as a common denominator across major brain disorders and explores the biological rationale for PBM as a therapeutic strategy. It summarizes the cellular and molecular basis of PBM, its effects on neuroinflammatory pathways, and preclinical and clinical findings across brain disease models. Preclinical findings consistently support a multi-target anti-inflammatory effect, whereas clinical investigation remains at an early stage, with encouraging results in Alzheimer's disease and multiple sclerosis but mainly negative data on primary outcomes in Parkinson's disease and major depressive disorder. Further research is needed to optimize treatment parameters, clarify mechanisms of action, and determine clinical efficacy across disease contexts.},
}

Humans
*Low-Level Light Therapy/methods
*Neuroinflammatory Diseases/radiotherapy/metabolism
Animals
*Brain Diseases/radiotherapy/therapy/metabolism

@article {pmid42965578,
year = {2026},
author = {Kumar, A and He, Y and Kim, S and Hsu, FC and Meade, CS and Kiraly, DD and Strowd, R and Lesser, GJ and Deep, G},
title = {Longitudinal plasma protein profiling in glioblastoma patients using NULISAseq reveals treatment-associated changes across radiation and chemotherapy.},
journal = {Journal of neuro-oncology},
volume = {180},
number = {2},
pages = {},
pmid = {42965578},
issn = {1573-7373},
mesh = {Humans ; *Glioblastoma/blood/therapy/radiotherapy/pathology/drug therapy ; *Brain Neoplasms/blood/therapy/radiotherapy/drug therapy/pathology ; Female ; *Temozolomide/therapeutic use ; Male ; *Proteomics/methods ; *Biomarkers, Tumor/blood ; Longitudinal Studies ; Middle Aged ; Antineoplastic Agents, Alkylating/therapeutic use ; Chemoradiotherapy ; Aged ; Adult ; },
abstract = {PURPOSE: Glioblastoma (GBM) is the most aggressive primary brain tumor with poor outcomes despite surgery, radiotherapy (RT), and temozolomide (TMZ). Monitoring relies on imaging, which is confounded by pseudoprogression and provides limited molecular insight. Circulating biomarkers may offer a minimally invasive approach to track disease and treatment effects.

METHODS: We performed targeted longitudinal proteomic profiling of plasma from post-surgery GBM patients (n = 11) at baseline (pre-radiotherapy (RT)), after RT with concomitant TMZ, and after adjuvant TMZ, alongside healthy controls (n = 15), using the NULISAseq CNS panel covering 131 proteins related to neurodegeneration, neuroinflammation, and vascular health. Differential expressions were assessed using volcano plots, hierarchical clustering, paired statistical comparisons and longitudinal trends analysis.

RESULTS: At baseline, GBM plasma showed elevated markers of neuroaxonal and glial injury, extracellular matrix regulators, and inflammatory signaling compared to controls. Several established neurodegeneration and Alzheimer's disease- related biomarkers were also higher in GBM plasma versus controls. Following radiotherapy and concomitant TMZ, cytokines including IL10, IL5, and IL33 increased, indicating systemic immune activation, while BDNF showed a modest decline. Adjuvant TMZ treatment attenuated radiotherapy-induced cytokine elevations and reduced neuronal injury markers, suggesting therapy-driven reduction of inflammatory and neurodegenerative signals. Longitudinal analysis confirmed dynamic shifts in specific proteins across baseline, radiotherapy, and TMZ phases.

CONCLUSION: High-sensitivity plasma proteomics suggested therapy-induced changes in CNS-specific and immune markers in GBM, highlighting candidate biomarkers that can be further developed for real-time monitoring of treatment response. These findings suggest candidate circulating markers that may complement imaging for monitoring disease biology and therapeutic response, and warrant validation in larger cohorts.},
}

Humans
*Glioblastoma/blood/therapy/radiotherapy/pathology/drug therapy
*Brain Neoplasms/blood/therapy/radiotherapy/drug therapy/pathology
Female
*Temozolomide/therapeutic use
Male
*Proteomics/methods
*Biomarkers, Tumor/blood
Longitudinal Studies
Middle Aged
Antineoplastic Agents, Alkylating/therapeutic use
Chemoradiotherapy
Aged
Adult

@article {pmid42957985,
year = {2026},
author = {Hu, P and Zhang, M and Wei, X and Xiao, S and Li, B and Liu, K and Su, G and Han, B and Shi, X and Wei, C and Sun, J and Zhang, Z and Han, Z and Shen, L},
title = {Total salvianolic acids protect APP/PS1 mice from Alzheimer's disease by attenuating neuroinflammation through hippocampal lipid regulation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498369},
doi = {10.1177/13872877261498369},
pmid = {42957985},
issn = {1875-8908},
abstract = {BackgroundTotal salvianolic acids (TSA) have been shown to exert neuroprotective effects in cognition-associated behavioral tests in APP/PS1 mice in our previous research; however, research on TSA-mediated modulation of hippocampal lipid metabolism remains limited.ObjectiveThis study elucidated the therapeutic mechanisms underlying prophylactic TSA administration by integrating lipidomic profiling and demonstrating TSA-induced neuroprotection through suppression of hippocampal neuroinflammation in APP/PS1 mice.MethodsTen 3.5-month-old APP/PS1 mice and ten age-matched wild-type mice received intraperitoneal saline injections as the disease model and healthy control groups. Another twenty APP/PS1 mice were allocated to two TSA treatment groups (30 mg/kg/day and 60 mg/kg/day). After fifteen weeks of intervention, memory performance was assessed using the Y-maze test. Hippocampal Aβ, IBA1, and GFAP protein expression levels were quantified by western blotting. Targeted UHPLC-MS/MS was used for quantitative detection of hippocampal lipid biomarkers.ResultsThe 60 mg/kg TSA group exhibited improved memory in Y-maze tests, with elevated spontaneous alternation rate (p < 0.05) and arm entries (p < 0.01). The latency to enter the novel arm was significantly reduced at both doses of TSA (p < 0.01). TSA at 60 mg/kg reduced hippocampal inflammation markers IBA1 (p < 0.05), GFAP (p < 0.05), and Aβ (p < 0.01) in APP/PS1 mice. Lipids revealed significant changes in 41 lipid species after TSA treatment. TSA suppressed the levels of glycerides, sterol lipids, and free fatty acids while increasing glycolipids including monogalactosyldiacylglycerols. TSA also regulated sphingomyelins by reducing acyl chain-modified PCs and increasing phosphatidylserines.ConclusionsThis study reveals TSA's preventive potential against Alzheimer's disease by modulating inflammation-associated lipid metabolism in APP/PS1 mice.},
}

@article {pmid42958467,
year = {2026},
author = {Dou, J and Zhu, Y and Du, Z and Zhang, G},
title = {LncRNA FBXL19-AS1 regulates the miR-650/ITGB3 axis to drive pathological progression in Alzheimer's Disease.},
journal = {Hereditas},
volume = {163},
number = {1},
pages = {},
pmid = {42958467},
issn = {1601-5223},
support = {Grant No. 2541ZF292//Baoding Science and Technology Program/ ; },
mesh = {Humans ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics/pathology ; *RNA, Long Noncoding/genetics ; Female ; *Integrin beta3/genetics ; Disease Progression ; Apoptosis ; Cell Proliferation ; Male ; Gene Expression Regulation ; Aged ; Amyloid beta-Peptides ; Cell Line, Tumor ; Cell Line ; DNA-Binding Proteins ; F-Box Proteins ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by complex and not yet fully understood pathological mechanisms. This study was designed to explore the molecular mechanisms of long non-coding RNA (lncRNA) FBXL19-AS1 in the pathological progression of AD.

METHODS: 110 AD patients and 110 healthy controls were recruited for this study. Relevant gene expression was measured using reverse transcription quantitative real-time PCR (RT-qPCR), and the diagnostic performance was assessed through receiver operating characteristic (ROC) curve analysis. AD cell models were established by treating SH-SY5Y and BV2 cells with amyloid β (Aβ)25-35. Cell proliferation was evaluated using the cell counting kit-8 (CCK-8) assay, cell apoptosis was analyzed by flow cytometry, and the secretion levels of inflammatory factors were determined via enzyme-linked immunosorbent assay (ELISA). A dual-luciferase reporter assay was performed to confirm the direct regulatory interactions.

RESULTS: In AD patients, the FBXL19-AS1 and integrin subunit beta 3 (ITGB3) expression were significantly elevated, whereas microRNA-650 (miR-650) expression was markedly reduced. FBXL19-AS1 showed certain diagnostic potential for AD, and its expression was negatively correlated with Montreal Cognitive Assessment (MoCA) scores. Following treatment with Aβ25-35, SH-SY5Y cells exhibited reduced proliferative capacity and increased apoptosis, while BV2 cells showed elevated levels of inflammatory factors. Additionally, Aβ25-35 treatment led to upregulated expression of FBXL19-AS1 and ITGB3, along with downregulated expression of miR-650. Knockdown of FBXL19-AS1 effectively reversed these effects. However, inhibition of miR-650 partially attenuated the changes induced by FBXL19-AS1 knockdown. Furthermore, knockdown of FBXL19-AS1 markedly reduced ITGB3 expression, whereas concurrent inhibition of miR-650 partially reversed this downregulatory effect.

CONCLUSION: FBXL19-AS1 appears to interact with and modulate miR-650, thereby affecting ITGB3 expression and potentially participating in the pathological progression of AD.},
}

Humans
*MicroRNAs/genetics
*Alzheimer Disease/genetics/pathology
*RNA, Long Noncoding/genetics
Female
*Integrin beta3/genetics
Disease Progression
Apoptosis
Cell Proliferation
Male
Gene Expression Regulation
Aged
Amyloid beta-Peptides
Cell Line, Tumor
Cell Line
DNA-Binding Proteins
F-Box Proteins

@article {pmid42959393,
year = {2026},
author = {Bermudez, C and Pillai, JJ and Burkett, BJ and McDonald, JS and Johnson, DR and Wiste, HJ and Weigand, SD and Jack, CR and Vemuri, P and Petersen, RC and Graff-Radford, J and Ramanan, VK and Cogswell, PM},
title = {Differences in anti-amyloid therapy eligibility assessment based on use of the SWI versus GRE sequence.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70524},
pmid = {42959393},
issn = {2352-8729},
abstract = {INTRODUCTION: The number of microhemorrhages (mHs) increases risk of amyloid-related imaging abnormalities (ARIAs) in those undergoing anti-amyloid treatments for Alzheimer's disease. It is unclear whether using different magnetic resonance imaging (MRI) sequences to detect mH would alter treatment decisions.

METHODS: We retrospectively analyzed 55 adults (mean age 72.1 ± 7.1 years) evaluated for cognitive concerns who had MRI exams including both susceptibility-weighted imaging (SWI) and gradient echo (GRE) sequences. Three neuroradiologists independently identified and then reached consensus on mH detection. Participants were classified into mH burden categories (none, 1, 2-4, ≥ 5).

RESULTS: Readers identified 83 mHs (mean 1.51) on SWI versus 54 (mean 0.98) on GRE. Burden categories agreed in 34 (61.8%) participants, was higher on SWI in 17 (30.9%) participants, and higher on GRE in 4 (7.3%) participants.

CONCLUSIONS: Readers on average identified more mHs on SWI than GRE, altering risk categories. Prospective studies are needed to establish SWI-based safety thresholds for anti-amyloid therapies.},
}

@article {pmid42959452,
year = {2026},
author = {Acquarone, E and Gutierrez, SBG and Zhang, H and Morin, A and Maccecchini, M and Arancio, O},
title = {Combined administration of buntanetap and dulaglutide counteracts synaptic dysfunction and memory loss in an Alzheimer's disease mouse model.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70336},
pmid = {42959452},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) results from disruptions in proteostasis, metabolism, and neurotrophic signaling that impair synaptic plasticity and memory. Dulaglutide, a blood-brain barrier (BBB)-permeant glucagon-like peptide-1 (GLP-1) receptor agonist, enhances phosphoinositide 3-kinase (PI3K)/Akt and cAMP response element-binding protein (CREB) signaling, while buntanetap reduces translation of aggregation-prone proteins such as amyloid precursor protein (APP), tau, α-synuclein, and transactive response DNA-binding protein of 43 kDa. Although both compounds show cognitive benefits individually, their potential synergistic effects remain unexplored.

METHODS: APP/presenilin 1 (PS1) mice and wild-type (WT) littermates were treated with dulaglutide or buntanetap at high or subthreshold doses, alone or in combination, beginning at plaque deposition. Spatial memory was assessed through the 2-day radial arm water maze (RAWM), associative memory using contextual fear conditioning, and hippocampal Schaffer collateral-CA1 long-term potentiation (LTP) was evaluated as a measure of synaptic plasticity. Motor, sensory, motivational, and shock-sensitivity controls were included to rule out confounding non-cognitive effects. Meso Scale Discovery and Western blotting analyses were performed on frozen hippocampal tissue to assess amyloid beta (Aβ) and the postsynaptic density protein 95 (PSD95) marker levels.

RESULTS: High doses of either dulaglutide or buntanetap alone rescued deficits in spatial and contextual memory as well as LTP in APP/PS1 mice, whereas lower doses produced minimal or partial benefit. Concurrent administration of low, individually ineffective doses of buntanetap (1 mg/kg) and dulaglutide (0.1 mg/kg) fully rescued RAWM performance, restored contextual fear memory and CA1 LTP, reduced Aβ levels, and restored PSD95. The combination treatment did not alter behavior in WT mice across control behavioral tasks, confirming treatment specificity for AD-related deficits.

DISCUSSION: Our findings demonstrate a strong synergistic interaction between BBB-permeant dulaglutide and buntanetap at subthreshold doses, showing that combined enhancement of neurotrophic signaling and reduction of proteotoxic stress can rescue hippocampal dysfunction in early AD. This convergence between GLP-1 receptor-mediated pathways and inhibition of neurotoxic protein synthesis supports the clinical evaluation of GLP-1-based combination therapies with proteostatic modulators such as buntanetap.},
}

@article {pmid42960557,
year = {2026},
author = {Benitez, A and Hickey, R and Baker, N and Thorn, K and Watson, Z and Nunn, L and McRae-Clark, A},
title = {Sex Differences in Stress Reactivity and Dementia Risk: A Pilot Study of Older Adults With Problematic or Frequent Cannabis Use.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261502978},
doi = {10.1177/08919887261502978},
pmid = {42960557},
issn = {1552-5708},
abstract = {IntroductionWe conducted a pilot study of older cannabis users with problematic or frequent (i.e. ≥4/7 days/week) use as a preliminary test of the hypothesis that compared to men, women would demonstrate greater stress reactivity and dementia risk.Methods47 participants ages 50-75 (55.3% male, 68% with cannabis use disorder) completed the Trier Social Stress Test, neuropsychological testing, 3T brain MRI, and blood draw.ResultsMen demonstrated: greater salivary cortisol, systolic blood pressure, and craving post-stress induction; worse memory and executive function; greater risk of heart disease or stroke and white matter hyperintensity volumes. There were no sex differences in Alzheimer's disease plasma biomarkers.ConclusionsAmong non-treatment-seeking older adults with problematic or frequent cannabis use, men may have greater risk for dementia due to stress reactivity and vascular risk factors. Future work must replicate and verify this unexpected sex difference and the specificity of these effects to cannabis use.},
}

@article {pmid42961631,
year = {2026},
author = {Dong, S and Gao, K and Lin, W and Chen, W and Liu, H and Wang, Q and Yi, Z},
title = {Cost-Effectiveness Analysis of Disease-Modifying Therapies for Early Alzheimer's Disease in China.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42961631},
issn = {2193-8253},
support = {72674010//National Natural Science Foundation of China/ ; MBRC0012025062//Talent Development Plan for the Future in Medical-Engineering Integration of BRA-CDCHE and ZTA/ ; },
abstract = {INTRODUCTION: Lecanemab and donanemab are disease-modifying therapies for early Alzheimer's disease, but their long-term economic value in China remains uncertain. This study evaluated their long-term cost-effectiveness in China.

METHODS: A lifetime Markov model compared lecanemab plus standard of care (SoC), donanemab plus SoC, and SoC alone from the Chinese healthcare system and societal perspectives. Treatment cohorts were stratified by apolipoprotein E ε4 genotype. The model incorporated Chinese real-world costs, treatment-related adverse events, discontinuation, and post-discontinuation benefits. Outcomes included costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses assessed parameter uncertainty, while scenario analyses examined drug prices, treatment populations, administration routes, and efficacy assumptions.

RESULTS: From the healthcare system perspective, ICERs (in United States dollars [USD]) for lecanemab plus SoC and donanemab plus SoC were USD 309,841.194/QALY and USD 232,793.705/QALY, respectively. Corresponding societal ICERs were USD 300,434.358/QALY and USD 212,256.111/QALY. All estimates exceeded the prespecified willingness-to-pay threshold. The ICER for lecanemab was driven mainly by treatment efficacy and drug price, whereas donanemab was most sensitive to the duration of residual treatment effect. Varying the treatment-eligible population had limited impact on the ICERs. From the healthcare system perspective, ICERs ranged from USD 304,889.902 to USD 310,071.658/QALY for lecanemab and USD 211,226.601 to USD 240,400.661/QALY for donanemab; the corresponding societal ranges were USD 293,467.938-312,810.263/QALY and USD 204,513.613-214,437.087/QALY. At assumed United States prices for subcutaneous lecanemab, intravenous administration had a slightly lower ICER from the healthcare system perspective (USD 309,841.194/QALY versus USD 317,811.454/QALY), whereas all-subcutaneous administration had a slightly lower societal ICER (USD 298,027.332/QALY versus USD 300,434.358/QALY).

CONCLUSION: Neither lecanemab nor donanemab was cost-effective at current Chinese prices. Patient selection had limited impact. The lower ICER for donanemab depended on the assumed residual treatment effect after discontinuation.},
}

@article {pmid42951505,
year = {2026},
author = {Zhou, J and Zhang, W and Yang, Y and Jin, Y and Li, X and Wang, Y and Lu, H and Gao, H and Jiang, X},
title = {CCA, a cassane diterpene from Caesalpinia bonduc ameliorates cognition impairment in Alzheimer's disease mice by regulating neuroinflammation and autophagy.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {11},
pages = {1392-1408},
doi = {10.1016/S1875-5364(26)61228-9},
pmid = {42951505},
issn = {1875-5364},
mesh = {Animals ; *Caesalpinia/chemistry ; *Alzheimer Disease/drug therapy/genetics ; *Autophagy/drug effects ; Mice ; *Diterpenes/pharmacology/administration & dosage ; Male ; *Cognitive Dysfunction/drug therapy ; Disease Models, Animal ; Microglia/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Humans ; Mice, Inbred C57BL ; Cytokines/metabolism ; },
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder, with persistent neuroinflammation and impaired autophagy recognized as key contributing factors. CCA is a naturally occurring cassane diterpene compound derived from the seed of Caesalpinia bonduc. Our research is the first to explore the role and mechanism of CCA in treating Alzheimer's disease. We assessed the levels of pro-inflammatory cytokines and autophagy in BV2 cells following lipopolysaccharide (LPS) treatment and anti-neuroinflammatory effects of CCA were evaluated in LPS-induced mice, with the underlying mechanisms explored using transcriptomic. Additionally, we examined the cognitive-enhancing effects of CCA in APP/PS1 mice and investigated Caesalpinia bonduc associated molecular mechanisms through proteomic analysis, immunohistochemistry (IHC) and immunofluorescence (IF) assays. Finally, the molecular target of CCA was validated using molecular dynamics simulations and cellular thermal shift assay (CETSA). CCA can down-regulate the mRNA levels of inflammatory factors in BV2 cells stimulated by LPS, and has good permeability of blood-brain barrier. Furthermore, CCA ameliorated cognitive impairment and neuronal damage in both LPS-induced and APP/PS1 mice. And demonstrated that CCA mitigates neuroinflammation by driving microglial polarization from M1 to M2, a process potentially mediated by the AMPK/NF-κB pathway, thereby reducing tau pathology. Proteomic profiling and IHC revealed that CCA upregulates FOXG1 expression in APP/PS1 mice. Furthermore, the scTenifoldKnk confirmed that AMPK has a significant impact on the regulation of autophagy and inflammation response. Our findings verified that CCA exhibits anti-neuroinflammatory activity by AMPK/NF-κB pathway and activates autophagy via the AMPK-mTOR-FOXG1 signaling axis, which underscores its potential as a novel therapeutic option for the treatment of AD.},
}

Animals
*Caesalpinia/chemistry
*Alzheimer Disease/drug therapy/genetics
*Autophagy/drug effects
Mice
*Diterpenes/pharmacology/administration & dosage
Male
*Cognitive Dysfunction/drug therapy
Disease Models, Animal
Microglia/drug effects
*Neuroinflammatory Diseases/drug therapy
Humans
Mice, Inbred C57BL
Cytokines/metabolism

@article {pmid42953259,
year = {2026},
author = {Tábuas-Pereira, M and Silva-Spínola, A and Agostinho, C and Alves, L and Araújo, R and Bernardes, C and Branco, M and Borbinha, C and Cabreira, V and Costa, S and Silva, AD and Durães, J and Faustino, P and Félix, C and Fernandes, A and Ferreira, J and Gago, M and Guarda, C and Ionel, C and Jesus-Ribeiro, J and Laranjinha, I and Leitão, A and Letra, L and Lopes das Neves, P and Maia, LF and Machado, Á and Martins, B and Massano, J and Mendonça, A and Mendonça, M and Miguel, R and Miranda, M and Morgado, J and Nóbrega, C and Coutinho, MP and Oliveira, T and Pita, F and Sabença, F and Rocha, S and Ruano, L and Santos, T and Simões do Couto, F and Taipa, R and Cruz, VT and Valverde, AH and Vélon, A and Verdelho, A and Viana Baptista, M and Vieira, D and Lima, M and Oliveira, TG and Santana, I and , },
title = {Current capacity of Portuguese specialized dementia centers in the era of anti-amyloid antibodies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70513},
pmid = {42953259},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) remains a major cause of cognitive decline and societal burden. The recent approval of disease-modifying therapies (DMTs) lecanemab and donanemab represents a paradigm shift in AD treatment. We assessed the preparedness of Portuguese centers to implement DMTs.

METHODS: A nationwide survey-based cross-sectional service-capacity study targeted memory clinics, focusing primarily on National Health System (NHS) centers. Data were collected on clinical capacity, diagnostic access, treatment capability, and research activity.

RESULTS: Among 51 responding units, 20 had organized memory clinics (17 in the NHS), covering 60.7% of the population. In 2024, these centers conducted 21,721 consultations, representing expert care for <10% of the total AD patients estimated to exist in Portugal. Bottlenecks included long waiting times and limited biomarker access (26.2% underwent cerebrospinal fluid or amyloid positron emission tomography). Nationwide, from experts' estimates, 701 patients could currently start treatment.

DISCUSSION: Portugal's current NHS capacity appears insufficient for broad DMT implementation, requiring major investment in diagnostics, training, infrastructure, and research to ensure equitable and effective treatment access.},
}

@article {pmid42953353,
year = {2026},
author = {Copeland, MH and Youngstrom, DE and Konrad, KS and Diering, GH and Letsinger, AC and Aksu, LR and Yakel, JL and Cushman, JD},
title = {Diphenhydramine disrupts sleep architecture in 5XFAD Alzheimer's disease model and wild-type mice.},
journal = {Neurobiology of sleep and circadian rhythms},
volume = {21},
number = {},
pages = {100154},
pmid = {42953353},
issn = {2451-9944},
support = {ZIC ES103330/ImNIH/Intramural NIH HHS/United States ; },
abstract = {Sleep disruption is common in Alzheimer's disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type female mice. Female 5XFAD (n = 16) and wild-type (WT) littermates (n = 14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG) and electromyography (EMG) continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD female mice had more time in NREM1 than WT female controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, and disrupted the light-dark distribution of sleep. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment resulted in NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model female mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.},
}

@article {pmid42953958,
year = {2026},
author = {Cerini, M and Leuci, R and Paparella, M and Roselli, V and Piemontese, L},
title = {Cholinergic-targeted molecular hybrids: a renewed strategy for Alzheimer's disease?.},
journal = {Expert opinion on drug discovery},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17460441.2026.2749525},
pmid = {42953958},
issn = {1746-045X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by a complex and multifactorial etiology that complicates its diagnosis, prevention, and treatment. Among the most historically and extensively investigated therapeutic targets are cholinesterases (ChEs), which have guided the development of most currently available symptomatic drugs. Consequently, anti-ChE activity is frequently incorporated into the design of potential multi-target anti-AD compounds.

AREAS COVERED: This critical perspective highlights recent advances in multi-target derivatives with a central anti-ChE property. Various structural scaffolds have been explored, bearing additive properties to the final hybrids, designed by combining structural features of anti-AD drugs (namely rivastigmine and donepezil). Many of these compounds have demonstrated promising outcomes, with some exhibiting greater potency than their reference drugs.

EXPERT OPINION: Multi-target small-molecule hybrids may represent a promising perspective for Alzheimer's disease, shifting the focus from cholinesterase-centered design to compounds primarily aimed at interfering with protein misfolding and aggregation, as well as other targets. In this framework, anticholinesterase activity would remain an accessory but still important component for symptomatic control.},
}

@article {pmid42955064,
year = {2026},
author = {Gordon, L and Buyuksandalyaci Tunc, E and Vaikutis, L and Grossberg, GT},
title = {Vitamin supplementation and Alzheimer's disease: what the evidence shows.},
journal = {Panminerva medica},
volume = {},
number = {},
pages = {},
doi = {10.23736/S0031-0808.26.05448-0},
pmid = {42955064},
issn = {1827-1898},
abstract = {Alzheimer's disease (AD) is the most common cause of major neurocognitive disorder worldwide, with growing prevalence and limited disease-modifying treatment options. Vitamin supplementation has attracted considerable interest as a potentially modifiable strategy in AD because several vitamins are involved in biological pathways implicated in AD pathogenesis, including oxidative stress, neuroinflammation, and homocysteine metabolism. However, the clinical relevance of these mechanistic associations remains uncertain, and findings from interventional studies have been inconsistent. This narrative review critically evaluates the current evidence regarding vitamin supplementation across the AD spectrum, including associations between vitamin deficiency and AD risk, the potential role of supplementation in AD prevention, and cognitive or functional outcomes among individuals with mild cognitive impairment or established AD. Among the vitamins reviewed, folic acid and vitamin B12 demonstrate the most consistent, although still limited, signal for potential cognitive benefit, particularly when used in combination although whether this benefit is concentrated among individuals with elevated homocysteine levels remains uncertain. Vitamin D deficiency has been relatively consistently associated with increased AD risk in observational studies, supporting consideration of vitamin D assessment and correction of documented deficiency as part of routine clinical care in older adults. Evidence for vitamin E suggests possible attenuation of functional decline at higher doses but does not support routine use for cognitive benefit or AD prevention. For vitamins A, C, thiamine, and niacin, clinical evidence remains sparse, indirect, and insufficient to support supplementation beyond correction of documented deficiencies. Overall, biological plausibility has consistently outpaced demonstrated clinical efficacy in vitamin literature. Vitamin supplementation should not be considered a disease-modifying intervention for AD; however, vitamin assessment, including baseline serum vitamin levels where clinically indicated, and supplementation should be individualized, with correction of documented deficiencies remaining appropriate for general health, particularly in older adults with poor intake, malabsorption risk, or medication-related deficiencies. Ensuring adequate B vitamin intake and correcting vitamin D deficiency when documented may be incorporated into a broader brain-health strategy alongside pharmacologic treatments and lifestyle interventions. Future research should prioritize adequately powered clinical trials with standardized outcomes, longer follow-up periods, and stratification by baseline nutritional status.},
}

@article {pmid42957107,
year = {2026},
author = {Hu, D and Li, D and He, L and Mao, S and Zhu, YA and Chen, X and Zhang, J and Zhou, C and Zhou, X},
title = {Integrative network pharmacology, machine learning, and experimental validation identify the TLR4/NF-κB/NLRP3 axis as a potential mechanism underlying the therapeutic effects of Lingguizhugan decoction in Alzheimer's disease.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122517},
doi = {10.1016/j.jep.2026.122517},
pmid = {42957107},
issn = {1872-7573},
abstract = {Lingguizhugan decoction, a traditional formula originating from Zhang Zhongjing's Treatise on Cold Damage and Miscellaneous Diseases, has shown cognitive benefits in APP/PS1 mice in our earlier study, partly through restoration of meningeal lymphatic drainage and enhancement of amyloid-β (Aβ) removal. Whether other molecular events contribute to its therapeutic action in Alzheimer's disease (AD) remains to be clarified.

AIM OF THE STUDY: This work was designed to clarify additional potential mechanisms by which LGZG may act against AD.

METHODS AND MATERIALS: The chemical constituents of LGZG were profiled by UPLC-Q-TOF-MS. Candidate targets and pathways were screened by integrating public databases, transcriptomic analysis, network pharmacology, and enrichment analysis. Eight machine learning models and SHAP analysis were subsequently used to prioritize candidate regulators. Molecular docking and molecular dynamics simulations were performed to evaluate the potential interactions between representative LGZG constituents and TLR4. APP/PS1 mice and BV2 microglial cells were used for experimental validation. Spatial learning and memory, hippocampal pathological alterations, Aβ deposition, inflammatory cytokines, microglial inflammatory phenotype-associated markers, and TLR4/NF-κB/NLRP3 signaling were evaluated using behavioral testing, histological staining, ELISA, immunofluorescence, qRT-PCR, and Western blotting. TAK-242 inhibition and TLR4 overexpression were further used to assess the involvement of TLR4 signaling.

RESULTS: Twenty-three candidate constituents were retained following chemical profiling and in silico screening of LGZG. Integrated analysis of network pharmacology, AD-related genes, and transcriptomic data identified 46 candidate LGZG-AD-DEG targets. Machine learning and SHAP analyses further prioritized several inflammation-related regulators, including RELA and NFKBIA, supporting inflammation-related signaling as a major direction for subsequent validation. Molecular docking and molecular dynamics simulations suggested potential interactions between representative LGZG constituents and the TLR4 receptor. In APP/PS1 mice, LGZG improved spatial learning and memory, attenuated hippocampal neuronal injury, reduced Aβ deposition, and decreased IL-1β, IL-6, and TNF-α levels. LGZG also reduced hippocampal TLR4, P-IκBα, P-NF-κB, and NLRP3 expression and decreased TLR4/NF-κB/NLRP3-related signals in Iba1-positive microglia. In LPS-stimulated BV2 cells, LGZG shifted inflammatory phenotype-associated markers toward a less pro-inflammatory profile and suppressed TLR4/NF-κB/NLRP3 signaling. TAK-242 treatment and TLR4 overexpression experiments further supported the involvement of TLR4 signaling in these effects.

CONCLUSION: LGZG alleviated cognitive impairment, hippocampal pathological alterations, Aβ deposition, and neuroinflammatory responses in APP/PS1 mice. Integrated bioinformatic analyses and experimental validation suggest that regulation of TLR4/NF-κB/NLRP3 signaling contributes to the anti-neuroinflammatory effects of LGZG in AD.},
}

@article {pmid42957394,
year = {2026},
author = {Veziroglu, E and Nikpanah, M and Farhadi, F and Kalbi, D and Hensley, C and McConathy, J},
title = {PET for Evaluation of Neurologic Diseases: Part one: Neurodegenerative Diseases.},
journal = {Radiologic clinics of North America},
volume = {64},
number = {6},
pages = {1023-1037},
doi = {10.1016/j.rcl.2026.07.008},
pmid = {42957394},
issn = {1557-8275},
mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging ; *Positron-Emission Tomography/methods ; Radiopharmaceuticals ; Fluorodeoxyglucose F18 ; Brain/diagnostic imaging ; },
abstract = {This review of PET for evaluation of neurological diseases is divided into two parts; part one examines the clinical use of positron emission tomography (PET) in neurodegenerative diseases. FDG-PET can identify characteristic patterns of cerebral metabolism and help distinguish among neurodegenerative disorders. Amyloid and tau PET have expanding diagnostic and theranostic roles in Alzheimer's disease, including assessment of disease-specific pathology and treatment eligibility. FDOPA-PET evaluates presynaptic dopamine synthesis and supports assessment of Parkinson's disease and other parkinsonian syndromes. Combined with structural imaging and clinical evaluation, PET can improve diagnostic confidence, refine prognosis, and inform treatment decisions.},
}

Humans
*Neurodegenerative Diseases/diagnostic imaging
*Positron-Emission Tomography/methods
Radiopharmaceuticals
Fluorodeoxyglucose F18
Brain/diagnostic imaging

@article {pmid42957517,
year = {2026},
author = {Li, J and Lin, T and Long, Z and Lin, J and Gao, F and Shen, Y},
title = {Endothelial BACE1 impairs insulin signaling to drive cerebral small vessel disease and stroke.},
journal = {Science bulletin},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.scib.2026.10.030},
pmid = {42957517},
issn = {2095-9281},
abstract = {Cerebral small vessel disease (CSVD) is a major cause of stroke and dementia, yet its molecular etiology remains incompletely understood, and no disease-modifying therapies are currently available. Here, we identify a non-canonical pathogenic mechanism linking β-secretase 1 (BACE1), a therapeutic target for Alzheimer's disease, to vascular insulin resistance. BACE1 was upregulated in the cerebral endothelium of patients with hypertensive arteriopathy and cerebral amyloid angiopathy. The upregulated endothelial BACE1 cleaved the β-subunit of insulin receptor (INSR), disrupting the INSR-Akt-endothelial nitric oxide synthase (eNOS) signaling axis required for vascular homeostasis. This disruption occurred early in disease progression in a relevant rodent model of CSVD, the stroke-prone spontaneously hypertensive rat fed a high-salt diet. Treatment with the clinical BACE1 inhibitor elenbecestat (E2609) restored endothelial function, ameliorated cerebrovascular pathology, and significantly reduced stroke incidence. INSR blockade abolished these protective effects, supporting an INSR-dependent mechanism. These findings identify an intersection between neurodegenerative and metabolic pathways in the vasculature and suggest that BACE1 inhibitors, previously abandoned in Alzheimer's disease treatment, may have therapeutic potential for stroke prevention and CSVD therapy.},
}

@article {pmid42957639,
year = {2026},
author = {Lista, S and Emanuele, E and Cuperlovic-Culf, M and Mahdi, A and Singh, V and López-Ortiz, S and Khoramipour, K and Merino-País, M and Minoretti, P and Cisale, GY and Heslegrave, A and Imbimbo, C and Sancesario, GM and Bendlin, BB and Imbimbo, BP and Zetterberg, H and Santos-Lozano, A},
title = {Artificial intelligence applications in microbiota-gut-brain axis research: Implications for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500124},
doi = {10.1177/13872877261500124},
pmid = {42957639},
issn = {1875-8908},
abstract = {Alterations in the gut microbiota (GM) are increasingly implicated in Alzheimer's disease (AD) pathogenesis through the microbiota-gut-brain axis (MGBA), influencing neuroinflammation, amyloid-β deposition, and tau aggregation. The inherent complexity of microbiota data necessitates artificial intelligence (AI) and machine learning (ML) to identify novel biomarkers and therapeutic targets. In this narrative review, we examined AI applications in AD-related GM research, including metataxonomic and metagenomic approaches. AI methods facilitate microbial signature identification and enterotype characterization associated with AD progression, enable multi-omics integration clarifying molecular pathways linking GM dysbiosis to neurodegeneration, support predictive modeling for early AD detection, and inform personalized MGBA-targeted interventions. Employed techniques include classical ML (e.g., random forests) for taxonomic classification, deep learning (e.g., neural networks) for complex pattern recognition, and explainable AI for identifying key bacterial taxa and metabolic functions. Significant challenges persist regarding methodological standardization, larger longitudinal cohorts, and ethical considerations in clinical applications. Future priorities include developing interpretable models, integrating longitudinal multi-omics data to establish causality, and validating AI-derived insights for precision AD prevention and treatment. AI uniquely enables high-dimensional, non-linear analyses that advance understanding of microbiome-brain interactions, though clinical translation requires rigorous validation and interdisciplinary collaboration.},
}

@article {pmid42944712,
year = {2026},
author = {Bannon, SM and McCage, SM and Elizalde Carrillo, R and Brandt, SA and Allison, GO and Aminpour, A and Walker, K and Cornelius, T and Parker, RA and Dams-O'Connor, K and Dickerson, B and Ritchie, C and Vranceanu, AM},
title = {Resilient Together Dyadic Intervention for Persons With Dementia and Their Partners: Protocol for a Feasibility Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e106005},
pmid = {42944712},
issn = {1929-0748},
mesh = {Humans ; *Dementia/psychology/therapy ; Feasibility Studies ; Randomized Controlled Trials as Topic ; *Resilience, Psychological ; Male ; Female ; Quality of Life ; *Sexual Partners/psychology ; Aged ; },
abstract = {BACKGROUND: Alzheimer disease and related dementias can impact emotional distress and individual and relational health among persons living with dementia and their romantic partners. There are limited skill-based interventions that can help couples build resilience while navigating dementia-related challenges.

OBJECTIVE: We aim to assess the feasibility, acceptability, and preliminary signal of improvement of Resilient Together for Alzheimer's Disease and Related Dementia (RT-ADRD), a novel dyadic skills-based intervention aimed at preventing chronic emotional distress early after diagnosis.

METHODS: Couples are randomized to complete either (1) six weekly conjoint intervention sessions of RT-ADRD or (2) a minimally enhanced usual care condition involving a self-guided pamphlet. Both partners must demonstrate capacity to consent to research participation, and at least 1 partner must exhibit clinically elevated emotional distress. Partners living with dementia must have received their diagnosis in the past 6 months. Participants complete baseline and posttest assessments of resiliency skills, emotional distress, relationship functioning, and quality of life and assessments of treatment satisfaction at posttest only.

RESULTS: This is aim 3 of a 5-year funded study that initially began in July 2022. Participant recruitment and data collection for this phase began in October 2024 and will continue until 40 couples (80 individuals) are randomized and complete the posttest. As of manuscript submission (July 2026), 25 couples have been enrolled and 25 couples have been randomized. Data collection is currently underway, and study completion is expected by early 2027.

CONCLUSIONS: This study will gather comprehensive information on the feasibility and acceptability of RT-ADRD relative to minimally enhanced usual care and assess the preliminary signal of improvement in proximal outcomes. Findings will directly inform plans for a larger efficacy trial.},
}

Humans
*Dementia/psychology/therapy
Feasibility Studies
Randomized Controlled Trials as Topic
*Resilience, Psychological
Male
Female
Quality of Life
*Sexual Partners/psychology
Aged

@article {pmid42946784,
year = {2026},
author = {Tong, J and Li, L and Zhang, D and O'Brien, KS and Lu, Y and Wu, Q and Zhou, T and Zhang, B and Lei, Y and Tang, H and Jing, N and Li, H and Xu, Z and Huang, Y and Hu, Y and Zhou, Y and Lin, F and Jiang, Y and Chu, H and Chen, Y and Wang, F and Bian, J and Xu, H and Wolk, DA and Chen, Y},
title = {FLAT-WHITE: from target trial emulation to federated high-throughput causal machine learning using decentralized real-world data.},
journal = {npj health systems},
volume = {3},
number = {1},
pages = {},
pmid = {42946784},
issn = {3005-1959},
support = {U01TR003709, U24MH136069, U24AG098157, RF1AG077820, R01AG073435, R01LM013519, 1R01LM014344, R01DK128237, R21AI167418, R21EY034179/NH/NIH HHS/United States ; },
abstract = {Randomized clinical trials remain the gold standard for evaluating treatment effects but are often infeasible for rapidly assessing drug repurposing opportunities, particularly in complex conditions such as Alzheimer's disease. Target trial emulation (TTE) provides a principled framework for causal inference with electronic health records and, when coupled with modern machine learning, enables scalable analyses across distributed health systems. We present FLAT-WHITE (Federated Lossless Algorithm for Target Trial Emulation with Overlap Weighting for Healthcare Data Integration via Trusted and Efficient Communication), a novel federated causal machine learning pipeline for high-throughput treatment effect estimation without sharing patient-level data. FLAT-WHITE is a one-shot, lossless algorithm, requiring a single communication round while achieving results equivalent to centralized pooled analyses. With overlap weighting on the propensity score, it robustly addresses heterogeneity in treatment assignment and ensures valid causal inference in decentralized settings. We demonstrate FLAT-WHITE in a Alzheimer's drug repurposing study, scanning 181 candidate drugs using data from four health learning systems encompassing approximately 150,000 patients with mild cognitive impairment. Findings were validated externally in 339,180 patients from the TriNetX global research network. FLAT-WHITE enables rapid, large-scale, and secure evaluation of treatment effects and establishes a foundation for collaborative clinical research across diverse healthcare systems.},
}

@article {pmid42947687,
year = {2026},
author = {Viola, KL and Chromy, BA and Nowar, R and Lambert, MP and Klein, WL},
title = {Safe and efficient intracellular delivery of functional antibodies into cultured neural cells shows a role for Alzheimer's-relevant tau phosphorylation in cell integrity.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1737082},
pmid = {42947687},
issn = {2813-3919},
abstract = {INTRODUCTION: Protein proteoforms generated by post-translational modification are increasingly recognized as important regulators of neuronal function and neurodegenerative disease. However, methods for acutely interrogating specific intracellular proteoforms in living neuronal populations remain limited. We evaluated cationic liposomal delivery (CLD) as a strategy for introducing full-length functional antibodies into living neurons and used this approach to investigate the role of a phosphorylated tau proteoform recognized by the monoclonal antibody PHF-1.

METHODS: Cationic liposomes composed of DOPC+ were complexed with antibodies or molecular probes and applied to cultured neuronal cell lines and primary mouse cortical neurons. Intracellular delivery, cellular localization, viability, and biological activity were assessed using fluorescence microscopy and live-cell imaging.

RESULTS: CLD efficiently delivered full-length antibodies and molecular probes into living neuronal cells and primary neurons without detectable toxicity. Internalized antibodies retained target specificity, producing intracellular staining patterns consistent with the known localization of tau, vinculin, paxillin, and Fyn. Delivery was observed across essentially all cells in treated cultures and remained effective under standard culture conditions. Intracellular delivery of PHF-1 produced a rapid and striking morphological response characterized by neurite retraction and cell-body rounding within hours of treatment. These effects were not observed with heat-inactivated PHF-1, vehicle controls, or other intracellular antibodies, supporting a specific effect of intracellular engagement of PHF-1-reactive tau species.

DISCUSSION: These findings establish CLD as a practical platform for the intracellular delivery of functional full-length antibodies into living neuronal populations. Beyond validating a delivery technology, the study demonstrates that acute intracellular engagement of PHF-1-reactive phosphorylated tau rapidly alters neuronal morphology, suggesting that this tau proteoform contributes to the maintenance of neurite integrity. CLD provides a versatile approach for probing the function of intracellular proteoforms that are difficult to study using conventional genetic or biochemical methods.},
}

@article {pmid42947905,
year = {2026},
author = {Majeed, Z and Majeed, J and Ponce, FA and Mahanti, H and Decourt, B and Burke, AD and Sabbagh, MN},
title = {Deep brain stimulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261441166},
pmid = {42947905},
issn = {2542-4823},
abstract = {Deep brain stimulation (DBS) is a well-established treatment for neurological disorders, but its efficacy and safety in Alzheimer's disease (AD) remain uncertain. This narrative review synthesizes nine clinical trials in patients with mild to severe AD, focusing on stimulation of the fornix, nucleus basalis of Meynert (NBM), and ventral capsule/ventral striatum. Literature was identified through PubMed using the terms "deep brain stimulation" and "Alzheimer's disease," and the results were restricted to clinical trials and case reports in English, with additional references identified through Google Scholar. Across studies, DBS was safe and well tolerated, with few adverse events. Stimulation produced short-term cognitive improvements, most commonly measured by Alzheimer's Disease Assessment Scale cognitive subscale, along with transient reversal of glucose hypometabolism and activation of memory-related networks. One study reported slowed hippocampal atrophy, suggesting neuroplastic effects. In severe AD, DBS targeting both the fornix and NBM yielded transient cognitive gains, with NBM-DBS showing greater benefit for neuropsychiatric symptoms and caregiver burden. Patients with higher baseline cognition and glucose metabolism responded more favorably to DBS. Age-related differences emerged: younger patients (<65 years old), with earlier onset and more aggressive progression, showed less favorable responses to DBS targeting the fornix, whereas older patients (≥65 years old) had comparatively better outcomes. Despite these benefits, DBS does not halt disease progression or reverse AD pathology. Larger, biomarker-stratified, sham-controlled trials with extended follow-up are needed to clarify durability, identify optimal patient subgroups, and determine the most effective stimulation targets.},
}

@article {pmid42947971,
year = {2026},
author = {Chigriai, M and Kraskovskaya, N and Bolshakova, A and Porozova, NO and Porozov, YB and Pešić, M},
title = {PP2A targeting: balancing anticancer potential and neurological risk.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1945801},
pmid = {42947971},
issn = {2296-634X},
abstract = {Protein phosphatase 2A (PP2A) is a multifunctional serine/threonine phosphatase that regulates cell-cycle progression, oncogenic signaling, neuronal development, synaptic homeostasis, and protein proteostasis. Its dysregulation contributes to cancer, whereas impaired PP2A activity in the nervous system is linked to neurodevelopmental disorders and neurodegenerative proteinopathies, including tau and α-synuclein pathology. These divergent roles create both opportunities and safety challenges for PP2A-directed therapies. This review examines PP2A as a modular holoenzyme system whose subunit composition determines substrate specificity and context-dependent biological effects. We discuss PP2A dysfunction in cancer, including genetic and regulatory alterations affecting PP2A subunits, assembly, and endogenous inhibitors, and compare therapeutic PP2A activation with transient inhibition. The latter approach is exemplified by LB100, which sensitizes treatment-stressed tumor cells to chemotherapy, radiotherapy, or immunotherapy by disrupting checkpoint adaptation and stress recovery. We further evaluate the neurological implications of systemic phosphatase inhibition, LB100 conversion to the active metabolite endothall, clinical safety and pharmacokinetic data, and the limited brain-tumor penetration of intact LB100. We propose that the clinical utility of PP2A inhibition depends on defining a therapeutic corridor that integrates dosing schedule, parent-drug and metabolite exposure, tumor target engagement, biomarker-informed patient selection, and preservation of PP2A-dependent homeostasis in normal tissues, particularly the nervous system.},
}

@article {pmid42948702,
year = {2026},
author = {Yin, J and Lv, W and Zhao, W and Ding, Z and Zhu, F and Liu, H and Li, S and Cao, X and Liu, L and Song, K and Gong, Y and Xu, J and Chen, Y and Zhang, Z and Fang, X and Xin, H},
title = {Lysosomal membrane damage repair and acidification impairment restoration triggered by smart lipid nanoparticles for Alzheimer's disease treatment.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {10},
pages = {7037-7053},
pmid = {42948702},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD), characterized by amyloid (Aβ) deposition in neurons, is the most serious neurodegenerative disorder, but lacks effective therapeutic drugs in the clinic. Impaired neuronal lysosomal function drives the pathological accumulation of intracellular Aβ. Targeted rehabilitation of lysosomal dysfunction may offer a potential strategy to restore neuronal homeostasis and mitigate AD progression. In this study, we developed a brain-targeted smart lipid nanoparticle (A-PSL@7BIO) to repair lysosomal membrane damage and restore impaired acidification in the brain for AD therapy. The system was composed of Angiopep-2 peptide-conjugated lipid nanoparticles, which were loaded with a Glycogen synthase kinase-3β (GSK-3β) inhibitor 7-bromoindirubin-3'-oxime (7BIO) and incorporated with dipalmitoyl-phosphatidylserine (DPPS) and a reactive oxygen species (ROS) responsive phospholipid. Through Angiopep-2-mediated blood-brain barrier (BBB) transcytosis, the smart lipid nanoparticles could enhance brain biodistribution with subsequent neuronal internalization. Pathologically elevated intracellular ROS levels in AD could induce stimulus-responsive payload release, wherein 7BIO selectively inhibited aberrant GSK-3β hyperphosphorylation to restore the physiological acidic lysosomal environment and DPPS structurally repaired compromised lysosomal membranes, synergistically addressing dual aspects of lysosomal pathology. This smart lipid nanoparticles synergistically restored physiological lysosomal homeostasis, reversed neuronal dysfunction, and ameliorated cognitive deficits in AD models, indicating that A-PSL@7BIO could be used as a potential nanomedicine for AD therapy.},
}

@article {pmid42948713,
year = {2026},
author = {Zhang, Q and Gong, X and Liu, H and Yao, X},
title = {Application of computational methods in the drug discovery and development of Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {10},
pages = {6526-6552},
pmid = {42948713},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder marked by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive decline. As the most common dementia, AD affects over 50 million individuals worldwide, with 10 million new cases each year. Despite many significant progresses in AD research fields, there is still no effective treatment. Advances in molecular modelling and artificial intelligence (AI) algorithm have facilitated the application of computational methods in AD drug development, offering advantages in terms of efficiency, cost-effectiveness, and resource conservation. These strategies, including molecular docking, molecular dynamics simulation, protein structure prediction, virtual screening, and de novo drug design, have been widely employed in the past decades. Additionally, AI pharmaceutical companies have revolutionized the traditional drug development pipeline such as AD biomarker discovery, accurate diagnosis and precision medicine, etc. This review offers a thorough summary of recent progresses in computational-based methodologies in the study of AD drug development, including the elucidation the pathological mechanism at the molecular level, target identification, target 3D structure prediction, lead compound discovery, de novo molecular generation, multi-target directed ligands, drug repurposing, biomarker discovery, etc., showing promising applications of molecular modelling and AI in the development of AD therapy.},
}

@article {pmid42948724,
year = {2026},
author = {Yao, W and Su, L and Lu, Z and Chen, J and Duan, L and Meng, X and Wan, H and Chen, S and Mi, Y and Ji, A},
title = {Genomic characterization of AP2/ERF transcription factors related to cannabinoids biosynthesis in Cannabis sativa.},
journal = {Chinese herbal medicines},
volume = {18},
number = {4},
pages = {1056-1066},
pmid = {42948724},
issn = {2589-3610},
abstract = {OBJECTIVE: Cannabinoids, secondary metabolites produced by Cannabis sativa (cannabis), have various pharmacological effects, such as anti-inflammatory and analgesic effects, and they can be used in the treatment of Alzheimer's disease. Although the biosynthetic pathway of cannabinoids has been elucidated, relatively few reports about the transcription factors involved in this pathway exist. APETALA2 (AP2)/ethylene-responsive factor (ERF) transcription factor (TF) families play an important role in plant growth and secondary metabolism.

METHODS: APETALA2 (AP2)/ethylene-responsive factor (ERF) transcription factor (TF) family was identified in cannabis plants via phylogenetic analysis, chromosomal distribution, gene structure, conserved motif identification, synteny analysis, alternative splicing event identification, response element prediction, and gene expression analysis.

RESULTS: A total of 111 AP2/ERF members belonging to the APETALA2 subfamily (17 genes), dehydration-responsive element-binding proteins subfamily (39 genes), and ethylene-responsive factor subfamily (53 genes), related to the ABI3/VP1 subfamily (two genes), exist in cannabis. Based on the expression profiles of AP2/ERFs in the genome, quantitative real-time PCR (qRT-PCR) detection and coexpression analysis results, the functional genes of six TFs were clustered with those of other species, and two gene clusters are speculated to be related to cannabinoid biosynthesis. A total of six CsERF proteins were found to be located in the cell nucleus by subcellular localization detection. CsERF02 and CsERF19 exhibited transcriptional activation activity through the AH109 yeast system.

CONCLUSION: CsERF02, CsERF05, CsERF18, CsERF19, CsERF21, CsERF46 and two gene clusters may function in cannabinoid biosynthesis. These results contribute to the characterization of functional AP2/ERF family members in cannabis and lay a foundation for regulating cannabinoid content through metabolic pathways.},
}

@article {pmid42949022,
year = {2026},
author = {Shah, RC and Borson, S and Luchsinger, JA},
title = {Using the 4Cs of Primary Care to Ensure Timely Diagnosis of Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000759},
pmid = {42949022},
issn = {1546-4156},
support = {//Novo Nordisk, Inc./ ; },
abstract = {BACKGROUND: Disease-modifying treatment is available for patients diagnosed with early symptomatic Alzheimer disease [AD, mild cognitive impairment (MCI), and mild dementia]. Recognition and diagnosis of MCI and dementia occur every day in the primary care setting, but diagnostic challenges and delays are common. Over 90% of MCI cases are missed, and more than half of AD diagnoses occur when the disease is in the moderate or advanced stage, when crises and emergencies are more likely to occur.

DISCUSSION: Diagnostic delays limit opportunities to organize and implement proactive, comprehensive patient care and treatment and to prepare individuals and caregivers for the long-term implications of progressive dementia. With the advent of new diagnostic methods, including blood-based biomarkers, AD can now be diagnosed with greater precision and ease at a lower cost. Given the expected increase in prevalence of AD in the next 2 decades and the growing shortage of geriatricians and memory disorders specialists, the role of the PCP in diagnosing AD will be of even greater importance. However, many PCPs do not feel confident or equipped to recognize and diagnose patients with early symptomatic AD. To empower PCPs as key participants in diagnosis, we propose an approach aligned with the fundamental strengths of primary care, codified in the 4Cs (first contact, comprehensiveness, coordination, and continuity of care).

CONCLUSION: Using the 4Cs framework, PCPs can increase the rate of timely diagnosis of symptomatic AD and be afforded more time to provide comprehensive care, using proactive rather than reactive management strategies throughout the diagnostic process.},
}

@article {pmid42950793,
year = {2026},
author = {Hung, NV and Hoang, VH and Long, LTB and Linh, VNH and Tien, LQ and Linh, TVT and Bang, LTT and Nguyen, TK and Pham, HTN and Minh, DT and Hien, TTT and Wang, S and Tran, PT},
title = {Discovery of novel pyridine-2-tetrazole derivatives as in vivo memory enhancement agents.},
journal = {Bioorganic chemistry},
volume = {184},
number = {},
pages = {110683},
doi = {10.1016/j.bioorg.2026.110683},
pmid = {42950793},
issn = {1090-2120},
abstract = {Despite the currently incurable nature of Alzheimer's disease (AD), acetylcholinesterase (AChE) inhibitors remain the primary therapeutic strategy for symptom management. In this study, twenty-five novel pyridine-2-tetrazole derivatives were designed, their binding affinities with AChE were predicted using machine learning models, and their drug-likeness were calculated. Following their synthesis, the compounds were evaluated in vitro for AChE inhibitory activity. Based on these findings, lead compounds 11 and 28 were selected for in vivo assessment to determine their effects on cognitive function in trimethyltin (TMT)-induced cognitive impairment mouse models at dosages of 20 mg/kg and 60 mg/kg. Although compound 28 exhibited modest in vitro AChE inhibition, it significantly improved cognitive performance in TMT-induced mice across both dosage groups. This cognitive enhancement was demonstrated through the Object Recognition Test, modified Y-maze, and Passive Avoidance Test. These findings suggest that compound 28 may exert its neuroprotective effects through a different molecular mechanism rather than exclusive AChE inhibition, highlighting its potential as a lead compound for the treatment of cognitive impairment and related neurodegenerative disorders such as AD.},
}

@article {pmid42941768,
year = {2026},
author = {Procopio, E and Accattatis, A and Stroscio, CA and Guzzi, G and Lavano, A and La Torre, D and Della Torre, A},
title = {Diagnostic and Predictive CSF Biomarkers in Idiopathic Normal Pressure Hydrocephalus (iNPH): A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941768},
issn = {1422-0067},
mesh = {*Hydrocephalus, Normal Pressure/cerebrospinal fluid/diagnosis ; Humans ; *Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {Idiopathic normal pressure hydrocephalus (iNPH) is a progressive disorder clinically characterized by Hakim's triad: gait disturbance, cognitive impairment, and urinary incontinence. iNPH treatment consists of neurosurgical implantation of a ventriculoperitoneal CSF diversion, whose outcome depends on an early and correct diagnosis. Currently, there is no specific diagnostic test to perform preoperatively. Still, the combination of neurological examination, gait analysis, neurocognitive evaluation, and the tap test is useful to suggest when surgery is indicated. Our systematic review aims to identify diagnostic and outcome predictor CSF biomarkers (BM) in iNPH. The present systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, and the Cochrane Library databases were first consulted in April 2025 and updated in May 2026. Studies were selected using the terms "idiopathic normal pressure hydrocephalus" and "CSF biomarkers" under Medical Subject Headings (MeSH) as inclusion criteria. The eligibility of a record was defined according to the study title and abstract. The QUADAS-2, QUIPS, ROBINS-I V2, and RobVis tools were used to assess the risk of bias. Ninety-nine records were included in this systematic review. Amyloid proteins (Aβ40-42), followed by tau (τT, τP-181) and neuroinflammatory proteins were the most frequently CSF BM analyzed in patients with iNPH. ELISA was the most used method to measure BM in CSF samples. Forty-seven records investigated the potential diagnostic role of CSF BM; comparisons were frequently made among iNPH, Alzheimer's disease (AD), and healthy control CSF samples. Regarding outcome prediction, 28 records examined CSF BM, with heterogeneous comparisons such as lumbar versus ventricular CSF or shunted versus non-shunted iNPH CSF samples, including healthy controls and iNPH. Seven records proposed both the diagnostic and predictive role of some CSF biomarkers, especially for tau proteins and Aβ42. On the other hand, 17 records concluded that neither a diagnostic nor a predictive role could be proposed for the CSF BM they analyzed. However, these records increased knowledge about an iNPH CSF pattern. Collecting and analyzing CSF samples from iNPH patients can be advantageous in differential diagnosis with other similar neurodegenerative disorders, especially AD, and therefore a predictor of neurosurgical outcomes. Combined biomarker panels should be integrated in standardized protocols, measuring: Aβ42, Aβ42/Aβ40, p-tau, total tau, ADAβ42/p-tau, L-PGDS, NFL and NRGN.},
}

*Hydrocephalus, Normal Pressure/cerebrospinal fluid/diagnosis
Humans
*Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid

@article {pmid42942158,
year = {2026},
author = {Tekin, E and Koldemir Gündüz, M and Yığman, Z and Aydoğan Kara, B and Küçük, A and Arslan, M},
title = {Safranal, a Natural Neuroprotective Compound, Modulates Plasma Iron Levels, Improves Behavioral Performance, and Demonstrates Dose-Specific Cytoprotection in Alzheimer's Disease Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942158},
issn = {1422-0067},
support = {224S564//The Scientific and Technological Research Council of Türkiye/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/blood/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Iron/blood ; Male ; *Cyclohexenes/pharmacology/therapeutic use ; Rats ; Humans ; *Terpenes/pharmacology/therapeutic use ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism/toxicity ; *Cytoprotection/drug effects ; Behavior, Animal/drug effects ; Cell Line, Tumor ; Apoptosis/drug effects ; Streptozocin ; Cell Survival/drug effects ; Antioxidants ; },
abstract = {Metal dyshomeostasis contributes to Alzheimer's disease (AD) by influencing amyloid aggregation, oxidative imbalance, and impaired clearance mechanisms. Safranal, a bioactive constituent of Crocus sativus, exhibits antioxidant properties, but its metal-modulating actions remain insufficiently understood. This study investigated whether safranal modulates metal (Fe, Cu, Zn) levels in an AD rat model while evaluating its cytoprotective rescue capacity against Aβ1-42 induced neurotoxicity in differentiated SH-SY5Y cells. AD was induced in male rats via intracerebroventricular streptozotocin, followed by a four-week safranal administration (0.5 mg/kg/day, ip). Behavioral performance, plasma metal levels (ICP-MS), and cerebral total antioxidant capacity (FRAP) were evaluated alongside histological assessment. Post-treatment protocols were employed to evaluate the effects of safranal on cell viability and apoptosis in differentiated SH-SY5Y cells exposed to Aβ1-42. Longitudinal analyses revealed that safranal attenuated exploratory deficits and recognition memory impairments in AD rats. Decreased plasma iron levels in the AD group were restored by safranal, accompanied by a return of cerebral antioxidant capacity to normal. Although overt hippocampal histological alterations were absent in this early phase, post-treatment with safranal successfully offered a therapeutic rescue window, preserving cell viability and attenuating Aβ1-42-induced apoptotic features in vitro. Safranal demonstrates beneficial neuroprotective effects in AD models by improving behavioral outcomes, partially correcting plasma iron levels, and mediating cytoprotective rescue windows against Aβ1-42-induced cellular toxicity. These findings suggest that safranal represents a promising natural candidate for reducing behavioral deficits, supporting peripheral iron status, and offering functional cell survival in AD models.},
}

Animals
*Alzheimer Disease/drug therapy/blood/pathology
*Neuroprotective Agents/pharmacology/therapeutic use
*Iron/blood
Male
*Cyclohexenes/pharmacology/therapeutic use
Rats
Humans
*Terpenes/pharmacology/therapeutic use
Disease Models, Animal
Amyloid beta-Peptides/metabolism/toxicity
*Cytoprotection/drug effects
Behavior, Animal/drug effects
Cell Line, Tumor
Apoptosis/drug effects
Streptozocin
Cell Survival/drug effects
Antioxidants

@article {pmid42942573,
year = {2026},
author = {Xu, S and Fu, X and Zuo, L and Wang, M},
title = {The Interplay Between Oophorectomy and Alzheimer's Disease: A Narrative Review.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {10},
pages = {},
pmid = {42942573},
issn = {1648-9144},
mesh = {Humans ; *Alzheimer Disease/etiology/physiopathology ; Female ; *Ovariectomy/adverse effects ; Risk Factors ; Cognitive Dysfunction/etiology ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide and affects women more frequently than men. Although age remains the main risk factor, reproductive aging and changes in ovarian hormone exposure may also contribute to this difference. Premenopausal bilateral oophorectomy causes an abrupt loss of ovarian hormones, including estradiol, progesterone, and testosterone, and several observational studies have associated this change with a higher risk of later cognitive impairment or dementia, particularly when surgery is performed at a younger age. However, these studies have assessed different outcomes, including dementia, mild cognitive impairment, subjective cognitive changes, and AD-related imaging findings, and current evidence does not establish a direct causal relationship between oophorectomy and AD. Possible biological pathways include neuroinflammation, synaptic dysfunction, amyloid-β and tau-related changes, and cerebrovascular dysfunction, although much of the mechanistic evidence remains experimental or indirect. Genetic background, vascular health, age at surgery, and the duration of hormone deprivation may further influence individual risk. Hormone replacement therapy has an established role in the management of premature or early surgical menopause when there is no contraindication, but its effect on long-term AD prevention remains uncertain; the timing of treatment may be important, but current evidence does not confirm a preventive effect. This review summarizes current epidemiological, neuroimaging, and experimental evidence linking oophorectomy with cognitive health and AD, and discusses hormone therapy, pharmacological and non-pharmacological management, emerging research approaches, and remaining knowledge gaps. Future studies with detailed information on surgical timing, hormone exposure, genetic risk, vascular factors, longitudinal cognition, and AD-related biomarkers are needed to better define which women may be most vulnerable after premenopausal oophorectomy.},
}

Humans
*Alzheimer Disease/etiology/physiopathology
Female
*Ovariectomy/adverse effects
Risk Factors
Cognitive Dysfunction/etiology

@article {pmid42942883,
year = {2026},
author = {Abbatecola, AM and Migliara, G and D'Agostino, F and Veronese, N and Giuliani, A and Caponnetto, S and Corbi, G and Signoriello, E and Incalzi, RA and Paolisso, G},
title = {Impact of GLP-1 Receptor Agonists on Cognitive Performance in Adults at Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.},
journal = {Nutrients},
volume = {18},
number = {20},
pages = {},
pmid = {42942883},
issn = {2072-6643},
mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/prevention & control/etiology ; *Cognition/drug effects ; *Cognitive Dysfunction/drug therapy ; *Diabetes Mellitus, Type 2/drug therapy/complications ; *Glucagon-Like Peptide-1 Receptor Agonists/pharmacology/therapeutic use ; Randomized Controlled Trials as Topic ; Risk Factors ; },
abstract = {Background/Objectives: Type 2 diabetes, a widely recognized risk factor of Alzheimer's disease (AD), is mainly due to the role played by insulin resistance on neuronal degeneration. Mild Cognitive Impairment (MCI) also significantly increases the risk of developing AD by approximately 40%. Epidemiological studies have demonstrated correlations between glucagon-like peptide-1 agonists (GLP-1RAs) on reducing the risk of AD. We synthesize current data from randomized controlled trials (RCTs) to summarize the effects of GLP-1RA treatment in adults with Type 2 diabetes or with MCI on cognitive performance. Methods: We searched databases from inception to 1 January 2026 investigating effects of GLP-1RA(s) on cognition. PubMed, Web of Science and Scopus databases were explored following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We selected only RCTs in adults investigating GLP-1RA(s) on cognitive performance. Results: Overall mean age was 64.5 yrs with an average follow-up period of 28.4 months. A total of 13,711 participants from five RCTs were included. Following a source-data audit, four randomized controlled trials contributed analytically compatible data to at least one cognitive domain. Cognitive domains were analyzed separately using Hedges' g. Random-effects models used restricted maximum likelihood (REML) estimation with Knapp-Hartung inference when at least two compatible studies contributed. For global cognition, three studies yielded g = 0.014 (95% CI: -0.061 to 0.088; p = 0.515; I[2] = 0%). For attention, two studies yielded g = 0.072 (95% CI: -2.164 to 2.308; p = 0.753; I[2] = 31.1%). For delayed memory, executive function, and verbal function, only one compatible study was available per domain; these were therefore reported as single-study estimates rather than pooled effects. A sensitivity analysis excluding the dominant Cukierman trial yielded an imprecise and non-significant effect estimate for global cognition (g = -0.205, 95% CI: -2.678 to 2.269) indicating that the robustness of the pooled result could not be established. Conclusions: Current randomized evidence is insufficient to establish a consistent beneficial effect of GLP-1RA(s) on cognitive function in adults at risk of AD. The available findings should be considered exploratory and hypothesis-generating because few analytically compatible trials were available within each cognitive domain.},
}

Aged
Female
Humans
Male
Middle Aged
*Alzheimer Disease/prevention & control/etiology
*Cognition/drug effects
*Cognitive Dysfunction/drug therapy
*Diabetes Mellitus, Type 2/drug therapy/complications
*Glucagon-Like Peptide-1 Receptor Agonists/pharmacology/therapeutic use
Randomized Controlled Trials as Topic
Risk Factors

@article {pmid42943270,
year = {2026},
author = {Kalkan Cakmak, R and Sarikamis Johnson, B and Ercin, N and Besli, N and Beker, M and Celik, U},
title = {Incensole Acetate Regulates the Sirtuin-Insulin Signaling Axis in an Experimental Alzheimer's Disease Model.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {10},
pages = {},
pmid = {42943270},
issn = {1424-8247},
support = {124S487//TÜBİTAK/ ; 2021/068//Scientific Research Projects (BAP) Coordination Unit of the University of Health Sciences Turkey/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is associated with impaired brain insulin signaling, oxidative stress, and neuroinflammation. This study investigated the effects of incensole acetate (IA) on sirtuin-associated insulin-signaling and cellular stress-response pathways using integrated computational and in vitro approaches. Methods: ADMET prediction, molecular docking, molecular dynamics simulations, and MM-PBSA analyses were performed for IA against SIRT1, SIRT3, and SIRT6 and compared with their corresponding reference ligands. An Aβ1-42-induced AD model was established in mesenchymal stem cell-derived neurons. The effects of IA on insulin-signaling components, sirtuins, Aβ, NF-κB, NRF2, and PPARα were evaluated using RT-qPCR, Western blotting, and immunofluorescence. Results: IA showed weaker docking affinities than the corresponding reference ligands for all three sirtuins, whereas trajectory-based analyses revealed target-dependent dynamic behavior. MM-PBSA-derived binding-energy estimates were -35.16 ± 3.32, -30.24 ± 3.63, and -38.26 ± 3.90 kcal/mol for IA with SIRT1, SIRT3, and SIRT6, respectively, with IA showing a more favorable relative energetic profile than 8L9 for SIRT6. In vitro, IA treatment was associated with reduced detectable Aβ levels and modulation of INSR, IRS, AKT, and AS160 expression. IA increased SIRT1 and SIRT6 expression, whereas SIRT3 protein levels were not significantly altered. IA also reduced NF-κB and increased NRF2 and PPARα expression. Conclusions: IA modulated insulin-signaling-related, sirtuin-associated, inflammatory, oxidative-stress, and metabolic markers in an Aβ1-42-induced cellular AD model. Computational analyses support potential IA-sirtuin interactions, particularly a favorable relative MM-PBSA energetic profile for SIRT6; however, direct sirtuin activation or causal sirtuin-mediated signaling was not established.},
}

@article {pmid42944683,
year = {2026},
author = {Xiong, C and Luo, J and Lu, R and Hartz, S and Kukull, W and Schindler, SE and Balls-Berry, JE and Hassenstab, J and Wolk, DA and Gleason, CE and Johnson, SC and Sperling, R and Johnson, K and Roberson, ED and Moulder, KL and Gremminger, E and Agboola, F and Grant, EA and Hornbeck, R and Massoumzadeh, P and Keefe, S and Dierker, D and Flores, S and Holtzman, DM and Benzinger, T and Morris, JC},
title = {Simpson's Paradox, Amyloid Paradox, and Racial Differences.},
journal = {JAMA network open},
volume = {9},
number = {10},
pages = {e2640868},
pmid = {42944683},
issn = {2574-3805},
mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease ; *Amyloid/metabolism ; *Black or African American/statistics & numerical data ; Cross-Sectional Studies ; *Dementia/epidemiology/ethnology ; Longitudinal Studies ; Positron-Emission Tomography ; Prevalence ; Retrospective Studies ; United States/epidemiology ; *White/statistics & numerical data ; *Race Factors ; },
abstract = {IMPORTANCE: The underlying mechanisms for the paradox of higher prevalence of dementia but lower prevalence of amyloid positivity in self-identified Black US residents than White US residents remain unknown and are important for designing and analyzing prevention and treatment trials of Alzheimer disease.

OBJECTIVE: To assess whether the age of mean amyloid onset (AMAO) explains the paradox of the reported racial differences in dementia and amyloid positivity.

This was a retrospective, multicenter, longitudinal cohort study with harmonized amyloid positron emission tomography (PET) and clinical data from self-identified Black and White individuals who were middle-aged or older across 5 academic institutes in the US conducting studies of memory and aging. The study was conducted from June 2020 to March 2026.

EXPOSURES: Self-identified race, vascular comorbidities, sex, age, educational attainment, and apolipoprotein E ε4 carrier status.

MAIN OUTCOMES AND MEASURES: Amyloid PET centiloid and cognition measured as a global cognitive composite constructed by averaging z scores across at least 6 cognitive tests in self-identified Black and White participants. Both cross-sectional and longitudinal analyses were conducted to compare racial groups in amyloid burden and cognition. Data were also analyzed using propensity score-matching of 2:1 (White:Black) by main covariates.

RESULTS: Of 2653 participants (mean [SD] age, 69.0 [8.8] years; 1574 [59.3%] female), 406 (15.3%) were Black and 2247 (84.7%) were White. Black participants had a delayed AMAO compared with White participants in the unmatched (83.86 [95% CI, 76.55-91.35] years vs 71.38 [95% CI, 67.74-73.17] years; difference, 12.48 [95% CI, 5.03-22.28 years) and covariate-matched (85.17 [95% CI, 80.16-91.38] years vs 72.61 [95% CI, 70.79-74.55] years; difference, 12.57 [95% CI, 7.25-19.54] years) analyses. Although Black participants had a lower overall prevalence of amyloid positivity than White participants (24.1% vs 31.7%, P = .002), they had a higher prevalence of amyloid positivity than White participants in almost every interval of expected years to amyloid onset (EYAO, defined as participants' simple chronological age minus the group-specific AMAO), hence Simpson's paradox, (eg, -15 to -10 years for Black minus White prevalence in the unmatched cohort, 15.30 percentage points [95% Wilson CI, 0.06-0.26]). No significant racial differences were found in the longitudinal rate of amyloid accumulation after adjusting for the covariates either before the AMAO (eg, unmatched cohort Black minus White difference in slope per year, -0.28 [95% CI, -0.64 to 0.08]; P = .13) or after the AMAO (eg, unmatched cohort Black minus White difference in slope, -1.23 [95% CI, -3.05 to 0.60]; P = .17). Black participants had a higher prevalence of vascular comorbidities than White participants (56.9% vs 39.3%; P < .001), and Black but not White participants showed significant cognitive decline before the AMAO (Black minus White difference in slope per year, -0.016 (95% CI, -0.028 to -0.004)]; P = .009).

CONCLUSIONS AND RELEVANCE: This cohort study found that Black participants had delayed AMAO compared with White participants, partially explaining the paradox of the reported racial differences in prevalence of amyloid positivity and dementia. This finding suggests that EYAO may be an important confounder to analyze racial differences and may serve as a better (than age) inclusion or exclusion criterion to improve the representation of Black US residents in clinical trials of Alzheimer disease.},
}

Aged
Female
Humans
Male
Middle Aged
*Alzheimer Disease
*Amyloid/metabolism
*Black or African American/statistics & numerical data
Cross-Sectional Studies
*Dementia/epidemiology/ethnology
Longitudinal Studies
Positron-Emission Tomography
Prevalence
Retrospective Studies
United States/epidemiology
*White/statistics & numerical data
*Race Factors

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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