@article {pmid41926304,
year = {2026},
author = {Senwar, KR and Dhillon, A and Yadav, M},
title = {Small Molecule Inhibitors Targeting Pathogenic Protein Aggregation in Neurodegenerative Diseases: Medicinal Chemistry and Mechanistic Insights.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266439510260223082224},
pmid = {41926304},
issn = {1873-4294},
abstract = {A hallmark of Neurodegenerative Diseases (NDs) is protein misfolding, aggregation, and accumulation in specific brain regions. The accumulation of insoluble, misfolded protein aggregates is usually referred to as amyloid formation. This process leads to cellular dysfunction, destruction of neurons, loss of neuronal connections in specific brain areas, and brain damage. Despite the involvement of distinct pathogenic proteins, the underlying mechanisms of misfolding and aggregate formation are remarkably similar across various NDs. In this review, we present a comprehensive overview of the medicinal chemistry and mechanistic insights into phytochemicals and synthetic small molecules with potential for the treatment of neurodegenerative disorders. Various small molecules have been reported to have therapeutic effects by inhibiting the misfolding, aggregation, and accumulation of pathogenic proteins, such as amyloid-β, tau, and α- synuclein. This review mainly covers natural product-derived small molecules, notably polyphenols (including flavonoids and non-flavonoid polyphenols), as well as other phytochemical classes, such as quinones and alkaloids, along with their possible mechanisms of action. In addition, synthetic small molecules, osmolytes, metal chelators, and repurposed drugs for neurodegenerative disorders are thoroughly discussed.},
}

@article {pmid41926844,
year = {2026},
author = {Beyrer, J and Sheff, Z and Payakachat, N and Chandler, JM and Chen, YF and Kubisiak, J and Lee, A and Holdridge, KC and Yaari, R and Aisen, P and Rafii, MS and Sperling, RA and , },
title = {Increase in healthcare utilization and Medicare payment with progression of preclinical Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100547},
doi = {10.1016/j.tjpad.2026.100547},
pmid = {41926844},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) begins with the preclinical stage (Stages 1 and 2) where individuals are cognitively unimpaired but have AD pathology. Healthcare utilization and medical cost of cognitively unimpaired (preclinical) AD have not been previously evaluated.

OBJECTIVES: To describe healthcare resource utilization (HRU) and Medicare payments among cognitively unimpaired individuals with and without elevated amyloid and to evaluate the association of AD progression with HRU and Medicare payments.

DESIGN: Retrospective cohort analysis of the randomized controlled trial (Anti-Amyloid Treatment in Asymptomatic AD [A4]) and companion observational study (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN]) linked with Medicare.

SETTING: Clinical trials sites in the United States PARTICIPANTS: 246 cparticipants with cognitively unimpaired AD in A4 and 121 amyloid-negative participants in LEARN Medicare cohorts.

MEASUREMENTS: Measures from Medicare claims included medical conditions (diagnosis codes), HRU (inpatient, emergency room, outpatient, professional, skilled nursing facility, home health), and Medicare payments. AD progression (or cognitive or functional decline) was measured using Clinical Dementia Rating Scale-Global Score (CDR-GS) in A4/LEARN and diagnosis codes for cognitive impairment, AD, and JEN Frailty Index (JFI) of ≥6 (high frailty) in Medicare data.

RESULTS: HRU and payments were overall similar between A4 and LEARN Medicare. Claims indicators suggesting AD progression in A4 Medicare were associated with higher inpatient, outpatient, emergency room, and home health utilization (any utilization) and increased number of inpatient stays. Payments were significantly greater in A4 Medicare with AD progression vs without progression: 45% payment increase for cognitive impairment (p=0.035) with a mean incremental cost of $140 per person per month (PPPM) (95% confidence interval [CI] $125-$155), 66% payment increase for AD (p=0.011) with a mean incremental cost of $207 PPPM (95% CI $188-$226), and 103% payment increase for high frailty (p<0.001) with a mean incremental cost of $303 PPPM (95% CI $283-$323).

CONCLUSIONS: Overall, individuals with cognitively unimpaired AD in A4 Medicare did not have increased utilization and payments vs LEARN. HRU and payments were significantly greater in A4 Medicare participants with AD progression indicators in claims vs those without progression. These results highlight the need for additional research on both health and economic impacts of progression in a real-world (routine care) cohort of individuals with cognitively unimpaired AD and the potential cost savings associated with effective therapy that delays AD progression in cognitively unimpaired AD.

NCT02008357, NCT02488720.},
}

@article {pmid41928631,
year = {2026},
author = {Huang, Y and Zhu, X and Yang, S and Zhang, Y and Tan, Z and Han, S},
title = {Digital Technology in Cognitive Decline: Bibliometric and Visualization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050420571260126043841},
pmid = {41928631},
issn = {1875-5828},
abstract = {With an increasing prevalence of cognitive decline diseases around the world, digital technologies are becoming an important tool for their prevention, diagnosis, and treatment. In this study, we present a comprehensive bibliometric study on the application of these digital technologies in the field of cognitive decline. This study intends to examine the trends of development and research hotspots of digital technology in cognitive decline field by bibliometric analysis. The literature has been analyzed in a systematic way. Bibliometrix R-package and VOSviewer were used to investigate publication tendency, country contribution, scholar influence, and research hotspots. A total of 1661 articles from 2006 to 2023 were analyzed. Results show an exponential increase in the number of annual publications on digital technologies applications and cognitive decline. The top journals, by volume of publication, are Alzheimer's & Dementia, the Journal of Alzheimer's Disease, and Neurology. The US is the dominant contributor of literature to this field, and the key countries for author impact include Greece, the USA, and Italy. Current research hotspots include virtual reality, machine learning, and artificial intelligence, based on analysis of keywords. This study characterizes the overall research progress and reveals research hotspots, trends, and the collaboration status among countries, on the utilization of digital technologies for cognitive decline. Moving forward, we call on researchers to increase developed/developing countries collaboration, to further implement digital technologies to counteract the public health burden of cognitive decline.},
}

@article {pmid41928975,
year = {2026},
author = {Ma, X and Koppelmans, V and Akcicek, H and Akcicek, EY and Shen, J and Chen, L and Balu, N and Yuan, C and King, JB},
title = {SNAP MRI Reveals Association Between Distal Cerebral Arterial Flow and Cognitive Function in an Aging Population.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.21.713392},
pmid = {41928975},
issn = {2692-8205},
abstract = {OBJECTIVE: Impaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population.

MATERIALS AND METHODS: Neurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

RESULTS: Significant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population.

CONCLUSION: Our findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.},
}

@article {pmid41929577,
year = {2026},
author = {Kandasamy, K and Narasimhamoorthi, SP and Arulselvan, P and Jaganathan, D},
title = {Protective effects of the natural polyphenol garcinol from Garcinia indica mitigates aluminium chloride-induced Alzheimer's-like neurodegeneration in Drosophila melanogaster.},
journal = {3 Biotech},
volume = {16},
number = {4},
pages = {154},
pmid = {41929577},
issn = {2190-572X},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects millions of people affected in worldwide. Natural resources such as medicinal plants have been utilized for the treatment of various memory disorders like amnesia, dementia, Alzheimer's, and Parkinson's for a long time. This study aimed to investigate plants with therapeutic bioactivities for a range of scientific investigations focused on the neuroprotective effects of garcinol from Garcinia indica against the Aluminium chloride (AlCl3)-induced AD in the Drosophila melanogaster model. Polar and non-polar solvents were active on the G. indica fruit rind and subjected to phytochemical investigation. Garcinol was extracted from the EtOH extract of G. indica fruit rind using TLC, column chromatography, GC-MS, UV-visible, and FT-IR. In vitro free radical scavenging effect of the EtOH extract of G. indica fruit rind was studied to determine its antioxidant properties. The effect of garcinol on the interaction and predicted binding interaction of the AD-associated enzymes Amyloid-β, Acetylcholinesterase (AChE), and β-secretase was studied by the in-silico analysis. AD condition was initiated in D. melanogaster by challenging them with AlCl3, and they were pre-treated with garcinol, which is isolated from the EtOH extract of G. indica fruit rind. The effect of garcinol on the AChE activity, oxidative stress markers, and pro-inflammatory cytokines was studied using the respective assay kits. The apoptotic proteins were studied using the RT-PCR analysis. The findings of the phytochemical analysis. In silico garcinol effectively interacts with and inhibits the intermolecular Amyloid-β, AChE, and β-secretase enzymes. AD, garcinol treatment successfully moderated the amendments in behavioural and cognitive impairments, regulated the oxidative stress markers, decreased AChE activity, and reduced the pro-inflammatory cytokine levels. The RT-PCR method proved that garcinol regulated the pro- and anti-apoptotic protein expressions in the AD-induced D. melanogaster. The findings suggested that garcinol from EEGIFR acts against AlCl3-induced AD in D. melanogaster because of its anti-inflammatory, antioxidant, and apoptosis-modulating capabilities, and it may develop as a capable therapeutic agent in treating AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04763-6.},
}

@article {pmid41929929,
year = {2025},
author = {Tang, Y and Zhuo, E and Li, P and Wang, C and Hu, X and Liu, X and Xu, G and Shen, Q},
title = {MANF improves cognitive function and attenuates neuroinflammation in APP/PS1 transgenic mice through the TLR4/MYD88/NF-κB signaling pathway.},
journal = {Journal of anesthesia and translational medicine},
volume = {4},
number = {4},
pages = {241-254},
pmid = {41929929},
issn = {2957-3912},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline, as well as pathological features such as β-amyloid (Aβ) plaque deposition, tau hyperphosphorylation, synaptic dysfunction, and neuronal loss. Growing evidence suggests that neuroinflammation, oxidative stress, and apoptosis play critical roles in the pathogenesis of AD, thereby contributing to neuronal damage and cognitive decline. Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible protein, has been shown to exert neuroprotective effects by modulating immune responses, alleviating oxidative stress, and suppressing apoptosis in various neurological disease models. These properties suggest that MANF could serve as a promising therapeutic candidate treating AD. This study investigated the therapeutic potential of MANF in improving cognitive function and ameliorating pathological changes in APP/PS1 transgenic (Tg) mice by modulating neuroinflammation and enhancing neural plasticity.

METHODS: Beginning at 10 months of age, male APP/PS1 transgenic mice received daily intraperitoneal injections of recombinant human MANF (rhMANF) at a dose of 1 μg/g for a duration of one month. Behavioral assessments, including the Morris water maze, open field, and fear conditioning tests, were conducted to evaluate cognitive function. Brain tissue was analyzed for β-amyloid (Aβ) deposition, neuroinflammation, oxidative stress, and neuronal apoptosis using immunofluorescence, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. RNA sequencing (RNA-seq) and a BV2 microglial/HT22 neuronal co-culture system were used to further elucidate the mechanisms underlying MANF's effects.

RESULTS: rhMANF treatment significantly improved cognitive function in APP/PS1 Tg mice by reducing Aβ deposition, inhibiting microglial activation, and suppressing inflammatory cytokines (TNF-α, IL-1β, and IL-6). MANF also mitigated oxidative stress, reduced neuronal apoptosis, and restored synaptic protein levels, including those of Postsynaptic density protein-95(PSD95) and synaptophysin (SYN). In vitro studies confirmed that MANF effectively counteracts Aβ1-42-induced toxicity in the BV2/HT22 co-culture system. Transcriptomic analysis identified that MANF exerts its protective effects by regulating the TLR4/MYD88/NF-κB signaling pathway, thereby reducing inflammation and promoting synaptic plasticity.

CONCLUSIONS: This study demonstrates the protective role of MANF in AD and establishes MANF as a promising therapeutic candidate for AD and aging-related neurodegenerative disorders.},
}

@article {pmid41929945,
year = {2026},
author = {Yang, Y and Meng, Y and Li, M and Xu, Z and Wu, H and Zhang, Q and Zhang, S and Kong, F and Wang, Z and Li, X and Zhu, Y},
title = {Identification of potential short-chain fatty acid biomarkers in Alzheimer's disease through bioinformatics analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261424808},
pmid = {41929945},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder. Accumulating evidence suggests that short-chain fatty acids (SCFAs) can regulate the central nervous system, thereby affecting cognitive and behavior function.

OBJECTIVE: This study aimed to investigate the association between the AD development and SCFA metabolism via bioinformatic analysis.

METHODS: Gene expression profiles were obtained from the GEO database. 1243 genes related to SCFA were screened from Genecards database. Through weighted gene co-expression network analysis (WGCNA) and differential analysis, 10 SCFA hub genes were screened. Machine learning algorithms, including support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression models, were used to identify candidate biomarkers. The CIBERSORT algorithm was utilized to evaluate the infiltration of immune cells and its relationship with the potential biomarkers. The candidate biomarker chemicals were identified in the Comparative Toxicogenomics Database as underlying targeted drugs for treating AD.

RESULTS: Five genes-EZR, SNCA, GFAP, NFKBIA, and SST-were identified as potential biomarkers for AD through LASSO and SVM-RFE analyses. These genes can also be used to predict the risk of AD and have good diagnostic effects. The candidate biomarkers are associated with plasma cells, activated dendritic cells, M1 macrophages and resting natural killer cells. Notably, valproic acid and tretinoin were found to target these candidate genes, suggesting a new treatment approach for AD.

CONCLUSIONS: This study identified EZR, SNCA, GFAP, NFKBIA, and SST as potential key SCFA-related genes associated with the progression of AD, providing new insights into the prevention and treatment of AD.},
}

@article {pmid41929949,
year = {2026},
author = {Zhang, Q and Almanie, L and Ouyang, Y and Cheng, Z and Zhang, H},
title = {From routine periodontal therapy to Alzheimer's disease early detection: A scoping review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261421629},
pmid = {41929949},
issn = {2542-4823},
abstract = {An epidemiological association has been observed between periodontitis and Alzheimer's disease (AD); however, salivary and blood assays often show low specificity. Periodontal tissues and fluids, which are routinely removed and discarded during periodontal treatment, may be collected to offer matrices useful for the early detection of AD. This study aimed to map current preclinical and clinical evidence on biomarkers measured in periodontal tissues and fluids for the early detection of AD and organize them within an AD-specificity pyramid anchored to brain-relevant endpoints. Following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews) guidance, we searched PubMed, Scopus, and Web of Science (January 1, 2015-August 31, 2025) for preclinical and clinical studies measuring AD-relevant biomarkers in periodontal matrices. The protocol was pre-registered (OSF DOI: 10.17605/OSF.IO/EDVU9; August 20, 2025). Two reviewers extracted the data, and other two independently verified them. The findings were organized using a four-tier AD-specificity pyramid. Results: Fourteen studies met the inclusion criteria. The biomarkers from the included studies were clustered into microbiome features, molecular signals, and genetic/transcriptomic findings. Evidence ranged from Tier-1 contextual inflammation/pathogens to Tier-4 core-pathology adjacency; five studies incorporated clinical/biological anchoring, with cerebrospinal fluid amyloid-β positivity providing the most brain-relevant anchor. Periodontal matrices are practicable, high-signal sources for AD-relevant biomarkers. However, translational validation linking periodontal biomarkers to brain endpoints is needed to assess the feasibility of multi-tier and chairside panels for early AD detection as part of routine periodontal care.},
}

@article {pmid41929950,
year = {2026},
author = {Lin, F and Yang, X and Xie, X and Qiu, L and Zheng, C and Zheng, X and Li, Z and Nie, B},
title = {The causal association between the new gut microbiota and Alzheimer's disease: A Mendelian randomization study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261422629},
pmid = {41929950},
issn = {2542-4823},
abstract = {BACKGROUND: There is a need for more studies to validate the role of gut microbiota in Alzheimer's disease (AD).

OBJECTIVE: This study aims to explore the causal association between new gut microbiota and AD using Mendelian randomization.

METHODS: Using genome-wide association study (GWAS) of 473 gut microbiota species and AD in IEU Open GWAS database, independent genetic loci related to gut microbiota were extracted as instrumental variables. The inverse variance weighting method was employed as the main indicator for evaluation. The stability and reliability of the results were further verified by heterogeneity test, outlier detection, horizontal pleiotropy test and leave-one-out analysis.

RESULTS: Following a thorough screening process, a total of 14 intestinal microbiota were included in the final analyses. The elevated abundance of Agathobacter, Citrobacter A, Clostridium E sporosphaeroides, Eubacterium R, Megamonas funiformis, and Pseudomonas aeruginosa can reduce the risk of AD. Higher abundance of Bifidobacterium, Holdemania massiliensis, Hydrogenophaga, Intestinimonas massiliensis, Megasphaera, Paenibacillus J, Prevotella, and Raoultella could increase the risk of AD. The MR-Egger analyses at 14 "genus" levels showed no horizontal pleiotropy and the p values were all more than 0.05. The leave-one-out analysis showed that results were relatively stable.

CONCLUSIONS: This study revealed a causal relationship between 14 specific gut microbiota and the risk of AD occurrence. Some bacteria are protective, while others increase the risk of AD. These findings are of clinical significance for the treatment and prevention strategies in clinical practice, and it also provides new perspectives for related research on the "gut-brain axis".},
}

@article {pmid41929952,
year = {2026},
author = {Huang, S and Guo, Y},
title = {Network meta-analysis of the efficacy of nine drugs for cognitive function in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261422205},
pmid = {41929952},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) remains a global challenge, and the comparative cognitive efficacy of emerging pharmacotherapies is still unclear.

OBJECTIVE: To compare and rank nine pharmacological agents against placebo in AD with respect to key cognitive outcomes using a network meta-analysis.

METHODS: We systematically searched randomized controlled trials published up to May 2025 that evaluated aducanumab, lecanemab, donanemab, gosuranemab, semorinemab, tilavonemab, zagotenemab, masupirdine, or sodium oligomannate in AD. The primary outcomes were Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); Mini-Mental State Examination (MMSE) was a secondary outcome. Treatments were ranked using the Surface Under the Cumulative Ranking curve (SUCRA).

RESULTS: Fifteen randomized trials encompassing 33 treatment arms were included. No drug demonstrated statistically robust superiority over placebo in primary outcomes. Semorinemab and tilavonemab achieved highest SUCRA rankings, but without significant pairwise advantage. For MMSE, aducanumab showed a modest mean difference versus placebo (1.98, 95% CI 0.03-3.93), though evidence of publication bias reduced confidence.

CONCLUSIONS: Current pharmacological treatments do not consistently outperform placebo in AD. Tau-targeted antibodies (semorinemab, tilavonemab) display modest but non-significant promise, whereas aducanumab's apparent benefit is likely confounded by publication bias. Further large, rigorous randomized controlled trials and improved preclinical models are essential.},
}

@article {pmid41929955,
year = {2026},
author = {Qiu, Q and Qian, W and Zhao, W and Xie, H and Cao, L and Ye, L and , },
title = {P-tau217 and %p-tau217 exhibited superior diagnostic accuracy over other blood biomarkers in the initial assessment of individuals being diagnosed with mild cognitive impairment and Alzheimer's disease dementia.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261439687},
pmid = {41929955},
issn = {2542-4823},
abstract = {BACKGROUND: High-performance blood tests may improve diagnostic accuracy and support personalized treatment for Alzheimer's disease (AD), but validation at the time of initial clinical diagnosis remains limited.

OBJECTIVE: To assess whether plasma biomarkers can aid diagnostic decision-making at first clinical assessment, particularly as tools to triage patients for confirmatory testing in routine practice.

METHODS: We analyzed 241 cognitively normal (CN) controls, 211 patients with mild cognitive impairment (MCI), and 59 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. Plasma aliquots underwent analysis with the C2N Diagnostics PrecivityAD2[®] and Roche Diagnostics Elecsys[®] assays.

RESULTS: The AD group showed a lower Aβ42/Aβ40 ratio than the CN group (p < 0.01) and a mild decrease compared to the MCI group (p < 0.05). The AD group had significant increases in p-tau181, p-tau217, and %p-tau217 (p < 0.001) versus both MCI and CN groups. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were also significantly elevated in AD. The MCI and CN groups only differed in p-tau217 and %p-tau217 (p < 0.05). The AD versus CN AUCs for p-tau181, p-tau217, and %p-tau217 were 0.84, 0.87, and 0.87; for AD versus MCI, they were 0.79, 0.80, and 0.81. The p-tau181, p-tau217, and %p-tau217 showed a moderate correlation with the Alzheimer's Disease Assessment Scale-cognitive subscale. %p-tau217 demonstrated a strong correlation with the p-tau181/Aβ42 ratio in CSF (R = 0.72, p < 0.001).

CONCLUSIONS: In the setting of first-presentation diagnosis of clinically defined MCI and AD, p-tau217, and %p-tau217 outperformed other plasma biomarkers and may help triage patients for further confirmatory evaluation.},
}

@article {pmid41929956,
year = {2026},
author = {Rahman-Filipiak, A and Lesniak, M and Burgei, A and Sadaghiyani, S and Roberts, JS and Lichtenberg, PA and Iordan, A and Mozersky, J and Hampstead, BM},
title = {Qualitative insights into participant and care partner perspectives on research-based Alzheimer's disease biomarker testing and disclosure.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261429997},
pmid = {41929956},
issn = {2542-4823},
abstract = {BACKGROUND: There is strong desire for the return of individual results, including biomarker testing, among participants in Alzheimer's disease and related dementias (ADRD) studies. However, it is not known whether participants accurately understand the utility, limitations, benefits and risks of biomarker disclosure, nor how they weigh these factors to inform their decision to undergo testing and learn results. Furthermore, little is known about how factors like participant race or diagnosis influence a desire to learn biomarker results.

OBJECTIVE: This mixed-methods study explored how clinically and racially diverse participant-care partner dyads perceive and plan to use AD biomarker testing in the context of research studies.

METHODS: 57 participants (Age: M = 74.28 ± 5.98; Race: n = 22 Black, n = 35 White; Diagnosis: n = 23 with mild cognitive impairment; n = 34 cognitively healthy) and care partners were recruited from AD studies wherein the participant completed amyloid-β and tau positron emission tomography without receiving results. Each completed an independent interview about their perspectives on learning the participant's results.

RESULTS: Responses suggested strong interest in learning results, driven by perceived benefits (e.g., informing treatment, lifestyle changes, and social support). Risks were rarely discussed, though some respondents cited concerns about psychological burdens of a positive result. Few nuanced differences in perceived risks or benefits were observed across race and diagnosis.

CONCLUSIONS: The decision to learn the results of biomarker testing is motivated by highly varied perceived benefits and minimal consideration of risks. Testing should be preceded by individualized counseling that carefully reviews potential benefits and risks.},
}

@article {pmid41929964,
year = {2026},
author = {Zhao, X and Wu, L and Li, P},
title = {TARDBP gene mutation in a Chinese family with frontotemporal dementia: A case report and literature review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251412416},
pmid = {41929964},
issn = {2542-4823},
abstract = {BACKGROUND: Mutations in the transactive response DNA binding protein (TARDBP) have never been reported in the population of familial frontotemporal dementia (FTD) in Chinese mainland.

OBJECTIVE: This study reports for the first time a familial FTD carrying TARDBP mutations in Chinese mainland and summarizes the genetic and clinical features of TARDBP mutant families.

METHODS: Case report of comprehensive clinical, genetic and neuroimaging examinations on a 68-year-old male patient diagnosed with behavioral variant FTD (bvFTD). A literature review was also conducted and clinical and genetic features of families with TARDBP mutations were summarized.

RESULTS: We reported the bvFTD patient in Chinese with heterozygous mutation of TARDBP. Brain MRI revealed bilateral frontal and temporal atrophy, predominant in the right side. FDG-PET demonstrated frontal and temporal hypometabolism. [18]F-DPA714-PET showed focally elevated bilateral temporal tracer uptake, and [18]F-MNI-1126-PET revealed a reduction in synaptic uptake throughout the brain, especially in the bilateral temporal lobes. In the literature, we found 68 patients from 24 families with 6 different TARDBP mutations in an exon 6. Nine patients presented with symmetrical atrophy involving the frontal, temporal, and parietal lobes, 11 with asymmetrical atrophy, and 5 without atrophy. More than 60.3% of the patients had an onset age earlier than 65 years old and there was a predominance of men.

CONCLUSIONS: Our discovery confirmed a pedigree of FTD families and expanded the pedigree mutation spectrum of TARDBP in China. The establishment between phenotype and genotype will aid the diagnosis and treatment of FTD.},
}

@article {pmid41929976,
year = {2026},
author = {Parmar, H and Walden, E and , },
title = {Towards practical application of deep learning in diagnosis of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261415808},
pmid = {41929976},
issn = {2542-4823},
abstract = {BACKGROUND: Accurate diagnosis of Alzheimer's disease (AD) is both challenging and time consuming. With a systematic approach to diagnosis, steps can be taken toward improved treatment and prevention of the disease.

OBJECTIVE: This study explores the practical application of deep learning models for the diagnosis of AD across different disease stages.

METHODS: Due to computational complexity, long training times, and limited availability of labeled datasets, full brain three-dimensional (3D) convolutional neural networks (CNNs) are not commonly used, and many studies rely on two-dimensional (2D) variants. In this work, full brain 3D versions of well-known 2D CNN architectures were designed, trained, and tested for the diagnosis of multiple stages of AD. More than 1500 full brain volumes were used for model training and evaluation.

RESULTS: The proposed deep learning approach demonstrated good performance in differentiating various stages of AD. In addition to classification, the models were able to extract discriminative features relevant to disease stage. These features aligned with meaningful anatomical landmarks that are currently considered important for AD identification by clinical experts. An ensemble of all algorithms was also evaluated and achieved superior performance compared to individual models, with a maximum classification accuracy of 87.4%.

CONCLUSIONS: The trained 3D CNNs and their ensemble show strong potential for assisting in the diagnosis of AD. These models may be incorporated into clinical software tools to support physicians and radiologists in improved diagnostic decision making.},
}

@article {pmid41929977,
year = {2026},
author = {Kasuga, K and Yuzawa, C and Nakamura, K and Shimizu, Y and Hara, N and Ikeuchi, T and Sekijima, Y},
title = {A novel PSEN2 missense variant in a Japanese woman with hereditary Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261424532},
pmid = {41929977},
issn = {2542-4823},
abstract = {Hereditary Alzheimer's disease (hAD) and PSEN2 variants are rare, and the benefit of anti-amyloid β-directed monoclonal antibody (mAb) therapy is unknown. We encountered a 51-year-old Japanese woman with PSEN2-associated hAD. A molecular diagnosis revealed a novel uniallelic missense variant (NM_000447:c.356T > G, p.Leu119Arg) in PSEN2. Intravenous mAb therapy was initiated at age 50, and serial amyloid positron emission tomography showed intense Pittsburgh compound B accumulation and a reduction in amyloid-β deposits in the cerebral cortex after 6 months. Our results suggest that treatment with mAbs has the potential to reduce amyloid deposits in the brain, even in patients with symptomatic hAD.},
}

@article {pmid41929981,
year = {2026},
author = {Zupanic, E and Stegnar, G and Rakuša, M and Rus Prelog, P and Švab, I and Gregoric Kramberger, M},
title = {Estimates of current capacity for diagnosing and implementation of new treatment Alzheimer's disease in Slovenia.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261424524},
pmid = {41929981},
issn = {2542-4823},
abstract = {BACKGROUND: The limited efficacy of current symptomatic treatments for Alzheimer's disease (AD) leads many patients to forgo medical help. However, new disease-modifying treatments (DMTs), such as donanemab and lecanemab, show potential to change this.

OBJECTIVE: To model the impact of these treatments on Slovenia's healthcare system by analyzing patient flow under both current and enhanced capacities, assuming DMT availability.

METHODS: The study estimates 76,923 potential DMT candidates aged 65 years and older with mild cognitive impairment or mild AD. Using data from Slovenia's three specialized centers for cognitive disorders, a Markov model simulated five five-year scenarios: baseline, real-life, real-life with capacity enhancement, biomarker integration, and biomarker integration with capacity enhancement.

RESULTS: Waiting times for specialist evaluation would increase from the current 3-12 months to 1.8 years. The primary bottleneck is lumbar puncture with cerebrospinal fluid (CSF) analysis, during which 64% of patients would become ineligible for DMT. The shortest waiting time to receive DMT occurs in the biomarker integration with capacity enhancement scenario, at 4 years, reducing ineligibility to 7%.

CONCLUSIONS: Current specialized outpatient facilities are limited, causing significant bottlenecks, especially in CSF analysis. Severe waiting times under current capacities mean many patients would progress to moderate or severe dementia or die before receiving treatment. Plasma biomarkers offer a promising triage approach to guide patients toward lumbar puncture or other confirmatory diagnostics, potentially easing this critical bottleneck. Substantial infrastructure and workforce improvements are essential to ensure timely and equitable access to DMTs in Slovenia.},
}

@article {pmid41929983,
year = {2026},
author = {Paez, K and Kopachik, C and Yilmaz, A and Vishweswaraiah, S and Ashrafi, N and Saiyed, N and Monacelli, N and Kerseviciute, I and Gordevicius, J and Ruff, S and Pai, A and Khaled, I and Maddens, ME and Graham, SF},
title = {Unraveling the impact of common medications on biomarker patterns in Alzheimer's disease and mild cognitive impairment.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251387281},
pmid = {41929983},
issn = {2542-4823},
abstract = {BACKGROUND: The aging global population faces significant challenges from Alzheimer's disease (AD). Metabolomics offers a non-invasive, cost-effective diagnostic alternative. Researchers identified significant variations in the level of salivary and urinary metabolites between AD patients and cognitively healthy controls. However, it's unclear whether differences in metabolites between AD patients and healthy controls are due to the disease or medications.

OBJECTIVE: This study aims to investigate the impact of common AD medications (cholinesterase inhibitors) and hypertension medications (ARBs) on the AD patient metabolome.

METHODS: A retrospective metabolomics analysis was conducted to elucidate whether observed metabolic perturbations were attributable to AD pathology or polypharmacy, with a specific focus on cholinesterase inhibitors and ARBs.

RESULTS: Linear models revealed that cholinesterase inhibitors did not significantly modulate potential urinary and salivary biomarkers for AD. However, these inhibitors were associated with significant changes in urinary metabolite concentrations, including increased isovaleric acid and L-leucine and decreased formate and L-histidine (q = 0.027 for all). Analysis of ARB treatment revealed significantly reduced urinary tryptophan levels (q = 0.001) in AD patients and increased salivary acetone and isopropyl alcohol concentrations (q = 0.028) across all groups. Further analysis of saliva metabolite ratios revealed notable differences in asymmetric arginine methylation between the AD group and the control group (q = 0.021). Additionally, variations in citrate synthesis were observed between the mild cognitive impairment group and the control group on ARBs (q = 0.024).

CONCLUSIONS: Our research confirms that distinct biomarker profiles characteristic of AD remain present regardless of cholinesterase inhibitor and ARB treatment, providing a foundation for future clinical studies and therapeutic development by providing better diagnostic tools.},
}

@article {pmid41930591,
year = {2026},
author = {Qin, J and Xu, X and Zou, Y},
title = {Herpes zoster, antiviral therapy, and Alzheimer's disease: Turning association into an actionable prevention pathway.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438524},
doi = {10.1177/13872877261438524},
pmid = {41930591},
issn = {1875-8908},
abstract = {Yang and Jiang synthesize evidence linking varicella-zoster virus exposure to Alzheimer's disease risk and lay out a clinically intuitive pathway from infection to intervention, spanning antiviral treatment and herpes zoster vaccination. The review is timely because it highlights potentially modifiable touchpoints in routine care for older adults. Building on their work, this commentary raises one pragmatic question: what additional evidence would most efficiently translate these associations into targeted, implementable prevention strategies-clarifying when risk is most actionable, which intervention features matter most, and which subgroups may benefit most?},
}

@article {pmid41930592,
year = {2026},
author = {Vijverberg, EGB and Scharre, DW and Woodward, M and Catalano, S and Hamby, ME and Grundman, M and Morgan, RE and Iaci, J and Devins, T and Caggiano, AO},
title = {Randomized, double-blind study of zervimesine in mild to moderate Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261437145},
doi = {10.1177/13872877261437145},
pmid = {41930592},
issn = {1875-8908},
abstract = {BackgroundZervimesine (CT1812) is a first-in-class, brain-penetrant sigma-2 receptor ligand that prevents binding and displaces Aβ42 oligomers from receptors on neuronal synapses.ObjectiveThis study evaluated the safety and efficacy of zervimesine in mild to moderate Alzheimer's disease (AD).MethodsThis was a Phase 2, randomized, double-blind, placebo-controlled study. Participants were randomized to zervimesine 100 mg or 300 mg or placebo. In addition to ADAS-Cog11, outcomes were evaluated from baseline plasma p-tau217 in prespecified subgroups.ResultsOf 153 adults randomized, 150 were included in the mITT population. Adverse events occurred in 70.6% with zervimesine 100 mg, 82.4% with zervimesine 300 mg, and 78.0% with placebo. At Day 182, the ADAS-Cog 11 increased from baseline (indicating a decline in cognitive function) with the LS mean (SE) change of 2.69 (0.81) points in the placebo group versus 1.66 (0.60) points in the pooled zervimesine group [δ = -1.03 (-3.01, 0.96), p = 0.310]. For participants with baseline plasma p-tau217 levels below the median (1.0 pg/mL), the pooled zervimesine group showed greater improvement on the ADAS-Cog 11 at Day 182 relative to placebo (δ = -2.66; p = 0.080).ConclusionsThis phase 2 study indicated that zervimesine was safe and well tolerated and showed consistently favorable numerical treatment differences versus placebo. More robust treatment differences were observed in the below median baseline plasma p-tau217 group suggesting potentially greater efficacy of zervimesine in less advanced AD. These results support larger pivotal trials with zervimesine.Registered at clinicaltrials.gov: NCT03507790.},
}

@article {pmid41930760,
year = {2026},
author = {Patel, S and Sood, R and Shrivastava, S and Jeengar, MK},
title = {Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X385491251208144807},
pmid = {41930760},
issn = {1875-6190},
abstract = {Neurodegenerative Disorders (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and other less prevalent conditions, represent a growing challenge in medical science due to their progressive nature and the absence of curative treatments. Cruciferous vegetables, such as those from the Brassicaceae family and other species in the Brassicales order, have been reported to offer potential benefits for treating and preventing NDDs. Their neuroprotective effects have been attributed to secondary metabolites, glucosinolates (GLs), and their hydrolytic products, isothiocyanates (ITCs). One of these ITCs is Erucin (ERU), chemically known as 4-isothiocyanatobutane, which is a specific type of ITC. ERU is the isothiocyanate derivative of erucic acid and is structurally related to sulforaphane (SFN), another well-known ITC. This review aims to synthesize current scientific knowledge on ERU's mechanisms of action in neurodegeneration, highlighting preclinical evidence supporting its neuroprotective effects in diseases such as AD and PD, and suggesting its potential as a treatment strategy for NDDs. Preliminary studies suggest that ERU may confer neuroprotection through antioxidative stress pathways, modulation of neuroinflammatory responses, and upregulation of neurotrophic factors. This article discusses ERU's chemical properties, pharmacokinetics, and observed impacts on neurodegenerative models, suggesting potential therapeutic pathways it may influence, thereby highlighting its promise as a future component of neuroprotective strategies against NDDs.},
}

@article {pmid41930762,
year = {2026},
author = {Singh, A and Mazumder, A and Das, S and Kumar, R and Kanda, A},
title = {Synergistic Anti-dementia Effects of Symplocos racemosa Nanoemulsion: Isolation, Molecular Docking, and In Vivo Evaluation.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026421409260119050357},
pmid = {41930762},
issn = {1875-5739},
abstract = {INTRODUCTION: Dementia, marked by a decline in mental abilities like memory that interferes with daily life, is primarily caused by Alzheimer's Disease (AD). Symplocos racemosa, rich in acetyl oleanolic acid, serves as a neuroprotective agent by lowering amyloid β levels in the brain. This study aims to develop a nanoemulsion for the targeted delivery of S. racemosa phytoconstituents to enhance therapeutic efficacy against dementia. The study also aims to find out the mechanism of the responsible molecules via molecular docking studies.

METHODS: S. racemosa bark was ultrasonically extracted with methanol and ethyl acetate, yielding six phytoconstituents: ellagic acid, betulinic acid, acetyl oleanolic acid, salireposide (from methanol), oleanolic acid, symlocoside (from ethyl acetate), isolated by column chromatography. Molecular docking against AChE and BACE-1 was conducted using CB Dock-2. A chitosan- based nanoemulsion containing all six compounds was prepared to enhance brain delivery and was physically characterized. All isolated phytoconstituents and nanoemulsions were evaluated for their in vitro enzyme inhibition (AChE and BACE-1) potential. Its anti-dementia efficacy was evaluated in scopolamine-induced rodent models using Hebb-Williams and Elevated Plus Maze tests, complemented by histopathological analysis of the brain cortex to assess therapeutic effects.

RESULTS: Docking studies showed acetyl oleanolic acid had stronger binding to BACE-1 and AChE than donepezil. This was further supported by an in vitro enzyme inhibition assay. Nanoemulsion at 200 and 400 mg/kg significantly reduced the time taken by memory-impaired mice to complete the Hebb-Williams Maze and transfer latency in the Elevated Plus Maze. Histopathological analysis showed a significant recovery of cortical damage. This indicates that the nanoemulsion has strong potential for the treatment of Alzheimer 's-related neurodegeneration.

DISCUSSION: The neuroprotective action of S. racemosa nanoemulsion (SRMN) is attributed to the large-scale presence of its phytoconstituents, which reportedly exhibit a better binding affinity and inhibitory action against AChE and BACE-1 than donepezil. Additionally, the nanoemulsion enhanced bioavailability, stability, and blood-brain barrier penetration, which in turn improved therapeutic outcomes. From behavioral and histological studies, we observed that SRMN performed well in terms of memory improvement and cortical protection, suggesting that it is a very good multi-target approach for dementia.

CONCLUSION: The prepared nanoemulsion from S. racemosa's isolated phytoconstituents is reported to exhibit synergistic action, thereby effectively managing dementia through BACE-1 and AChE inhibition.},
}

@article {pmid41930767,
year = {2026},
author = {Parashar, AK and Saraogi, GK and Sethi, VA and Ahmad Yasin, HK},
title = {Nanocarriers in Alzheimer's Therapy: A Comprehensive Review on Nanoparticulate Drug Delivery Systems.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026435071260129105648},
pmid = {41930767},
issn = {1875-5739},
abstract = {INTRODUCTION: Neurodegenerative disorders, particularly Alzheimer's Disease (AD), pose a major global health challenge, characterized by progressive neuronal degeneration and cognitive decline. The blood-brain barrier (BBB) significantly limits the efficacy of conventional therapeutics, preventing adequate drug delivery to the central nervous system. Nanoparticulate Drug Delivery Systems (NPDDS) have emerged as a promising approach to overcome these limitations and enhance the therapeutic potential of AD interventions.

METHODS: This review comprehensively examines recent advancements in NPDDS for AD therapy. Various nanoparticle classes, including polymeric nanoparticles, solid lipid nanoparticles, gold nanoparticles, liposomes, microemulsions/nanoemulsions, dendrimers, and hydrogels, are evaluated with respect to their physicochemical characteristics, drug-loading capacities, BBBpenetrating strategies, and potential for targeted cerebral delivery. Relevant preclinical and clinical studies were analyzed to summarize the pharmacokinetic and pharmacodynamic benefits of these systems.

RESULTS: The reviewed NPDDS demonstrate enhanced drug solubility, stability, and controlled release profiles. Multiple strategies, such as surface functionalization, intranasal administration, and receptor-mediated transcytosis, facilitate BBB penetration and site-specific drug delivery. Nanocarriers improve drug accumulation at pathological sites, potentially enhancing therapeutic efficacy while reducing systemic side effects. Each nanoparticle class offers distinct advantages: polymeric and lipid-based systems provide controlled release and biocompatibility, while metallic and dendrimeric platforms offer theranostic capabilities and high drug-loading potential.

DISCUSSION: Despite their promise, challenges remain in translating NPDDS to clinical applications. Efficient and reproducible BBB crossing, potential cytotoxicity, long-term biocompatibility, and scalable manufacturing processes require further optimization. Multifunctional and hybrid nanocarriers, stimuli-responsive systems, and biomimetic designs are emerging to address these limitations. Continuous advancements in nanotechnology offer tunable physicochemical properties to tackle the complex pathogenesis of AD, enabling more precise, effective, and patient- compliant therapies.

CONCLUSION: NPDDS represent a transformative frontier in Alzheimer's disease management, offering targeted, efficient, and adaptable drug delivery solutions. Strategic development and rigorous evaluation of these systems may improve CNS bioavailability of therapeutic agents, enhance clinical outcomes, and potentially shift the paradigm in the treatment of neurodegenerative disorders. Future research should focus on overcoming translational challenges to realize the full potential of nanocarrier-based AD therapy.},
}

@article {pmid41930874,
year = {2026},
author = {Xiao, S and Han, Y and Yan, J and Wu, L and Lin, H and Yuan, C and Song, C and Ye, J},
title = {Salvianolic acid a inhibits neuroinflammation and ameliorates Alzheimer's disease pathology via the p38 MAPK/NF-κB pathway based on network pharmacology and experimental validation.},
journal = {International immunopharmacology},
volume = {178},
number = {},
pages = {116594},
doi = {10.1016/j.intimp.2026.116594},
pmid = {41930874},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) represents the most prevalent form of neurodegenerative disorder, characterized by progressive cognitive impairments and a scarcity of effective treatments. Salvianolic acid A (SalA), a natural phytochemical endowed with antioxidative, antiapoptotic, and anti-inflammatory properties, emerges as a promising therapeutic candidate for AD. This study explored the therapeutic efficacy and underlying mechanisms of SalA in mitigating AD-related pathologies. Through integrative network pharmacology, molecular docking, and pathway enrichment analysis, p38 MAPK and NF-κB were identified as potential targets of SalA in the context of AD. SalA treatment inhibited the activation of the p38 MAPK/NF-κB pathway via targeting p38 MAPK, leading to decreased levels of IL-1α and IL-1β in lipopolysaccharide (LPS)-stimulated HMC3 cells. In an in vivo 3 × Tg-AD mouse model, SalA administration ameliorated cognitive decline associated with AD, decreased tau protein hyperphosphorylation in the hippocampus and cortex, and reduced amyloid-β (Aβ) accumulation and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) levels. Furthermore, SalA attenuated the activation of the p38 MAPK/NF-κB pathway and the expression of related inflammatory cytokines in the brains of 3 × Tg-AD mice. In conclusion, this study elucidates the promising ameliorative effects of SalA on improving AD pathology, primarily through the modulation of the p38 MAPK/NF-κB signaling pathway.},
}

@article {pmid41931967,
year = {2026},
author = {Sun, X and Xi, Y and Chen, Y and Zhou, J and Ni, J and Ding, Y and Zhang, H},
title = {Dysfunctional microglia-targeted nanoscavenger synergistically accelerates Aβ clearance and inhibits inflammatory cascade.},
journal = {Biomaterials},
volume = {333},
number = {},
pages = {124163},
doi = {10.1016/j.biomaterials.2026.124163},
pmid = {41931967},
issn = {1878-5905},
abstract = {Amyloid-β (Aβ) clearance holds promise in Alzheimer's disease (AD) treatment, but the clinical application is limited by poor clearance efficacy and microglial inflammatory cascade caused by overloaded Aβ degradation. In this study, a polymeric lipoprotein-curcumin nanoscavenger (CP/[Man]Disc-Cur) with dysfunctional microglia-specific targeting capability is designed to synergistically promote Aβ clearance and inhibit microglial inflammatory cascade. For preparation, curcumin is post-encapsulated into mannose-modified Disc ([Man]Disc-Cur), followed by assembly with chitosan derivatives (CP) to obtain CP/[Man]Disc-Cur. After intranasal administration and triggered by the nasal acidic microenvironment, CP/[Man]Disc-Cur is depolymerized into [Man]Disc-Cur and protonated CP that adheres to reversibly open the tight junctions, promoting [Man]Disc-Cur penetration into the brain via the olfactory pathway. Thereafter, [Man]Disc-Cur captures Aβ oligomer with a high binding affinity (KD = 5.90 × 10[-8] M) and selectively targets dysfunctional microglia where Aβ catabolism is accelerated with inflammation inhibition by curcumin. After nasal treatment of CP/[Man]Disc-Cur for 4 weeks, Aβ burden, microglial inflammation, and memory deficits of APPswe/PS1dE9 transgenic AD mice are significantly attenuated without the obvious side effects. Collectively, this study provides a promising strategy for synergistically improving Aβ clearance and inhibiting microglial inflammatory cascade for enhanced AD treatment.},
}

@article {pmid41931990,
year = {2026},
author = {Gao, J and Yi, Y and Ran, W and Cheng, Y and Deng, W and Duan, S and Shi, F and Wei, Y and Zhang, Y and Gong, Q},
title = {Targeting astrocytic Nrf2 by Trilobatin alleviates lipopolysaccharide-induced depressive-like behaviors and cognitive impairment in mice: Mechanistic insights into gut microbiota and metabolites modulation.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158118},
doi = {10.1016/j.phymed.2026.158118},
pmid = {41931990},
issn = {1618-095X},
abstract = {BACKGROUND: Clinical and preclinical evidence links major depressive disorder (MDD) and Alzheimer's disease (AD), suggesting MDD treatment could prevent some AD. Dysfunction within the microbiota-gut-brain axis contributes to MDD and AD pathogenesis via dysregulated microbial metabolites. Trilobatin (TLB) functions as a neuroprotective agent modulating gut microbiota. However, its capacity to alleviate depressive-like behavior and cognitive deficits through restoration of gut microbial ecology and metabolite profiles requires clarification.

OBJECTIVE: The present research was designed to examine the impact of TLB on depressive-like behavior and cognitive impairments, and the role of the gut microbiota and metabolites.

METHODS: Neuroprotective effects of TLB on MDD and AD were evaluated using an LPS mouse model exhibiting depressive-like behavior and memory impairment. The principal molecular target of TLB was identified through a combination of single-cell sequencing, surface plasmon resonance, and gene knockout approaches. Mechanistic insights into gut microbiota and metabolites were gained through 16S rRNA sequencing and fecal microbiota transplantation (FMT).

RESULTS: TLB attenuated LPS-induced depressive-like behaviors manifested as lowered sucrose preference, extended immobility, and improved cognitive deficits as reflected by Y-maze and novel object recognition. Mechanistically, TLB directly bound Nrf2, enhanced Nrf2-ARE activity, and suppressed neuroinflammation and oxidative stress. TLB restored gut microbiota homeostasis, elevated Akkermansia muciniphila (AKK) abundance and short-chain fatty acids, and strengthened intestinal tight junction proteins. FMT from TLB-treated mice replicated these benefits in wild-type but not Nrf2-knockout mice. AKK supplementation similarly ameliorated behavioral and cognitive deficits via Nrf2 activation.

CONCLUSION: Our findings reveal that TLB mitigates neuropsychiatric deficits by activating Nrf2, remodeling restructuring gut microbiota and fortifying intestinal barrier function. The Nrf2-mediated microbiota-gut-brain axis is suggested as a potential therapeutic target for MDD and AD, positioning TLB as a promising natural Nrf2 activator.},
}

@article {pmid41931996,
year = {2026},
author = {Liu, XY and Wang, K and Zhong, JJ and Lin, CL and Zhu, JR and Wang, PP and Guo, R and Shao, SS and Lim, HSD and Siow, KL and Shan Kek, R and Ng, YH and Chen, M and Han, RC and Yao, H and Zheng, GQ and Wen, L},
title = {Modified Kai-Xin-San ameliorates cognitive impairment in Alzheimer's disease model mice by regulating neuroinflammation and synaptic dysfunction.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158102},
doi = {10.1016/j.phymed.2026.158102},
pmid = {41931996},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by debilitating cognitive decline. Despite its escalating global prevalence, effective disease-modifying therapies remain limited. Modified Kai-Xin-San (MKXS), a derivative of a classic Chinese herbal formula, has shown promise in AD management; however, its precise pharmacological mechanisms require further elucidation.

PURPOSE: This study aimed to evaluate the therapeutic effects of MKXS and identify the molecular mechanisms underlying its impact on cognitive function in an AD mouse model.

METHODS: The chemical profile of MKXS was characterized using HPLC-Q-TOF-MS, with 24 major constituents quantified via UPLC-PDA. MKXS was administered intragastrically to 5 × FAD mice daily for two consecutive months. Cognitive performance was evaluated using Morris water maze, T-maze, and Y-maze tests. Neuropathological changes, including β-amyloid (Aβ) deposition and neuronal loss, were analyzed via immunostaining, Nissl staining, ELISA, and Western blotting. Synaptic plasticity was assessed through Golgi staining and electrophysiological recordings. Furthermore, network pharmacology and experimental validation were conducted to identify core therapeutic targets with the application of GEO database.

RESULTS: Chemical analysis identified 125 constituents in MKXS, with 24 validated against reference standards. In 5 × FAD mice, MKXS treatment significantly ameliorated cognitive impairment, reduced hippocampal Aβ plaque burden, and attenuated neuronal loss. Network pharmacology highlighted neuroinflammation and synaptic regulation as core therapeutic mechanisms. Subsequent validation demonstrated that MKXS suppressed glial overactivation and lowered pro-inflammatory cytokine levels, effectively restoring synaptic plasticity and dendritic spine integrity within the hippocampus. Notably, MKXS significantly upregulated the CaMKIIα/CREB signaling pathway in the hippocampus of 5 × FAD mice. Crucially, pharmacological inhibition of CaMKIIα with KN93 significantly abolished these beneficial effects on synaptic function and memory, confirming the essential role of this signaling axis in MKXS-mediated neuroprotection.

CONCLUSION: MKXS alleviated cognitive impairment in 5 × FAD mice by attenuating neuroinflammation and restoring synaptic integrity. These neuroprotective effects were mediated, at least in part, by the activation of the CaMKIIα/CREB signaling pathway. Collectively, these findings underscore the potential of MKXS as a promising multi-target therapeutic intervention for AD.},
}

@article {pmid41932135,
year = {2026},
author = {Lin, WJ and Li, CY and Shi, WP and Liu, TA and Wang, YJ and Li, YJ},
title = {Ferulic acid inhibits Tau-441 liquid-liquid phase separation to restore glycolytic metabolism.},
journal = {International journal of biological macromolecules},
volume = {358},
number = {},
pages = {151806},
doi = {10.1016/j.ijbiomac.2026.151806},
pmid = {41932135},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and effective clinical treatment currently remains lacking. Ferulic acid (FA) has shown clinical effects in the treatment of AD, but the underlying mechanism of action remains unclear. Here, we showed that FA significantly enhances glycolytic metabolism by inhibiting Tau-441 liquid-liquid phase separation (LLPS). Through molecular docking and solution experiments, we demonstrated that FA binds to Tau-441 via hydrogen bonds, significantly reducing its β-sheet content, thereby effectively preventing the formation of Tau-441 droplets and their transition into solid aggregates. Immunofluorescence staining further confirmed that FA inhibits Tau-441 LLPS formation and reduces the recruitment of hexokinase (HK) during droplet formation. Metabolomic and network analyses revealed that FA significantly alters cellular metabolic profiles, particularly enhancing glycolytic pathway activity. Consistently, FA markedly increased the activities of three key enzymes (HK, PFK, and PK) in the glycolytic pathway, thereby elevating cellular ATP levels and cell viability. These results demonstrate that FA significantly improves glycolytic metabolic efficiency by inhibiting Tau-441 LLPS, thus providing critical experimental and theoretical support for the potential application of FA in treating AD. Overall, this study offers new molecular targets and natural compound intervention strategies for AD treatment.},
}

@article {pmid41932344,
year = {2026},
author = {Geldenhuys, WJ and Mersch, J and Cicala, D and Sarker, R and Roknuzzaman, ASM and Maghareh, M and Carerra, EM and Lade, DM and Menze, MA and Konkle, ME and Huber, JD},
title = {Medicinal Chemistry Review of the NEET Protein Family.},
journal = {ChemMedChem},
volume = {21},
number = {7},
pages = {e202500969},
doi = {10.1002/cmdc.202500969},
pmid = {41932344},
issn = {1860-7187},
mesh = {Humans ; *Mitochondrial Proteins/metabolism/antagonists & inhibitors/chemistry ; Animals ; Ligands ; *Iron-Sulfur Proteins/metabolism/antagonists & inhibitors/chemistry ; },
abstract = {Members of the NEET family of proteins are of interest as drug targets in several age-related diseases, including cancer, diabetes, obesity, Alzheimer's and Parkinson's disease, stroke, and traumatic brain injury. These proteins share a CDGSH motif and redox-active [2Fe-2S] clusters. MitoNEET (CDGSH iron-sulfur domain-containing protein 1) is an outer mitochondrial membrane protein that was recently discovered as an off-target of the antidiabetic drug pioglitazone, and plays an essential role in mitochondrial bioenergetics, mitophagy, and iron metabolism. CDGSH iron-sulfur domain-containing protein 2 (nutrient-deprivation autophagy factor 1) is located on the endoplasmic reticulum and is found to be antiaging and associated with Wolfram Syndrome 2, while CDGSH iron-sulfur domain-containing protein 3 (mitochondrial inner NEET protein) is present in the mitochondrial matrix. In this review, we will evaluate the state of the field in the development of NEET protein interacting ligands, which can serve as pharmacological tools to study the biology/biochemistry of NEET family proteins in disease. The NEET family represents a novel class of drug targets, enabling the development of novel treatment modalities to modulate disease progression in various human disorders.},
}

Humans
*Mitochondrial Proteins/metabolism/antagonists & inhibitors/chemistry
Animals
Ligands
*Iron-Sulfur Proteins/metabolism/antagonists & inhibitors/chemistry

@article {pmid41867219,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Showalter, J and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Streamlining Eligibility Assessment for Alzheimer's Disease-Modifying Therapies: Prediction of MMSE Scores Using the Digital Clock and Recall.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {41867219},
abstract = {INTRODUCTION: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks perpetuating health disparities due to the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR[™]) - a rapid, FDA-listed digital cognitive assessment - to crosswalk to MMSE scores using machine learning, thereby offering a faster, scalable, and equitable mechanism for patient triage.

METHODS: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 study (NCT04733989, N=945). Participants were clinically classified as cognitively unimpaired, mild cognitive Impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was tested for generalizability using an independent external validation cohort from the Apheleia study (NCT05364307, N=238).

RESULTS: The machine learning model predicted MMSE scores with a root mean squared error (RMSE) of 2.31 in the training cohort. This error margin falls within the established test-retest reliability range of the manual MMSE itself (2-4 points), suggesting the prediction is statistically non-inferior to human administration. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE = 2.62). Crucially, the model exhibited demographic fairness, maintaining consistent accuracy across Race (White RMSE = 2.34; Non-White RMSE = 2.14) and Ethnicity (Hispanic RMSE = 2.26; Non-Hispanic RMSE = 2.31).

DISCUSSION: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.},
}

@article {pmid41922883,
year = {2026},
author = {Shah, D and Akarte, K and Patel, S and Patel, A and Kushwaha, N and Panjwani, D and Patel, V and Ahlawat, P and Shah, A},
title = {Recent Progress on Selenium Nanoparticles: Synthesis and Neuroprotective Effects for the Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41922883},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Neuroprotective Agents/chemical synthesis/therapeutic use/pharmacology ; Animals ; *Nanoparticles/chemistry/therapeutic use ; *Selenium/therapeutic use/chemistry ; },
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia, affecting over 50 million individuals worldwide, with projections suggesting a tripling of cases by 2050. Current Food and Drug Administration (FDA)-approved treatments, including cholinesterase inhibitors, N-Methyl-D-aspartic acid (NMDA) receptor antagonists, and monoclonal antibodies, provide only modest symptomatic relief or partial disease modification. Their limitations include poor blood-brain barrier penetration, systemic side effects, and reduced efficacy in advanced stages. This has caused the exploration of novel nanotechnology-based interventions. This review synthesizes recent evidence from preclinical and translational studies on SeNPs for AD therapy. Also covering their synthesis methods (physical, chemical, and biological), surface engineering approaches, drug loading strategies, and mechanisms of action were systematically examined. SeNPs exhibit dual functionality as therapeutic agents and drug carriers. Functionalized SeNPs have shown the ability to cross the BBB, but this efficiency depends on particle size (typically < 100 nm) and surface ligands such as transferrin, rabies virus glycoprotein 29-peptide (RVG29), or transferrin-guiding peptide (TGN). Studies using ligand-modified SeNPs demonstrate improved BBB transport and enhanced modulation of oxidative stress, amyloid-β (Aβ) aggregation, and neuroinflammation. SeNPs exhibit neuroprotective activity in several preclinical models, primarily attributed to antioxidant and anti-inflammatory mechanisms. Although encouraging preclinical data support their promise, systematic toxicological assessment and optimization of stability are required. With advances in green synthesis, surface engineering, and theranostic applications, SeNPs may represent a new Framework in precision nanomedicine for Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy
Humans
*Neuroprotective Agents/chemical synthesis/therapeutic use/pharmacology
Animals
*Nanoparticles/chemistry/therapeutic use
*Selenium/therapeutic use/chemistry

@article {pmid41922909,
year = {2026},
author = {Dai, Q and Lin, Q and Chen, J and Deng, Z and Jin, W and Ye, P and Zuo, Y and Yang, Y and Xiao, S and Tang, Y},
title = {Prevalence and burden of neurological diseases in the Chinese mainland: An analysis from the Global Burden of Disease Study 2021.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {41922909},
issn = {2542-5641},
abstract = {BACKGROUND: Neurological diseases represent a growing challenge to the Chinese public health system. However, a comprehensive analysis of neurological diseases in China is lacking. This study aimed to analyze disease burden and risk factors of neurological diseases in the Chinese mainland to identify priorities for disease control and prevention.

METHODS: Disease burden and risk factors in the Chinese mainland were analyzed for 12 neurological disorders using data from the Global Burden of Diseases 2021 study and the Chinese Center for Disease Control and Prevention. Prevalence, deaths, years of life lost, years lived with disability (YLDs), and disability-adjusted life years (DALYs) were used as metrics.

RESULTS: Intracerebral hemorrhage (ICH) (1930.3 [95% uncertainty interval (UI): 1605.3-2296.7] per 100,000), ischemic stroke (1646.8 [95% UI: 1400.0-1893.1] per 100,000), Alzheimer's disease and other dementias (dementia) (708 [95% UI: 347.7-1561.7] per 100,000) made the greatest contributions to DALY rates in the Chinese mainland in 2021. The fastest growing contributors to DALY rates were dementia (208.2% [95% UI: 166.4-255.7%]), Parkinson's disease (160.7% [95% UI: 121.8-208.3%]), and ischemic stroke (95.2% [95% UI: 56.9-140.6%]). Migraine was the leading contributor to DALY rates among populations aged 10-39 years, ICH for those aged 40-74 years, ischemic stroke for those aged 75-89 years, and dementia for those aged >90 years. Ischemic stroke accounted for the highest age-standardized DALY rates in North and Northeast China, whereas ICH ranked first in other regions. High systolic blood pressure had the highest attributable DALYs for all diseases combined. Metabolic risk factors, alcohol use, secondhand smoke, and low physical activity contributed to higher YLDs in females, whereas alcohol use, smoking, and a high-sodium diet contributed to higher YLDs in males.

CONCLUSIONS: Neurological diseases present a growing public health challenge, characterized by significant disparities in their prevalence and presentation across age, sex, and geographic regions. Addressing these disparities requires coordinated strategies encompassing prevention, treatment, rehabilitation, and supportive care at the national level.},
}

@article {pmid41923420,
year = {2026},
author = {Luzzi, S and Snowden, JS},
title = {Low Sensitivity of Neuropsychological Scales Hinder Detection of Potential Benefit of Treatments in Alzheimer's Disease: A Position Paper.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70590},
pmid = {41923420},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/diagnosis/drug therapy/psychology ; *Neuropsychological Tests/standards ; Cognitive Dysfunction/diagnosis ; Sensitivity and Specificity ; },
abstract = {BACKGROUND: Despite the advent of Disease Modifying Therapies (DMTs) for Alzheimer's Disease (AD), the approval and commercialization of anti-amyloid monoclonal antibodies has been slow and contentious, particularly in Europe. The primary source of debate is the discrepancy between robust biological effects-namely, effective β-amyloid clearance-and modest clinical improvements, which, although statistically significant, often fail to reach the minimal clinically important difference (MCID) compared to placebo.

METHODS: This paper highlights a confounding factor in the interpretation of the results of clinical trials: limited sensitivity of neuropsychological outcome measures. These tools, developed in the 1980s and only marginally updated, are not suited to detect subtle but meaningful cognitive changes in early disease stages.

RESULTS: The ADAS-Cog, the most commonly used cognitive endpoint, suffers from a substantial ceiling effect, impairing its ability to capture cognitive decline over short durations in prodromal populations. Likewise, functional scales such as the CDR-SB are inherently insensitive in mild cognitive impairment (MCI), as functional independence is, by definition, preserved. Moreover, the use of composite multidomain scales with high baseline scores may mask domain-specific improvements, further limiting a drug's capacity to reach MCID thresholds.

CONCLUSION: Methodological limitations risk undervaluing the therapeutic impact of treatment, particularly in trials targeting early or preclinical phases where changes are subtle and domain-specific. Urgent reconsideration of outcome measures is necessary to ensure accurate assessment of clinical efficacy and to avoid prematurely discarding potentially beneficial therapies.},
}

Humans
*Alzheimer Disease/diagnosis/drug therapy/psychology
*Neuropsychological Tests/standards
Cognitive Dysfunction/diagnosis
Sensitivity and Specificity

@article {pmid41924980,
year = {2026},
author = {Chaulagain, B and Gothwal, A and Mahanta, AK and Jarajapu, YPR and Singh, J},
title = {Cannabidiol and pBDNF Cotreatment Attenuates Pathological Symptoms and Improves Cognition in 3 month-Old 5XFAD Mice.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c01009},
pmid = {41924980},
issn = {1948-7193},
abstract = {The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a synaptic modulation and cognitive maintenance agent, is declined and, thus, aggravates pathology and cognition in AD. BDNF expressed from the liposome nanoparticles supplements the reduced BDNF and aids in ameliorating AD pathology. We found four weekly doses of our formulation reduced the amyloid burden by 3.04-fold (p-value < 0.0001), declined pro-inflammatory cytokines TNF-α by 2.51-fold (p-value < 0.0001), IL-1β by 2.34-fold (p-value < 0.0001) and microglial activation by 2.15-fold (p-value < 0.0001) than saline controls. In addition, it increased the synaptic markers level and promoted adult hippocampal neurogenesis, eventually improving cognitive functions. These findings suggest the use of CBD and pBDNF has a potential therapeutic combination for AD management if intervened early.},
}

@article {pmid41925793,
year = {2026},
author = {Ramanan, S and Johnson, GVW},
title = {A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimer's and Parkinson's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {41925793},
issn = {1559-1166},
support = {R01AG073121/GF/NIH HHS/United States ; },
mesh = {Humans ; *Parkinson Disease/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics ; *Transcription Factors/metabolism/genetics ; Computational Biology ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Signal Transduction ; *Apoptosis Regulatory Proteins/metabolism/genetics ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.},
}

Humans
*Parkinson Disease/metabolism/genetics
*Alzheimer Disease/metabolism/genetics
*Transcription Factors/metabolism/genetics
Computational Biology
*DNA-Binding Proteins/metabolism/genetics
Animals
*Adaptor Proteins, Signal Transducing/metabolism/genetics
Signal Transduction
*Apoptosis Regulatory Proteins/metabolism/genetics

@article {pmid41925947,
year = {2026},
author = {Patwekar, F and Patwekar, M and Wei, LS and Sharma, R and Varghese, R and Mohammed, A},
title = {Advancing diagnostic biomarkers in Alzheimer's disease: interdisciplinary innovations and technological frontiers.},
journal = {Human cell},
volume = {39},
number = {4},
pages = {},
pmid = {41925947},
issn = {1749-0774},
mesh = {*Alzheimer Disease/diagnosis/metabolism/genetics ; Humans ; *Biomarkers/metabolism ; Biosensing Techniques ; Machine Learning ; tau Proteins ; Nanotechnology ; Precision Medicine ; *Inventions/trends ; Positron-Emission Tomography ; *Interdisciplinary Research ; Magnetic Resonance Imaging ; Amyloid beta-Peptides ; Early Diagnosis ; Artificial Intelligence ; },
abstract = {Developing diagnostic biomarkers for Alzheimer's disease (AD) is at the cutting edge of interdisciplinary research and technical advancement. This comprehensive analysis investigates potential options for improving diagnostic accuracy and early detection of AD. Identifying biomarkers other than Aβ and tau proteins, such as synaptic dysfunction markers and metabolic indicators, is a novel technique. Integrating multi-omics data provides a comprehensive picture of AD pathophysiology, assisting in the discovery of biomarkers and treatment targets. Advances in technology, notably nanotechnology and biosensors, show promise for highly sensitive and specific platforms capable of identifying AD-related biomarkers in physiological fluids. AI and machine learning algorithms are critical in analyzing large datasets, improving pattern identification, and increasing diagnostic accuracy. Predictive models based on various biomarkers and clinical data open the way for personalized medicine methods in the treatment of AD. More advancements in PET and MRI tracers are required for targeted and sensitive imaging of specific AD-related clinical alterations. Wearing gadgets and seeing digital health signs have helped us to find diseases early and track them over time. They even allow monitoring from afar and all the time. This comprehensive review brings together new developments and teamwork across different fields. In this way, it guides to enhance how to identify AD. By mixing these new methods, we aim to change the diagnosis of AD early and accurately. This allows us to focus on treatments and push forward new cures for AD.},
}

*Alzheimer Disease/diagnosis/metabolism/genetics
Humans
*Biomarkers/metabolism
Biosensing Techniques
Machine Learning
tau Proteins
Nanotechnology
Precision Medicine
*Inventions/trends
Positron-Emission Tomography
*Interdisciplinary Research
Magnetic Resonance Imaging
Amyloid beta-Peptides
Early Diagnosis
Artificial Intelligence

@article {pmid41925951,
year = {2026},
author = {Feng, JQ and Yang, LL and Luo, YX and Yao, XQ},
title = {Alzheimer's disease: from molecular pathways to therapies.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {41925951},
issn = {2662-8651},
support = {No.82371427//National Natural Science Foundation of China/ ; No.82401656//National Natural Science Foundation of China/ ; CSTB2023NSCQ-MSX0323//Natural Science Foundation of Chongqing Municipality/ ; 2025MSXM044//Joint project of Chongqing Health Commission and Science and Technology Bureau/ ; CYB240199//Postgraduate Research and Project of Chongqing Province/ ; },
mesh = {*Alzheimer Disease/therapy/metabolism/pathology/etiology ; Humans ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Animals ; Immunotherapy/methods ; Gastrointestinal Microbiome ; Signal Transduction ; },
abstract = {Alzheimer disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide. With accelerating population aging, its incidence continues to rise, imposing a substantial burden on public health systems and society. Despite extensive advances in research, currently available therapies remain largely symptomatic and have limited capacity to halt or reverse disease progression. Recent progress in understanding the molecular and cellular mechanisms underlying AD has driven the development of targeted therapeutic strategies, particularly immunotherapies directed against amyloid-β (Aβ) and tau pathology. However, the pathogenesis of AD is highly complex and multifactorial, underscoring the need for a more integrated understanding of the interactions among diverse pathological processes and the identification of additional therapeutic targets. Here, we provide a systematic synthesis of the core pathological mechanisms of AD and their interconnected molecular pathways, together with a comprehensive overview of current targeted therapeutic strategies. We highlight recent advances in Aβ- and tau-directed immunotherapies and further examine emerging interventions targeting neuroinflammation, metabolic dysregulation, the gut microbiota, lifestyle-related factors, and neurogenesis, evaluating their potential based on evidence from both clinical and preclinical studies. By integrating mechanistic insights with therapeutic developments, this review outlines key opportunities and challenges in the evolving landscape of AD treatment. These perspectives may inform the development of next-generation disease-modifying therapies and contribute to a more comprehensive framework for understanding the pathogenesis and treatment of AD.},
}

*Alzheimer Disease/therapy/metabolism/pathology/etiology
Humans
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Animals
Immunotherapy/methods
Gastrointestinal Microbiome
Signal Transduction

@article {pmid41926104,
year = {2026},
author = {Devanand, DP and Wei, R and Qian, M},
title = {Treatment of Early Symptomatic Alzheimer Disease With Valacyclovir-Reply.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.1105},
pmid = {41926104},
issn = {1538-3598},
}

@article {pmid41926105,
year = {2026},
author = {Kosaka, M and Kami, M},
title = {Treatment of Early Symptomatic Alzheimer Disease With Valacyclovir.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.1102},
pmid = {41926105},
issn = {1538-3598},
}

@article {pmid41903899,
year = {2026},
author = {Green, MC and Braun, DJ and Leibold, CT and Van Eldik, LJ and Bailey, CS},
title = {Specific inhibition of p38α MAPK dampens neuroinflammation during acute alcohol withdrawal in mouse BV2 microglial cell line and rat organotypic hippocampal slice cultures.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {133},
number = {},
pages = {32-37},
doi = {10.1016/j.alcohol.2026.03.007},
pmid = {41903899},
issn = {1873-6823},
abstract = {Neuroinflammation is implicated in anxiety and negative affect in alcohol withdrawal, potentially contributing to relapse. The mitogen-activated protein kinase p38α (p38) is a critical driver of neuroinflammation in such excitatory neural contexts, and its inhibition reduces neuroinflammatory cytokine production in the context of various insults generally corresponding with improved cellular and synaptic health. Although heretofore unexamined, we hypothesized that inhibition of p38 by small-molecule MW150 would reduce neuroinflammation during the acute alcohol withdrawal period. Immortalized mouse BV2 and post-natal day 8 rat organotypic hippocampal slice cultures received 50mM ethanol in media for 24 h followed by 24 h withdrawal, or for 48 h continuously, with administration of 5 μM MW150 or saline for the final 24 h of treatment. Control tissue never received ethanol. Levels of cytokines in the culture media were analyzed after 48 h by MesoScale ELISA assays. Elevated CXCL1 and TNFα levels were ameliorated by MW150 during ethanol withdrawal in culture media from BV2 and female OHSC, respectively. Further, MW150 reduced TNFα, but increased IL6, across all conditions in the BV2 microglia. Preliminary evidence suggests that p38 inhibition during early ethanol withdrawal in vitro reduces select inflammatory cytokines. Given that MW150 is presently in clinical trials for neuroinflammation in Alzheimer's disease, its preclinical validation for use in alcohol withdrawal in vivo is crucial to determine its feasibility to modulate neuroinflammation and problem drinking in humans.},
}

@article {pmid41916153,
year = {2026},
author = {Wang, C and Xu, X and Zhu, H and Wu, D and Liang, J and Wang, X and Song, R and Shen, L and Hu, Y and Wang, D and Zhu, H and Cheng, X and Qi, Y},
title = {Acori tatarinowii Rhizoma-Curcumae Radix herbal pair ameliorates cognitive impairment and suppresses neuro-inflammation via Ca[2+]/CaMKKβ/AMPK/mTOR pathway in Alzheimer's disease.},
journal = {Journal of ethnopharmacology},
volume = {365},
number = {},
pages = {121606},
doi = {10.1016/j.jep.2026.121606},
pmid = {41916153},
issn = {1872-7573},
abstract = {Effective activation of neuronal autophagy and clearance of amyloid-beta (Aβ) represents a promising therapeutic strategy in the treatment of Alzheimer's disease (AD). The Acori Tatarinowii Rhizoma-Curcumae Radix Herbal pair (ACHP), derived from the traditional Changpu Yujin Decoction, has a long history in Traditional Chinese Medicine for addressing conditions related to cognitive function. However, the precise mechanisms underlying its role in autophagic dysfunction-related dementia remain unclear.

AIM OF THE STUDY: This study aims to investigate the neuroprotective effects of ACHP and the underlying mechanisms in AD.

MATERIALS AND METHODS: Analysis of prototype constituents in drug-containing serum was performed using UHPLC-Triple-TOF/MS. The neuroprotective effects of ACHP were evaluated in APP/PS1 mice using behavioral tests, including the Y-maze and Morris water maze. Transcriptomic analysis was conducted to identify potential neuroprotective pathways activated by ACHP. Neuronal damage and structural recovery were assessed through HE and Nissl staining. In addition, the anti-inflammatory and autophagy-regulating effects of ACHP were further investigated in N2a/APP cells. The molecular mechanisms were further elucidated using Western blot, immunofluorescence, ELISA, and qRT-PCR in both in vivo and in vitro models.

RESULTS: Twenty-five compounds in ACHP-treated mouse serum were identified. ACHP improved spatial learning and memory performance, increased intracellular Ca[2+] levels and downregulated the expressions of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, while significantly promoting autophagy. ACHP increased CaMKKβ protein expression and activated the AMPK signaling pathway (elevated p-AMPK/AMPK ratio), as well as those of autophagy-related proteins, while improving neuronal morphology.

CONCLUSION: These findings indicate that ACHP alleviates neuro-inflammatory damage and cognitive impairment potentially through modulation of the Ca[2+]/CaMKKβ-AMPK-mTOR signaling pathway involved in autophagy.},
}

@article {pmid41916976,
year = {2026},
author = {Parent, O and Alasmar, Z and Osborne, S and Bussy, A and Costantino, M and Fouquet, JP and Quesada, D and Pastor-Bernier, A and Fajardo-Valdez, A and Pichet-Binette, A and McQuarrie, A and Maranzano, J and Devenyi, GA and Steele, CJ and Villeneuve, S and , and , and Dadar, M and Chakravarty, MM},
title = {Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-70832-2},
pmid = {41916976},
issn = {2041-1723},
abstract = {White matter hyperintensities (WMHs) are neuroimaging markers widely interpreted as caused by cerebral small vessel disease, yet emerging evidence suggests that a subset may have a neurodegenerative etiology. Current imaging methods have lacked the specificity to disentangle biological processes underlying WMHs in vivo. Here, we used voxel-level normative modeling and seven microstructural MRI markers with complementary biophysical sensitivities to generate single-subject high-resolution WMH pathophysiology maps in a large cohort (n = 32,526). We calculated data-driven spatial patterns of similar WMHs, revealing distinct periventricular, posterior, and anterior clusters. We identified a reproducible WMH signature linked to dementia and Alzheimer's disease, characterized by a posterior predominance and a pathophysiological pattern indicative of selective fiber degeneration. Posterior WMHs connected cortical regions vulnerable to tau pathology. Our framework helps parsing vascular and neurodegenerative contributions of WMHs in vivo, which could alter the course of treatment strategies and provide nuanced interpretations of research findings.},
}

@article {pmid41918193,
year = {2026},
author = {Behrouzfar, H and Mortazavi, P and Hassani, S and Aghebat Bekheir, S},
title = {Exploring the Effects of Empagliflozin Administration and Physical Training on Cognitive Functions in an Amyloid Beta-Induced Alzheimer's Rat Model.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673434008260121111535},
pmid = {41918193},
issn = {1875-533X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a widely prevalent and neurodegenerative disorder that leads to dementia and mortality worldwide. Previous investigations have reported the beneficial effects of physical exercise on brain function, linked to anti-inflammatory effects in the brain vasculature and elevated BDNF production. Empagliflozin, a conventional antidiabetic agent, has shown potential neuroprotective properties in the central nervous system, evidenced by its ability to elevate BDNF and mitigate oxidative stress and inflammation.

MATERIALS AND METHODS: In the present investigation, AD was induced in control, exercise, empagliflozin (10 mg/kg BW, PO), and combined intervention groups using intrahippocampal injections of an amyloid-beta (Aβ) prepared solution via stereotaxic surgery. The therapeutic effects of each treatment, exercise alone, empagliflozin alone, and exercise plus empagliflozin, were studied. After 28 days, spatial memory tests were used to assess memory and learning. Furthermore, histopathological (H&E and Congo red) and immunohistochemical (GFAP) analyses were performed, and the ADP/ATP ratio in isolated brain mitochondria was measured by HPLC.

RESULTS: Our results showed that the combined program of physical training and empagliflozin treatment in the Aβ-induced AD model drastically improved cognitive functions and neurological parameters, including target-finding time, traveled distance, time spent in the target quadrant, and ADP/ATP ratios in brain mitochondria. Additionally, it diminished necrotic cell death and reduced Aβ plaques but did not notably affect astrocyte activity.

DISCUSSION: Exercise and empagliflozin, by affecting mitochondrial energy balance and reducing amyloid deposition, play key roles in mitigating AD pathophysiology.

CONCLUSION: The combined effects of the treatments used in this experimental method yielded significant improvements in cognitive functions. These findings provide a basis for further clinical studies for the exploration of the synergistic impact of the aforementioned therapeutic methods.},
}

@article {pmid41918201,
year = {2026},
author = {Sharma, S and Sharma, D and Sharma, A},
title = {Targeting Vascular Dementia: Pharmacological Mechanisms and Therapeutic Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273440657260226125023},
pmid = {41918201},
issn = {1996-3181},
abstract = {INTRODUCTION: Vascular dementia is a leading cause of cognitive deterioration worldwide, caused by a complex interplay of pathological mechanisms such as disrupted cerebral blood flow, oxidative stress, neuroinflammation, and endothelial dysfunction. A clear knowledge of these mechanisms is crucial for developing efficient treatment strategies. Various drug classes, including statins, cholinesterase inhibitors, anti-diabetic drugs, leukotriene antagonists, and nootropics, offer promising approaches by addressing different facets of this multifaceted condition. This review's objective is to offer a comprehensive analysis of the functional mechanisms of diverse pharmacological agents in curing vascular dementia. It further aims to identify their therapeutic potential, limitations, and areas requiring future research.

METHODOLOGY: A review of the literature was conducted to examine evidence from preclinical and clinical research. Pharmacological chemicals were evaluated for their effects on key pathological pathways, including oxidative stress, inflammation, endothelial dysfunction, and impaired neurotransmission.

RESULT AND DISCUSSION: Each class of drugs reviewed demonstrates distinct benefits in addressing specific aspects of vascular dementia. Statins primarily mitigate vascular risk factors and neuroinflammation, while cholinesterase inhibitors enhance neurotransmitter availability to support cognitive function. Anti-diabetic drugs exhibit neuroprotective properties through metabolic regulation and antiinflammatory effects, and leukotriene antagonists show potential in reducing oxidative damage and inflammation. Nootropics, on the other hand, focus on enhancing synaptic plasticity and memory. Despite these promising mechanisms, limitations such as inconsistent clinical outcomes, potential adverse effects, and the absence of individualized treatment protocols remain significant challenges.

CONCLUSION: This review emphasizes the need for developing integrated therapeutic strategies that target the diverse pathological mechanisms underlying vascular dementia. While current pharmacological approaches show considerable potential, there is a desperate need for long-term clinical validation and the development of personalized medicine frameworks. Advances in diagnostic tools, biomarkers, and imaging technologies will be crucial for early diagnosis and effective disease monitoring, paving the way for improved patient results and a more profound understanding of vascular dementia's complexity.},
}

@article {pmid41918343,
year = {2026},
author = {Lopes, SP and Emídio, JJ and Duarte, ABS and Orhan, IE and Deniz, FSS and Salmas, RE and de Sousa, DP},
title = {Synthesis of p-Coumarates With Potential Anti-Alzheimer's Action: Enzyme Inhibition and In Silico Studies.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {4},
pages = {e03857},
doi = {10.1002/cbdv.202503857},
pmid = {41918343},
issn = {1612-1880},
support = {306661/2016-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology ; *Butyrylcholinesterase/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism ; Humans ; *Coumaric Acids/chemistry/chemical synthesis/pharmacology ; Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Structure ; Dose-Response Relationship, Drug ; Propionates/chemistry/chemical synthesis/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a fatal neurodegenerative disorder that affects cognition, memory, and behavior. Such a disease is considered the most common cause of dementia and affects a large portion of the elderly population worldwide. Currently, cholinesterase inhibitors are used to reduce the symptoms and rate of progression of this disease. Thus, the present study evaluated the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of a set of 22 p-coumarate derivatives using the spectrophotometric method. The inhibitory activity of the compounds against AChE and BChE was measured using the adapted Ellman spectrophotometric method; the reported inhibition percentages were determined at a final concentration of 100 µM. The structures of the synthesized compounds were characterized by FTIR, [1]H-NMR, [13]C-NMR, and HRMS spectroscopy. Among the compounds tested, three showed moderate inhibitory activity against AChE and good activity against BChE: (E)-4-chlorobenzyl 3-(4-hydroxyphenyl)acrylate (14) (56.36%; 75.17%), (E)-4-bromobenzyl 3-(4-hydroxyphenyl)acrylate (15) (61.11%; 76.09%), and (E)-naphthalene 3-(4-hydroxyphenyl)acrylate (18) (59.18%; 65.39%), respectively. Compound 15 had an IC50 of 22.22 ±1.50 mM against BChE, which is notably better than galantamine's BChE inhibition. The in silico analysis suggested that compounds 14, 15, and 18 interact with AChE and BChE. Thus, p-coumaric acid derivatives represent promising prototypes for the search for new drug candidates for the treatment of AD.},
}

*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology
*Butyrylcholinesterase/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Acetylcholinesterase/metabolism
Humans
*Coumaric Acids/chemistry/chemical synthesis/pharmacology
Structure-Activity Relationship
Molecular Docking Simulation
Molecular Structure
Dose-Response Relationship, Drug
Propionates/chemistry/chemical synthesis/pharmacology

@article {pmid41919006,
year = {2026},
author = {Buchanan, TJ and Ewen, C and Rebollo Mesa, I and Germani, M and Watanabe, S and Jose, J and Famodimu, O and Colson, AO and De Bruyn, S},
title = {Two phase 1 randomised studies investigating the safety and pharmacokinetics of bepranemab in healthy participants of different ethnicities.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001395},
pmid = {41919006},
issn = {2632-6140},
abstract = {BACKGROUND: Bepranemab is a recombinant, humanised, full-length IgG4 monoclonal antibody targeting a mid-region tau epitope. Two phase 1 studies assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of bepranemab.

METHODS: UP0047 (NCT03464227) and UP0065 (NCT03605082) were phase 1, double-blind, placebo-controlled, single-dose, dose-escalation studies of intravenous bepranemab in healthy participants (Caucasian and Japanese descent, respectively). Primary endpoint: safety and tolerability of single ascending doses of bepranemab. PK were assessed in serum and cerebrospinal fluid (CSF); PD (levels of free tau) in CSF. A physiologically based PK/PD (PBPK/PD) model was developed to predict dose response.

RESULTS: UP0047: Caucasian participants (N=52) were randomised to bepranemab 0.3 mg/kg, n=2; 1 mg/kg, n=6; 3 mg/kg, n=6; 10 mg/kg, n=6; 30 mg/kg, n=6; 60 mg/kg, n=6; 120 mg/kg, n=6; placebo, n=14). UP0065: participants of Japanese descent (N=24) were randomised to bepranemab 30 mg/kg, n=6; 60 mg/kg, n=6; 120 mg/kg, n=6; placebo, n=6). No serious treatment-emergent adverse events (TEAEs) or discontinuations due to TEAEs were observed. One participant (bepranemab 60 mg/kg) experienced treatment-related TEAEs of headache (moderate intensity), nausea and vomiting (mild intensity). There was no effect of ethnicity on PK parameters. A dose-response effect of bepranemab on free tau levels was observed. Data applied to a PBPK/PD model supported a dose of 90 mg/kg of bepranemab every 4 weeks to achieve a reduction in mean change from baseline in free tau levels of up to 90%.

CONCLUSIONS: Safety, PK and PD data support continued investigation of bepranemab for the treatment of tauopathies.},
}

@article {pmid41919455,
year = {2026},
author = {Fujioka, S and Nagaishi, Y and Imamura, T and Minagawa, H and Uwatoko, K and Yukitake, M and Kira, JI and Tsuboi, Y},
title = {Amyloid PET-guided anti-amyloid therapy in corticobasal syndrome associated with clinical improvement.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.110307},
pmid = {41919455},
issn = {0028-3843},
abstract = {AIM OF THE STUDY: Corticobasal syndrome (CBS), a heterogeneous clinical phenotype, can be associated with various underlying pathologies. Although neuropathological studies show that CBS cases can be attributed to Alzheimer's disease (AD), in vivo confirmation and subsequent disease-modifying therapy remain rarely reported. In our patients presenting with clinical features consistent with CBS, amyloid positron emission tomography (PET) facilitated the diagnosis of underlying AD pathology and enabled the initiation of anti-amyloid therapy.

MATERIAL AND METHODS: We retrospectively reviewed patients with probable corticobasal degeneration from two tertiary centers who underwent amyloid PET confirming AD, systematically collecting clinical, imaging, and treatment data.

RESULTS: Two patients were identified who fulfilled the inclusion criteria. In both patients, episodic memory was impaired, which was inconsistent with a typical corticobasal syndrome phenotype. Amyloid PET demonstrated widespread cortical and subcortical amyloid deposition, confirming underlying AD pathology. Based on these findings, anti-amyloid therapy was initiated, and clinical improvement was observed in both patients, although causality cannot be inferred from this uncontrolled retrospective observation.

CONCLUSIONS: Corticobasal syndrome may be an atypical clinical presentation of AD pathology. Importantly, molecular imaging allowed an in vivo diagnosis of AD and facilitated the timely initiation of anti-amyloid therapy.

CLINICAL IMPLICATIONS: This novel report documents the clinical implementation of amyloid PET guided anti-amyloid therapy in patients presenting with CBS.},
}

@article {pmid41920507,
year = {2026},
author = {Lan, H and Zhang, J and Zhao, Z and Liu, X and Rao, C},
title = {Focal-DenseNet: A Risk Assessment Framework for Alzheimer's Disease in Heterogeneous MRI Data.},
journal = {Interdisciplinary sciences, computational life sciences},
volume = {},
number = {},
pages = {},
pmid = {41920507},
issn = {1867-1462},
support = {S202410497177//National Undergraduate Innovation and Entrepreneurship Training Program/ ; 25YJAZH138//Planning Fund Project of the Ministry of Education's Humanities and Social Sciences Research/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease of the nervous system, which has become an important public health issue attracting global attention. However, its exact causes and pathogenesis have not been fully elucidated, and the existing treatment methods and intervention measures have limited efficacy. Therefore, how to establish a scientific and efficient risk assessment mechanism has become the key to the prevention and treatment of AD. Aiming at this problem, this paper optimizes the convolutional neural network structure of DenseNet and proposes a Focal-DenseNet model that integrates the focal loss function for the risk assessment and diagnostic prediction of AD. First of all, preprocess the collected data to ensure the data quality for subsequent analysis. Secondly, establish the Focal-DenseNet model. Finally, use the model for training and testing. The test results show that the test set accuracy of the model reaches 98.98%, indicating that the model performs well. In addition, this paper also compares the proposed model with the DenseNet model without using the focal loss function and other common deep learning models (such as VGG16, ResNet, etc.). The results show that the model in this paper exhibits superiority in multiple performance indicators. In particular, it has achieved high scores in key indicators such as accuracy, AUC (the area under the receiver operating characteristic curve), precision, and recall. This study provides an efficient technical support for the early risk assessment of AD, and holds significant clinical application value and academic reference significance for improving the prevention and treatment level of AD and reducing the global public health burden.},
}

@article {pmid41920573,
year = {2026},
author = {Pathak, US and Mehralizade, A and Goldberg, TE and Zoghbi, AW},
title = {Dementia in Severe Schizophrenia.},
journal = {JAMA psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamapsychiatry.2026.0171},
pmid = {41920573},
issn = {2168-6238},
abstract = {IMPORTANCE: Dementia develops in individuals with schizophrenia 4- to 20-fold more frequently than in the general population, but its etiology remains unexplained.

OBJECTIVE: To characterize the cognitive, clinical, and genetic features of dementia in individuals with severe, extremely treatment-resistant schizophrenia (SETRS).

This retrospective cohort study among individuals with SETRS was conducted at New York state hospitals from December 2017 through July 2019. All participants met DSM-5 schizophrenia criteria and were continuously hospitalized for 5 years or more. Exclusion criteria included forensic hospitalization, known medical causes of psychosis, or recent substance abuse. Cognitive, clinical, and genetic data were compared to data from individuals from the National Alzheimer Coordinating Center dataset, including those with Alzheimer disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), or vascular dementia (VD), along with healthy controls. Data were analyzed from January 2025 through December 2025.

MAIN OUTCOMES AND MEASURES: Multiple regression was used to analyze the effects of demographic, clinical, and genetic factors on the Montreal Cognitive Assessment (MoCA).

RESULTS: In this study's cohort of 155 individuals with SETRS (mean [SD] age, 59.3 [10.3] years; 56 female participants [36.1%]), 153 of 155 (98.7%) scored below the cutoff of 26 for mild cognitive impairment, and 73 of 155 (47.1%) scored below the cutoff of 10 for severe dementia (mean [SD] MoCA score, 9.8 [6.4]). At the item level, the MoCA profile of SETRS differed from those of AD and FTD but paralleled that of community-dwelling individuals with schizophrenia (Pearson r = 0.86; P < .001). No participants carried pathogenic variants in mendelian dementia genes; APOE4 allele frequency was significantly lower in SETRS (14.4%) than in AD (33.6%; odds ratio [OR], 0.33; 95% CI, 0.20-0.53; P < .001) or LBD (24.7%; OR, 0.51; 95% CI, 0.29-0.89; P = .01). Cognitive impairment was not attributable to premorbid intellectual disability, poor effort, medications, cardiometabolic risk factors, or institutionalization.

CONCLUSIONS AND RELEVANCE: In this cohort study of 155 individuals with SETRS, none of the commonly proposed explanations for schizophrenia dementia (eg, comorbid Alzheimer disease or cardiovascular risk factors) proved viable. The pattern of cognitive impairments differed from those of Alzheimer disease, frontotemporal dementia, and Lewy body dementia, but recapitulated and intensified that of community-dwelling schizophrenia.},
}

@article {pmid41921123,
year = {2026},
author = {Bukhbinder, AS and Ling, Y and Jhin, L and He, E and Harris, K and Rodriguez, M and Thomas, J and Cruz, G and Phelps, K and Kim, Y and Chen, L and Jiang, X and Schulz, PE},
title = {Risk of Alzheimer Dementia After High-Dose vs Standard-Dose Influenza Vaccination.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214782},
doi = {10.1212/WNL.0000000000214782},
pmid = {41921123},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; *Influenza Vaccines/administration & dosage ; Aged ; Female ; Male ; Retrospective Studies ; Aged, 80 and over ; *Vaccination ; Influenza, Human/prevention & control ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunizations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesized that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.

METHODS: This retrospective cohort study analyzed data spanning 2014-2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic or pharmacotherapeutic indicators of cognitive impairment. Vaccinations were identified by name and Current Procedural Terminology codes. Participants were followed for up to 3 years postvaccination. Incident AD was defined using International Classification of Diseases codes and AD medication dispenses (anticholinesterase inhibitors, memantine). We emulated a target trial using sequential nested trials to align eligibility, treatment assignment, and time-zero with vaccination dates, preventing immortal time bias. Inverse probability weighting adjusted for measured confounding, emulated randomization, and mitigated selection bias. Effects were estimated as risk difference, number needed to treat (NNT), risk ratio; 95% CIs were obtained via bootstrapping. Secondary analyses examined potential effect modifiers such as sex.

RESULTS: The H-IIV group included 120,775 unique participants (185,183 person-trials; mean age 74.4 years, SD 5.5; 57.3% female), and the S-IIV group included 44,022 participants (53,918 person-trials; mean age 73.0, SD 6.1; 56.4% female). H-IIV was associated with significantly lower AD risk during months 1-25 postvaccination (minimum NNT = 185.2 at 25 months). After sex stratification, risk reduction persisted longer among women (months 1-13, minimum NNT = 416.7) than men (months 17-24, significant only in intention-to-treat analysis, minimum NNT = 232.6).

DISCUSSION: High-dose influenza vaccination is associated with reduced AD risk compared with standard-dose vaccination in adults ≥65 years, with a stronger effect among women. Significant study limitations included duration of follow-up (≤3 years) and lack of sociodemographic, lifestyle, biomarker, and mortality data. Further research is needed to clarify whether the observed difference reflects protection against influenza infection or non-infection-related mechanisms.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that treatment with H-IIV vs S-IIV was associated with decreased incident dementia in individuals ≥65 years of age captured in this US health care claims database.},
}

Humans
*Alzheimer Disease/epidemiology/prevention & control
*Influenza Vaccines/administration & dosage
Aged
Female
Male
Retrospective Studies
Aged, 80 and over
*Vaccination
Influenza, Human/prevention & control
Cohort Studies

@article {pmid41921847,
year = {2026},
author = {Dong, YR and Wang, JR and Yang, Y and Chen, QZ and Jiang, YQ and Yang, X and Zhou, MC and Cao, SP and Zeng, SX and Zang, CX and Li, FF and Bao, XQ and Zhang, D},
title = {Unveiling the UFMylation Pathway: Implications in neurodegenerative diseases.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169772},
doi = {10.1016/j.jmb.2026.169772},
pmid = {41921847},
issn = {1089-8638},
abstract = {UFMylation is a recently characterized post-translational modification (PTM) system that conjugates Ubiquitin-Fold Modifier 1 (UFM1) to target proteins via a dedicated enzymatic cascade. This modification system regulates critical cellular processes by controlling protein subcellular localization, modulating protein-protein interactions, and coordinating with ubiquitination to regulate protein stability. Emerging evidence highlights UFMylation as a critical modifier of pathological proteins, including tau and α-synuclein, while impaired UFMylation pathways are observed in the brains of individuals with neurodegenerative disorders. In this review, we summarize the current role and mechanism of UFMylation in the pathogenesis of neurodegenerative diseases, offering the first comprehensive framework for targeting UFMylation in the treatment of neurodegenerative diseases.},
}

@article {pmid41922490,
year = {2026},
author = {Holmes, SE and Smith, GS},
title = {Trajectories of late-life depression: insights from molecular imaging.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41922490},
issn = {1740-634X},
support = {R01NS125482//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01AG059390//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Late-life depression is associated with greater disability, suicide risk and mortality than depression in mid-life, and is a risk factor/prodrome for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Many depressed, older adults fail to respond to first line antidepressant treatment, experience relapse and exhibit persistent symptoms, including anxiety, apathy and cognitive impairment, that may reflect underlying neurodegenerative processes. Advances in molecular imaging, particularly positron emission tomography (PET) allow direct in-vivo investigation of neurobiological mechanisms underlying late-life depression symptom trajectories, treatment response and the potential links to neurodegenerative disease. Molecular imaging studies in late-life depression have revealed alterations across neurotransmitter systems and Alzheimer's disease pathology (beta-amyloid and Tau) and a potential role of neuroinflammation. In late-life depression, variability in symptom presentation and treatment response arises from interacting neurotransmitter, inflammatory, and neurodegenerative processes and potentially other molecular mechanisms that impair synaptic plasticity. Future directions include the application of next-generation PET tracers targeting glutamatergic signaling, mitochondrial function, histone deacetylase activity, and cell-type-specific inflammation, along with multi-modal image analysis methods to test mechanistic models . Molecular imaging holds significant promise for guiding the development of targeted, mechanism-based treatments that reduce the burden of late-life depression and its associated vulnerability to neurodegenerative disease.},
}

@article {pmid41913059,
year = {2026},
author = {Macheda, T and Hawkins, MR and Johnson, CE and Lapid, MG and Whitlock, HR and Shepard, SM and Cox, MF and Roberts, KN and Bytyqi, L and Hash, HM and El-Ezz, OAA and El-Ezz, MA and Kohler, K and Sunderam, S and O'Hara, BF and Van Eldik, LJ and Murphy, MP and Duncan, MJ and Bachstetter, AD},
title = {Glial cytokine modulation improves sleep and circadian disruption in female SAA knock-in mice of Alzheimer's-related pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71314},
doi = {10.1002/alz.71314},
pmid = {41913059},
issn = {1552-5279},
support = {AG068215/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/pathology/genetics ; Mice ; Female ; *Cytokines/metabolism ; Mice, Transgenic ; Male ; *Circadian Rhythm/drug effects ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; *Neuroglia/metabolism/drug effects ; *Sleep/drug effects ; Gene Knock-In Techniques ; Mice, Inbred C57BL ; *Sleep Wake Disorders/drug therapy ; },
abstract = {INTRODUCTION: Sleep and circadian disturbances are early Alzheimer's disease (AD) features, yet mechanisms linking amyloid pathology, neuroinflammation, and sex differences remain unclear.

METHODS: We longitudinally assessed sleep, circadian rhythms, and cognition in female and male hAPP[SAA] knock-in and control mice from 2 to 19 months using piezoelectric monitoring. Aged mice (15 months) received MW151, a glial cytokine inhibitor (2.5 mg/kg, every other day, 6 weeks).

RESULTS: Only females exhibited midlife reductions in light-phase sleep, increased rhythm fragmentation, and reduced rhythm stability, coinciding with selective reversal learning deficits, effects independent of amyloid or cytokine burden. MW151 increased light-phase sleep and reduced cortical TNF-α without altering amyloid beta (Aβ) accumulation.

DISCUSSION: HAPP[SAA] mice recapitulate female-predominant non-cognitive AD features, including sleep fragmentation and circadian instability preceding memory deficits. Sleep improved within weeks of MW151 treatment without Aβ reductions, implicating neuroinflammatory signaling as a rapid, modifiable driver of AD-related sleep disruption.},
}

Animals
*Alzheimer Disease/pathology/genetics
Mice
Female
*Cytokines/metabolism
Mice, Transgenic
Male
*Circadian Rhythm/drug effects
Disease Models, Animal
Amyloid beta-Peptides/metabolism
*Neuroglia/metabolism/drug effects
*Sleep/drug effects
Gene Knock-In Techniques
Mice, Inbred C57BL
*Sleep Wake Disorders/drug therapy

@article {pmid41914305,
year = {2026},
author = {Xie, JL and Hu, XH and Wu, CL and Jin, Q and Pan, JP},
title = {DHA Ameliorates Alzheimer's Disease by Attenuating Microglial Pyroptosis via Regulation of the HOXA9-NLRP3 Pathway.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {3},
pages = {46572},
doi = {10.31083/FBL46572},
pmid = {41914305},
issn = {2768-6698},
support = {20232BAB206049//Jiangxi Provincial Natural Science Foundation General Project/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Docosahexaenoic Acids/pharmacology/therapeutic use ; Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Pyroptosis/drug effects ; Mice ; Humans ; *Homeodomain Proteins/metabolism/genetics ; *Microglia/drug effects/metabolism ; Amyloid beta-Peptides ; Signal Transduction/drug effects ; Male ; Mice, Transgenic ; Disease Models, Animal ; Peptide Fragments ; Neuroprotective Agents/pharmacology ; Mice, Inbred C57BL ; Cell Line ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) involves a progressive deterioration of cognitive abilities, memory loss, and persistent brain inflammation. Emerging evidence indicates that pyroptosis mediated by the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, contributes significantly to AD development. Docosahexaenoic acid (DHA) has demonstrated neuroprotective properties; however, the precise mechanisms by which it modulates pyroptosis in AD have yet to remained incompletely elucidated.

OBJECTIVE: To explore the role of DHA in modulating microglial pyroptosis via the HOXA9-NLRP3 pathway in an AD model.

METHODS: Effects of DHA on Aβ25-35-induced pyroptosis were assessed in human microglial clone 3 (HMC3) human microglial cells using CCK-8, western blotting, immunofluorescence, and Enzyme-linked Immunosorbent Assay (ELISA) assays. The role of homeobox A9 (HOXA9) in pyroptosis regulation was evaluated through overexpression and knockdown experiments. Dual-luciferase reporter assays together with chromatin immunoprecipitation (ChIP) were used to verify the interaction of HOXA9 to NLRP3 promoter. Amyloid precursor protein / Presenilin-1 double-transgenic (APP/PS1) transgenic AD mice underwent DHA treatment in vivo, and cognitive performance was assessed using the Morris water maze paradigm. Expression of HOXA9, NLRP3, and pyroptosis-related proteins were analyzed by Quantitative Real-time Reverse Transcription PCR (qRT-PCR), Western blotting, and immunofluorescence.

RESULTS: DHA treatment significantly reduced Aβ25-35-induced microglial pyroptosis, as indicated by decreased levels of p30-Gasdermin D (GSDMD), cleaved-caspase-1, IL-1β, and IL-18. HOXA9 overexpression reversed the protective effects of DHA, whereas NLRP3 inhibition by MCC950 enhanced DHA inhibition of pyroptosis. Dual-luciferase and ChIP assays confirmed that HOXA9 directly regulates NLRP3 transcription. In APP/PS1 mice, DHA administration enhanced cognitive performance while simultaneously decreasing the expression of pyroptosis-related markers and inflammatory mediators in brain. Inhibition of NLRP3 signaling by MCC950 further strengthened the neuroprotective actions of DHA.

CONCLUSION: DHA ameliorates AD-related cognitive decline and reduces microglial pyroptosis through suppressing the HOXA9-NLRP3 axis. These results offer novel insights into the molecular basis of DHA-mediated neuroprotection and highlight potential therapeutic targets for AD.},
}

*Alzheimer Disease/drug therapy/metabolism
*Docosahexaenoic Acids/pharmacology/therapeutic use
Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
*Pyroptosis/drug effects
Mice
Humans
*Homeodomain Proteins/metabolism/genetics
*Microglia/drug effects/metabolism
Amyloid beta-Peptides
Signal Transduction/drug effects
Male
Mice, Transgenic
Disease Models, Animal
Peptide Fragments
Neuroprotective Agents/pharmacology
Mice, Inbred C57BL
Cell Line

@article {pmid41914924,
year = {2026},
author = {Stagge, F and Saylor, AK and Dallas, ON and Johnson, AL and Palmer, KM and Fromm, D and Lanzi, AM},
title = {Increasing Educator Resources for Mild Cognitive Impairment and Dementia Using a Knowledge-to-Action Framework: The Development of DementiaBank Grand Rounds.},
journal = {American journal of speech-language pathology},
volume = {},
number = {},
pages = {1-21},
doi = {10.1044/2026_AJSLP-25-00396},
pmid = {41914924},
issn = {1558-9110},
abstract = {PURPOSE: An educational gap exists in content knowledge and clinical education for speech-language pathologists concerning the treatment and assessment of cognitive-communication disorders from mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). This gap may result in less effective speech-language pathology services for this population. The overarching goal of this project was to enhance graduate speech-language pathology education about MCI and dementia due to AD to improve the quality of future service providers.

METHOD: To achieve this goal, this project had two objectives: first, to conduct a survey to understand speech-language pathology graduate school education practices in clinical and classroom settings regarding cognitive-communication disorders from MCI or dementia due to AD and, second, to conduct focus groups to guide the development of an online educational resource, informed by speech-language pathology graduate school educators. A knowledge-to-action (KTA) conceptual framework provided guidance to translate findings from the survey and focus groups into a highly implementable educational resource.

RESULTS: Educators of graduate speech-language pathology students reported a crucial need for additional accessible resources to assist them in teaching or supervising cognitive-communication disorders from MCI or dementia due to AD. The existing TalkBank educational resource, Grand Rounds, was explored through educator focus groups, and feedback directly informed the creation of a new educational resource tailored for this population.

CONCLUSIONS: Overall, an educational resource, DementiaBank Grand Rounds, was successfully developed for cognitive-communication disorders associated with MCI and dementia due to AD, utilizing the KTA framework. DementiaBank Grand Rounds may serve as a resource to support learners and educators and address the current gap in content knowledge and clinical education.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.31839664.},
}

@article {pmid41915579,
year = {2026},
author = {Ashchi, A and Lachapelle, AA and Nassirou, S and Huston, J},
title = {Leqembi (Lecanemab) in Early Alzheimer's Disease: A Review of Clinical Trial Evidence and Therapeutic Implications.},
journal = {Reviews on recent clinical trials},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115748871418305260224075827},
pmid = {41915579},
issn = {1876-1038},
abstract = {Lecanemab is an IgG1 monoclonal antibody that has emerged as the first FDAapproved drug to slow the progression of Alzheimer's disease by targeting amyloid plaques, with the potential to serve as a disease-modifying therapy. Ongoing clinical studies are evaluating the efficacy and safety of the medication; however, much of the current literature remains mixed regarding the clinical effectiveness of lecanemab. The results from the Clarity AD study, the largest clinical study regarding the effectiveness of lecanemab to date, revealed a statistically significant 27% reduction in the progression of cognitive decline and favorable secondary endpoints in patients with mild cognitive impairment or mild dementia, particularly in male patients as well as heterozygous APOE4 carriers. However, approximately 21% of participants who received lecanemab treatment developed amyloid-related imaging abnormalities, with a higher incidence in homozygous APOE4 carriers. These findings highlight the need to thoroughly screen patients to confirm amyloid pathology with an amyloid PET scan or CSF biomarkers, and to determine APOE4 status before treatment. Additional barriers to care include the financial cost of the medication as well as the need to administer the drug intravenously at a healthcare facility to ensure proper management. Additional studies must continue to explore the clinical impact and safety of the medication and increase its accessibility. Future research may also include analyzing the utilization of the drug in combination therapies to optimize patient outcomes. This paper aims to provide a comprehensive review of current data on lecanemab, its clinical implications, and potential future directions for the use of lecanemab.},
}

@article {pmid41916100,
year = {2026},
author = {Gong, H and Liu, J and Wang, Y and Lin, X and Wu, G and Ou, Y and Zhou, M and Yang, L and Peng, J and Ye, X and Wang, Y and Xu, F and Zhou, H and Feng, Z},
title = {Semaglutide treatment reverses HFD induced hippocampal microglia activation and improves cognitive dysfunction.},
journal = {Tissue & cell},
volume = {101},
number = {},
pages = {103495},
doi = {10.1016/j.tice.2026.103495},
pmid = {41916100},
issn = {1532-3072},
abstract = {Long-term high-fat diets (HFD) induce obesity, neuroinflammation, and cognitive decline, increasing Alzheimer's disease (AD) risk. This study explores whether Semaglutide, a GLP-1 receptor agonist, mitigates these effects by modulating microglia via IGFBPL-1 and the PI3K/AKT pathway. In HFD-fed C57/BL6 mice, Semaglutide improved cognitive function, reduced hippocampal microglia activation, and decreased AD-like pathology (phospho-Tau, Aβ). IGFBPL-1, a neuroprotective factor downregulated by HFD and restored by Semaglutide. Direct IGFBPL-1 supplementation replicated Semaglutide's benefits, while PI3K/AKT inhibition blocked them. These findings reveal IGFBPL-1 as a key mediator of Semaglutide's neuroprotection, offering novel insights into combating obesity-linked neurodegeneration.},
}

@article {pmid41905824,
year = {2026},
author = {Fremont, R and Karim, A and Estevez, TP and McDonough, C and LaBarbiera, A and Feder, A and Naasan, G and Delgado, A and Charney, DS and Murrough, JW},
title = {KET-MCI: A Pilot Safety and Tolerability Study of Single Infusion Intravenous Ketamine for Older Adults with Depression and Mild Cognitive Impairment.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.02.005},
pmid = {41905824},
issn = {1545-7214},
abstract = {OBJECTIVE: This open-label clinical trial primarily examined the safety and tolerability of ketamine treatment in patients with mild cognitive impairment and Major Depressive Disorder (MCI-D). Preliminary efficacy was also explored.

METHODS: The trial was conducted between November 2023 and March 2025. Patients with MCI-D and moderate to severe symptom levels of depression received a single intravenous ketamine infusion (0.5 mg/kg). Safety and tolerability were evaluated. Antidepressant efficacy was also explored by evaluating change in the Montgomery-Asberg Depression Rating Scale (MADRS) scores from baseline to 24 hours after the infusion.

RESULTS: Thirteen eligible patients received treatment and completed study procedures. No serious adverse events were reported and all participants tolerated study procedures. The treatment was associated with large-magnitude improvement in depression symptom severity from baseline (mean MADRS = 27.4[SD = 6.4]) to 24 hours after the infusion (mean MADRS = 5.7[SD = 4.7]) in all patients with improvements in MADRS persisting for 8 individuals up to 1 month after treatment (mean MADRS = 12.1[SD = 6.9], ≥50% improvement).

CONCLUSIONS: Findings from this open-label clinical trial support the safety and tolerability of ketamine treatment is in individuals with MCI-D. Ketamine may also be effective for improving depression in this population. Large-scale randomized controlled trials are needed to determine the efficacy and potential cognitive effects of this promising treatment in this patient population.},
}

@article {pmid41906332,
year = {2026},
author = {Park, I and Lee, D and Hong, RS and Kim, HY and Kim, Y},
title = {Small Molecule Therapeutics Targeting Amyloid-β in Alzheimer's Disease: Mechanisms, Clinical Progress, and Future Strategies.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en25040},
pmid = {41906332},
issn = {1226-2560},
abstract = {Alzheimer's disease (AD) imposes a growing burden on global healthcare systems. Current therapeutic interventions primarily alleviate cognitive and functional symptoms but have limited impact on the underlying neurodegenerative processes driving disease progression. This underscores the urgent need for treatments that target the pathogenic mechanisms of the disease. Advances in monoclonal antibody therapies against amyloid-β (Aβ) provide encouraging evidence for disease modification, though challenges related to dosing, cost, and safety constrain their broader application. Small molecule therapeutics represent a compelling alternative owing to advantageous properties such as enhanced brain penetration, oral bioavailability, and suitability for long-term administration in elderly patients. Building on these attributes, this review evaluates small molecule therapeutics as promising candidates for AD treatment. It summarizes small molecule compounds targeting Aβ across mechanisms that include modulating production, inhibiting aggregation, disassembling aggregates, enhancing clearance, and mitigating neurotoxicity. A comprehensive assessment of current data emphasizes the importance of continued research to overcome ongoing challenges and fully leverage the potential of small molecules. The limited number of candidates in late-stage clinical trials indicates that substantial efforts are still required to identify and refine effective agents. Continued investigation into their mechanisms and optimization of compound profiles will advance the development of small molecule-based therapies for AD.},
}

@article {pmid41908799,
year = {2025},
author = {Feng, JX and Zheng, MQ and Tian, X and Zimmermann, A and Wang, AX and Meng, X},
title = {Ginkgo biloba extract EGb 761 in patients with dementia and a history of cerebral infarction-meta-analysis of pooled data from randomised clinical trials.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1658064},
pmid = {41908799},
issn = {1664-2295},
abstract = {INTRODUCTION: Ginkgo biloba leaf extracts belong to the most popular herbal medicines for the treatment of neurological disorders, including Alzheimer's disease (AD) or stroke. EGb 761, a proprietary ginkgo leaf extract, has been shown to improve brain cell energy supply, to enhance neurogenesis and neuroplasticity, to decrease blood viscosity and improve brain perfusion. Thereby it improves cognitive performance, neuropsychiatric symptoms and activities of daily living in patients with dementia or mild cognitive impairment. It has further been shown to be beneficial for patients after ischaemic stroke. Therefore, the aim of this meta-analysis was to evaluate the treatment effects of EGb 761 in patients who had developed dementia following a cerebral infarction.

METHODS: We performed a meta-analysis of pooled data from clinical trials with EGb 761 in mild to moderate dementia in the subgroup of patients who had a cerebral infarction. Four randomised, placebo-controlled trials with homogeneous patient selection and design were included. Previous stroke was diagnosed by neuroimaging. The analysis focused on the comparison of treatment effects in the domains of cognition, activities of daily living and global assessment.

RESULTS: The meta-analysis included data from 488 patients. Significant treatment effects of 240 mg EGb 761 daily versus placebo were found for cognition (p = 0.0467), activities of daily living (p = 0.0230), and global clinical impression (p = 0.0371). The rates of adverse events and adverse drug reactions in the EGb 761 group were like those in the placebo group.

CONCLUSION: The results of our meta-analysis of patients with mild to moderate dementia who had previously had a cerebral infarction verified by neuroimaging showed statistically significant and clinically relevant benefits of EGb 761. The drug was shown to be safe and well tolerated and is a promising treatment option for patients developing dementia after cerebral infarction. Further dedicated clinical trials are needed to confirm these results.},
}

@article {pmid41909522,
year = {2026},
author = {Salini Jancy Rani, A and Balamurugan, BJ},
title = {Novel Roman domination-based graph energies for QSPR analysis of neuroprotective herbal compounds in Alzheimer's disease treatment.},
journal = {Frontiers in chemistry},
volume = {14},
number = {},
pages = {1731656},
pmid = {41909522},
issn = {2296-2646},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which U.S. Food and Drug Administration (FDA)-approved drugs provide only temporary symptomatic relief and often cause adverse effects. Plant-derived bioactive phytochemicals are emerging as promising alternatives due to their multi-targeted neuroprotective properties and reduced toxicity. In this article, herbal anti-Alzheimer's compounds are analyzed using a novel graph molecular modeling. In chemical graph theory, molecular structures are represented as isomorphic molecular graphs G V , E , where V and E denote the set of vertices (atoms) and edges (chemical bonds) respectively. Classical graph matrices such as adjacency and Laplacian matrices capture the molecular connectivity but fail to account for hierarchical differences in atomic influence. To address this limitation, Roman domination is employed to represent the hierarchical dominance of atoms within molecular structures. A Roman domination function (RDF) on a graph G V , E is a mapping f : V → 0 , 1 , 2 such that every atom v with f v = 0 has at least one adjacent atom u with f u = 2 , reflecting the hierarchical dominance within the isomorphic molecular graph. Based on this principle, the Roman domination-based matrices and corresponding graph energies are introduced in this article. Quantitative Structure-Property Relationship (QSPR) graph models are developed using the Roman energies through linear, quadratic and cubic regression analysis. The results demonstrate superior performance compared to classical approaches, with the quadratic regression showing the strongest correlations and lowest standard error. Internal validation through the Y-randomization and Leave-One-Out Cross-Validation methods confirmed the stability of the models, while external validation on the herbal compound Kaempferol (r = 0.993) further supported their predictive reliability. These findings underscore the robustness of Roman energies, establishing them as powerful molecular descriptors that offer enhanced accuracy in the QSPR analysis and hold promise for applications in drug design, materials informatics and computational chemistry.},
}

@article {pmid41910461,
year = {2026},
author = {Kong, X and Han, R and Fan, X and Wei, K and Ma, Z and Yang, G and Zhao, Y and Yang, Y and Yang, Y and Hong, J and Liu, J and Zhang, D and Ma, X},
title = {Acupuncture as an adjunct therapy for mild Alzheimer's disease: A randomized clinical trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435880},
doi = {10.1177/13872877261435880},
pmid = {41910461},
issn = {1875-8908},
abstract = {BackgroundPreclinical studies suggest acupuncture may offer symptomatic relief or modify disease progression in Alzheimer's disease (AD), yet clinical evidence remains limited.ObjectiveThis study evaluated whether adding acupuncture to cholinesterase inhibitors improves outcomes in patients with mild AD and whether any benefits persist after treatment ends.MethodsIn this randomized, single-blind trial, participants with mild AD received either active or sham acupuncture three times per week for 14 weeks in addition to ongoing donepezil therapy, followed by a 14-week washout phase during which acupuncture was discontinued while donepezil was maintained. The primary outcome was change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog12) from baseline.ResultsA total of 160 participants were enrolled, and 157 were included in the primary analysis (78 active, 79 sham). At week 14, the mean change in ADAS-cog12 was -1.20 for the active acupuncture group versus 0.36 for the sham acupuncture group, yielding a difference of -1.50 (p < 0.001). After washout, no significant difference remained (difference, -0.31; p = 0.54). Adverse events occurred in 37.2% of the active and 45.6% of the sham group. Donepezil-related adverse events were less frequent with active acupuncture (6.4% versus 16.5%; p < 0.05).ConclusionsAcupuncture, when added to donepezil, improved cognition during active treatment and was associated with fewer cholinergic side effects in patients with mild AD. The cognitive benefits did not persist after acupuncture was discontinued, suggesting that acupuncture serves as an adjunctive symptomatic therapy rather than a disease-modifying intervention.Trial registrationClinicalTrials.gov [NCT05078944].},
}

@article {pmid41910814,
year = {2026},
author = {Tripathi, P and Shah, J},
title = {Vitamin D3 Attenuates Alzheimer's Disease-Like Pathology via Remodeling Amyloid Protein Production and Clearance Pathway in Wistar Rats.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41910814},
issn = {1573-6903},
support = {GSBTM/MD/PROJECTS/SSA/4887/2016-17//Gujarat State Biotechnology Mission, Government of Gujarat, India/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology/chemically induced ; *Cholecalciferol/therapeutic use/pharmacology ; Male ; Rats, Wistar ; Rats ; *Amyloid beta-Peptides/metabolism ; Streptozocin ; Plaque, Amyloid/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease widely affects millions of people worldwide, accounting for 60% of dementia cases. Clinically classified by the presence of cognition impairment, pathophysiological representation includes deposited senile plaques, neurofibrillary tangles, and neuroinflammation. The pathogenesis of Alzheimer's disease (AD) remains multifaceted and is governed by multiple hypotheses. However, it undeniably involves amyloid-β (Aβ) accumulation and hyperphosphorylated tau (p-tau) pathology as the crucial events in disease initiation. Substantial evidence has correlated Vitamin D3 as a vital supplementation for the prevention of dementia and delays the progression of AD. The presence of localized Vitamin D receptors (VDR) in the brain and their capacity to convert absorbed Vitamin D to its active form have established a robust link between Vitamin D3 and Alzheimer's disease. The current study aims to explore the role of Vitamin D3 on specific parameters related to Alzheimer's disease in the Streptozotocin ICV-induced sporadic AD rat model. The study protocol included a single bilateral ICV STZ intrahippocampal injection to induce AD, followed by 21 days of treatment with two different doses of Vitamin D3 or Calcitriol (1alpha,25-dihydroxyvitamin D3)i.e., 2.5 μg/kg and 5.0 μg/kg. Results demonstrated that Vitamin D3 attenuates AD-specific parameters of amyloid plaque (Aβ1-40 and Aβ1-42), p-tau, and BACE-1. Moreover, a significant increase in the levels of both neprilysin (NEP) and insulin-degrading enzyme (IDE) was observed, both of which play a crucial role in the clearance of senile plaques. Vitamin D3 treatment also demonstrated a significant improvement in cognitive performance, along with attenuation of neuroinflammatory and oxidative stress parameters. Conclusively, optimal levels of Vitamin D3 impart neuroprotection in AD by attenuating production and increasing clearance of amyloid proteins.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology/chemically induced
*Cholecalciferol/therapeutic use/pharmacology
Male
Rats, Wistar
Rats
*Amyloid beta-Peptides/metabolism
Streptozocin
Plaque, Amyloid/metabolism
tau Proteins/metabolism

@article {pmid41910849,
year = {2026},
author = {Akram, SW and K, C},
title = {Enhancing Parkinson's Disease Staging: An Integrative Deep Learning Framework for Multimodal Feature Selection.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {41910849},
issn = {1559-1166},
mesh = {Humans ; *Parkinson Disease/diagnostic imaging/genetics/pathology/diagnosis ; *Deep Learning ; Neuroimaging/methods ; Magnetic Resonance Imaging ; Male ; Female ; },
abstract = {Parkinson's disease (PD) affects 10 million globally, with accurate staging essential for personalized treatment planning. Current UPDRS assessments achieve < 93% accuracy due to subjective clinical judgment and unimodal data limitations, failing to capture complex genetic-neuroimaging-clinical interactions driving disease heterogeneity. This study introduces MAFNet, a novel deep learning framework pioneering Iterative Adaptive Vold-Kalman Filter (IAVKF) temporal denoising, Accelerated Binary Particle Swarm Optimization (ABPSO) swarm feature selection, Multilayer Perceptron-Lagrangian Support Vector Machine (MLP-LSVM) classification, and Graph-Attention Based Multimodal Fusion Network (GAMF). Applied to PPMI cohort (200 patients) with genetic SNPs (50), neuroimaging voxels (1,024), and UPDRS-III scores, the end-to-end pipeline delivers 97.6% accuracy, 98.2% precision, 96.8% recall, and 97.3% F1-score-outperforming CNN (92.4%), Autoencoder (90.8%), InceptoFormer (96.6%), and HCT (97.0%). IAVKF boosts SNR + 15.2dB (+ 2.9% accuracy vs. PCA/t-SNE); ABPSO reduces 1,276→340 features (73% reduction); regularization cuts overfitting gap to 0.9% (vs. 4.2% baseline). SHAP interpretability validates clinical plausibility (top predictors: LRRK2 SNPs, UPDRS-III tremor, hippocampal volume). Five-fold CV confirms stability with the Indian cohort external validation. Real-time inference (0.2s/patient, RTX 3090) enables clinical deployment. Future scope includes longitudinal temporal modelling, modality-agnostic fusion, edge deployment, federated learning, and extension to Alzheimer's/ALS. MAFNet transforms PD staging from subjective assessments to objective precision medicine, enabling biomarker discovery, progression forecasting, and personalized therapies across diverse global populations.},
}

Humans
*Parkinson Disease/diagnostic imaging/genetics/pathology/diagnosis
*Deep Learning
Neuroimaging/methods
Magnetic Resonance Imaging
Male
Female

@article {pmid41910964,
year = {2026},
author = {Banerjee, G and Mok, TH and Hyare, H and Cousins, O and Jaunmuktane, Z and Mead, S and Collinge, J},
title = {High-Level Alzheimer Disease Neuropathological Change Following Iatrogenic Exposure.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0437},
pmid = {41910964},
issn = {2168-6157},
abstract = {IMPORTANCE: Alzheimer disease (AD) is pathologically characterized by the deposition of amyloid-β (Aβ) and hyperphosphorylated tau. Human transmission of Aβ pathology in a prion-like fashion has resulted in iatrogenic cerebral amyloid angiopathy. More recently, iatrogenic Alzheimer disease (iAD) was described in recipients of cadaveric pituitary-derived human growth hormone (c-hGH) contaminated with Aβ amyloid seeds.

OBJECTIVE: To describe the clinical and postmortem findings in iAD.

This case series describes 4 c-hGH recipients who were referred to the UK National Prion Clinic. Between February 2024 and February 2025, 14 c-hGH recipients had been referred to this service, with clinical assessments ongoing. The current study included 4 of 14 people treated with c-hGH who were referred since the original report. These data were analyzed during February and March 2025.

EXPOSURE: c-hGH contaminated with Aβ amyloid seeds.

MAIN OUTCOMES AND MEASURES: Clinical and histopathological description.

RESULTS: The study describes 4 males who developed dementia following confirmed or suspected c-hGH treatment in childhood (age at symptom onset between 47 and 60 years) with cognitive syndromes characterized by prominent language involvement. Results include clinical and postmortem findings for 1 patient (onset at age 47 years) in whom postmortem examination (at age 57 years) showed unequivocal neuropathological features of AD, including severe tauopathy. Brief descriptions of 3 additional patients with prominent language involvement are also provided.

CONCLUSIONS AND RELEVANCE: These results demonstrate that patients with iAD can have histopathological findings classically found in sporadic AD and that prominent language involvement might be an important phenotypic feature in this AD subtype.},
}

@article {pmid41910973,
year = {2026},
author = {Grill, JD and Raman, R and Wang, S and Ernstrom, K and Andrews, PS and Appleby, BS and Bhangu, J and Dhadda, S and Irizarry, M and Johnson, K and Lenio, S and MacDonald, S and Ramanan, VK and Rosenberg, PB and Weisman, D and Aisen, P and Sperling, R and Sultzer, D and Karlawish, J},
title = {Amyloid Imaging and APOE Genotype Disclosure and Short-Term Psychological Distress.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e263845},
doi = {10.1001/jamanetworkopen.2026.3845},
pmid = {41910973},
issn = {2574-3805},
mesh = {Humans ; Female ; Aged ; Male ; Middle Aged ; *Alzheimer Disease/genetics/psychology/diagnostic imaging ; Aged, 80 and over ; Positron-Emission Tomography ; Genotype ; *Apolipoproteins E/genetics ; *Psychological Distress ; Cohort Studies ; Biomarkers ; *Disclosure ; Amyloid ; },
abstract = {IMPORTANCE: Alzheimer disease (AD) biomarker and genetic testing results are increasingly disclosed to cognitively unimpaired adults in research and could in the future inform clinical treatment decisions in this population.

OBJECTIVES: To assess psychological outcomes after returning 3 categories of amyloid biomarker results as well as apolipoprotein E (APOE) genotypes.

This cohort study was a secondary analysis of data collected as part of screening for the multisite AHEAD preclinical AD trial. Participants were individuals aged 55 to 80 years undergoing screening from July 14, 2020, to October 15, 2024.

EXPOSURE: Participants were informed whether they had not-detected, intermediate, or elevated amyloid positron emission tomography levels, as well as their APOE genotype, which were categorized as noncarrier, ε4 heterozygote, or ε4 homozygote.

MAIN OUTCOMES AND MEASURES: Impact of Events Scale (IES; 15 items to assess intrusive thoughts and avoidance; each item is scored as not at all [0], rarely [1], sometimes [3], or often [5]; total range, 0-75), collected 24 to 72 hours after disclosure, and change in a scale measuring concerns about AD dementia (adapted scale using 6 items in which participants indicated their level of agreement with statements related to their perceived probability of developing AD dementia; items scored as strongly disagree [1] through strongly agree [5]; total range, 6-30), calculated by subtracting the score collected before biomarker testing from 1 collected after biomarker and genetic test results disclosure.

RESULTS: Among 3414 included individuals, the mean (SD) age was 68.8 (6.0) years and 2116 (62%) were female. Group mean IES scores were below clinically significant thresholds. Nevertheless, across genetic groups, learning an elevated amyloid result (1184 participants) was associated with higher IES (mean [SD], 10.5 [10.9]) than intermediate amyloid (482 participants; mean [SD] IES, 8.8 [9.8]), and intermediate amyloid was associated with higher scores than not-detected amyloid (1748 participants; mean [SD] IES, 6.5 [8.4]). Across amyloid groups, learning APOE ε4 homozygosity (337 participants) was associated with higher mean (SD) IES (12.7 [11.6]) than heterozygosity (1609 participants; 9.1 [10.2]), and heterozygosity was associated with higher IES than noncarrier status (1468 participants; mean [SD] IES, 6.2 [8.1]). Both types of information were significant in an analysis of covariance model; no interaction effect was observed. In contrast, only biomarker disclosure was associated with differential change in concerns about AD dementia. Those with elevated amyloid showed a mean (SD) increase in concern (0.8 [3.5]), those with intermediate amyloid showed a smaller increase (0.4 [3.7]), and those with not-detected amyloid showed decreased concerns (-1.1 [4.2]).

CONCLUSIONS AND RELEVANCE: In this cohort study of cognitively unimpaired adults, associations with intrusive thoughts were observed to differ among genetic and biomarker subgroups; such associations were limited to biomarker subgroups for measures of perceived dementia risk.},
}

Humans
Female
Aged
Male
Middle Aged
*Alzheimer Disease/genetics/psychology/diagnostic imaging
Aged, 80 and over
Positron-Emission Tomography
Genotype
*Apolipoproteins E/genetics
*Psychological Distress
Cohort Studies
Biomarkers
*Disclosure
Amyloid

@article {pmid41911040,
year = {2026},
author = {Kaur, P and Kumari, S and Singh, AK and Koley, T and Rai, N and Samath, EA and Dey, S},
title = {Targeting GSK3β with a Synthetic Small Molecule Rescues Neurotoxicity in a Cellular Model of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00772},
pmid = {41911040},
issn = {1948-7193},
abstract = {The neuropathological presentation of Alzheimer's disease (AD) constitutes amyloid-β plaques and Tau tangles. Activation of GSK3β contributes to neurodegeneration by directly promoting tau hyperphosphorylation and amyloid-β formation. An earlier study also reported the overexpression of GSK3β in AD patients. This work designed and synthesized tetrapeptides [VYS(p)W, AKS(p)F, and DKS(p)F] containing a phosphate group attached to the serine residue, which mimicked the primed phosphorylated substrate of GSK3β. According to the network study, through interaction with various proteins and alteration of the molecular pathway of AD, the DKS(p)F peptide may exhibit a wide range of effects. The binding study of the peptide was performed by label-free surface plasmon resonance. The rescue effect of peptide on neurotoxicity was measured by MTT assay in SH-SY5Y cells. The peptide DKS(p)F was found to have the best docking score and binding energy with GSK3β. The low dissociation constant, (9.58 × 10[-8] M), indicates strongest binding capacity with GSK3β. The reduction in neurotoxicity of SH-SY5Y cells was observed after treatment with DKS(p)F by suppressing the levels of amyloid-β, Tau, and p-Tau proteins. This peptide can be one of the promising molecules for ongoing efforts to develop therapeutic molecules for the neurodegenerative disorder of Alzheimer's disease.},
}

@article {pmid41911320,
year = {2026},
author = {Ali, S and Kuo, YF and Shan, Y and Tzeng, HM and Raji, MA},
title = {Impact of annual wellness visits on preventing falls and fractures for Alzheimer's disease and related dementias older adults.},
journal = {Age and ageing},
volume = {55},
number = {3},
pages = {},
doi = {10.1093/ageing/afag065},
pmid = {41911320},
issn = {1468-2834},
mesh = {Humans ; *Accidental Falls/prevention & control/statistics & numerical data ; Aged ; Female ; Male ; United States/epidemiology ; *Alzheimer Disease/complications/diagnosis/epidemiology ; Aged, 80 and over ; *Fractures, Bone/prevention & control/epidemiology/etiology ; Medicare ; Risk Factors ; *Dementia/complications ; Risk Assessment ; },
abstract = {BACKGROUND: Falls and fractures are leading causes of disability and premature death among older adults with Alzheimer's Disease and Related Dementias (ADRD). Annual Wellness Visits (AWVs), which Medicare reimburses, can screen and manage fall/fracture-related risk factors. This study evaluates the association between AWV and falls/fractures prevention among Medicare beneficiaries with ADRD.

METHODS: We analysed a cohort of Medicare beneficiaries in 2017 aged ≥68 years with ADRD and continuous enrollment from 2014 to 2016 (n = 1 610 637). AWV recipients were stratified by the number of visits before 2017 (0, 1, 2 or ≥ 3). Kaplan-Meier methods estimated rates of falls and fractures. Patients were censored at end of study (12/31/2021), if they lost Medicare coverage, or switched to HMO. We used inverse probability treatment weighting (IPTW) with propensity score in Cox proportional hazards models to assess the effect of AWVs.

RESULTS: AWVs were associated with reduced risks for falls (HR: 0.976 for 2 AWVs; 0.936 for ≥3 AWVs) and fractures (HR: 0.978 for 1 AWV; 0.960 for 2 AWVs; 0.927 for ≥3 AWVs), with greater reductions observed with more AVWs. Time-dependent models revealed AWV in follow-up period had stronger effects on fall and fracture risk (HR: 0.921 and 0.929, respectively). In subgroup analyses, AWV risk reduction was weaker for falls in Black and rural residents with no significant fracture risk reduction.

CONCLUSIONS: Our studies indicate more AWVs are associated with greater risk reduction of falls/fractures in older adults with ADRD. This study emphasizes expanding awareness of AWVs to prevent falls/fractures in this population.},
}

Humans
*Accidental Falls/prevention & control/statistics & numerical data
Aged
Female
Male
United States/epidemiology
*Alzheimer Disease/complications/diagnosis/epidemiology
Aged, 80 and over
*Fractures, Bone/prevention & control/epidemiology/etiology
Medicare
Risk Factors
*Dementia/complications
Risk Assessment

@article {pmid41911332,
year = {2026},
author = {Zhu, Z and Song, H and Liu, W and Tian, M and Hoang, T and Reddiar, SB and Trevaskis, NL and Han, S and Hu, L},
title = {Cervical Lymph Duct-Cannulated Rat Model for Assessing Lymphatic Transport from the Head and Brain.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {229},
pages = {},
doi = {10.3791/70217},
pmid = {41911332},
issn = {1940-087X},
mesh = {Animals ; Rats ; *Brain/metabolism ; *Lymphatic Vessels/physiology/metabolism ; *Head ; Neck ; Rats, Sprague-Dawley ; Models, Animal ; Male ; },
abstract = {Lymph flows from the central nervous system (CNS) via a series of lymphatic vessels (LVs) and lymph nodes that converge at the cervical lymph ducts. In addition to maintaining fluid balance, these lymphatic ducts play a key role in transporting a wide array of substances, including endogenous metabolites, signaling molecules, immune cells, and small and macromolecular drugs. This is critical for physiological homeostasis and immune function in both intracranial (e.g., brain) and extracranial regions (e.g., nasal and oral cavities). Impaired lymphatic drainage from the brain has increasingly been linked to a range of neurological and neurodegenerative disorders. Cervical lymph duct cannulation enables the collection of lymph draining the head and brain, allowing the measurement of the concentration and transport rate of various substances via the lymphatic system. Changes in these factors in response to different challenges (e.g., drugs, stress, trauma) and diseases (e.g., stroke, infection, Alzheimer's disease) can also be determined. Here, we describe an anesthetized, deep cervical lymph duct cannulated rat model that enables lymph collection for several hours following surgery. The method may be combined with imaging and multi-omics technologies for the measurement of a wide range of parameters of interest in the lymph. This facilitates fundamental physiological and pathophysiological research of the head and neck region, as well as pharmacokinetic/pharmacodynamic studies of drugs, particularly for the treatment of CNS diseases.},
}

Animals
Rats
*Brain/metabolism
*Lymphatic Vessels/physiology/metabolism
*Head
Neck
Rats, Sprague-Dawley
Models, Animal
Male

@article {pmid41911661,
year = {2026},
author = {Martínez, RF and Sánchez-Gallardo, M and Cintas, P},
title = {Memantine: A look ahead. Insights into structure, syntheses, receptor binding mechanisms, drug hybrids and formulations, and potential repurposing.},
journal = {European journal of medicinal chemistry},
volume = {310},
number = {},
pages = {118791},
doi = {10.1016/j.ejmech.2026.118791},
pmid = {41911661},
issn = {1768-3254},
abstract = {Since its approval for clinical use more than two decades ago, memantine has become a blockbuster drug against Alzheimer's disease (AD). Unlike other FDA approved small molecules for the treatment of AD, essentially acetyl cholinesterase inhibitors, memantine behaves as N-methyl-d-aspartate (NMDA) receptor antagonist. However, it is a weak and non-specific NMDA receptor channel blocker that has shown to be safe in slowing the decline of moderate to advanced AD symptoms. In fact, those of us familiarized with AD, are aware of clinical protocols where memantine is usually prescribed to mitigate late stages of this neurological disorder, following previous treatment with donepezil and other inhibitors. The role of memantine for either preventing or disrupting amyloid formation, yet promising, remains unconclusive. The pharmacological basis and mode of action of memantine are well known and have been reviewed from different standpoints, often within the context of adamantane scaffolds. In recent times, further analyses combining experiment and computational simulation have disclosed subtle features of memantine-receptor interactions and previously unrecognized mechanistic insights, which are summarized herein. Likewise, there is a growing interest in memantine derivatives, not only against neurodegeneration, but also versus unrelated pathologies. Such studies arising from lab observations and preclinical assessments at most, point to memantine's repurposing and open the door to further explorations and translation. It is noteworthy that some structural aspects of memantine, including crystal packing and polymorphism, are usually overlooked. This review pays attention to such key elements and updates synthetic protocols, including the first preparation of memantine in continuous flow.},
}

@article {pmid41912089,
year = {2026},
author = {Hoveizi, E and Karimi, A and Khajehpour, L and Ghotbeddin, Z and Pyecroft, S},
title = {Astrocyte-Derived Exosomes in Cognitive Recovery: A Comparative Assessment of Neurobehavioral, Molecular, and Electrophysiological Dimensions.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116196},
doi = {10.1016/j.bbr.2026.116196},
pmid = {41912089},
issn = {1872-7549},
abstract = {BACKGROUND: Despite the growing interest in cell- and exosome-based therapies for neurological diseases including Alzheimer's disease (AD), there is still a gap in the investigation of more effective treatments in terms of efficacy, safety, and durability of effect. This study aimed to compare the therapeutic potential of astrocyte cells and their derived exosomes (AS-Exos) in restoring cognitive function in a mouse model of AD.

METHODS: AD model was induced by bilateral electrical lesioning of the nucleus basalis of Meynert (NBM). Astrocytes were isolated from neonatal rat brains, and AS-Exos were harvested from astrocyte-conditioned media using an AnaCell extraction kit. Seven days after lesion induction, astrocytes and AS-Exos were stereotaxically injected into the NBM. Four weeks later, behavioral assessments (passive avoidance and locomotor activity), electrophysiological recordings (EEG), and biochemical measurements of hippocampal brain-derived neurotrophic factor (BDNF) and acetylcholine (ACh) levels were performed.

RESULTS: AS-Exos were confirmed as cup-shaped vesicles (30-150nm) expressing the exosomal surface markers CD9, CD63, and CD81. NBM lesions significantly reduced step-through latency (STL), hippocampal BDNF and ACh levels, and disrupted EEG oscillatory patterns. Treatment with AS-Exos markedly improved STL and produced greater increases in hippocampal BDNF and ACh levels compared with AD and AD+saline groups. EEG analysis also revealed enhanced beta, alpha, and gamma power, with the most robust normalization observed in the AS-Exos group.

CONCLUSIONS: AS-Exos demonstrated superior biochemical and electrophysiological benefits compared with astrocyte transplantation and provided equal or greater improvement in behavioral outcomes. These findings highlight AS-Exos as a promising cell-free therapeutic strategy for alleviating cognitive deficits associated with AD.},
}

@article {pmid41912358,
year = {2026},
author = {Gai, J and Sharma, H and Kaskie, B and Jogerst, GJ},
title = {Evaluating the Effect of National Background Check Program on Nursing Home Deficiency Citations.},
journal = {Health services research},
volume = {61},
number = {2},
pages = {e70108},
doi = {10.1111/1475-6773.70108},
pmid = {41912358},
issn = {1475-6773},
support = {R21 AG082047/AG/NIA NIH HHS/United States ; },
mesh = {*Nursing Homes/standards/statistics & numerical data/organization & administration ; Humans ; United States ; *Elder Abuse/prevention & control/statistics & numerical data ; Aged ; *Quality of Health Care/statistics & numerical data ; Alzheimer Disease ; Dementia ; *Homes for the Aged/standards/statistics & numerical data ; Female ; },
abstract = {OBJECTIVE: To evaluate the impact of the National Background Check Program (NBCP) on nursing home (NH) health deficiencies and citations related to abuse, neglect, and exploitation.

STUDY SETTING AND DESIGN: This study uses the Callaway and Sant'Anna Difference-in-Differences (CSDID) quasi-experimental method to analyze data from US nursing homes from 2009 to 2016. The study includes nursing homes from 18 states that received NBCP grants as treatment group and nursing homes from 24 states that did not receive NBCP grants as control group. We exclude eight pilot NBCP states.

We used facility-level deficiency data from NH Care Compare (CC), NH characteristics data from Certification and Survey Provider Enhanced Reports (CASPER), and Alzheimer's Disease and Related Dementias diagnosis data from Minimum Data Set (MDS) assessments, covering 96,261 nursing home-year observations.

PRINCIPAL FINDINGS: Overall, NBCP implementation was associated with a significant reduction in health deficiencies (-0.760, p < 0.01) and a decrease in the probability and number of citations for abuse, neglect, and exploitation (-0.029, p < 0.01; -0.048, p < 0.01). Subgroup analyses showed that NBCP was associated with reductions in health deficiencies in nursing homes, regardless of whether they had a high or low census of residents with Alzheimer's Disease and Related Dementias, and in both metropolitan and nonmetropolitan areas. However, the effects varied across states depending on when they adopted NBCP.

CONCLUSIONS: Our findings suggest that NBCP is an effective regulatory tool for improving nursing home deficiencies and reducing incidents of abuse-related violations. We need more research to assess if background check programs improve nursing home quality using resident-level outcomes.},
}

*Nursing Homes/standards/statistics & numerical data/organization & administration
Humans
United States
*Elder Abuse/prevention & control/statistics & numerical data
Aged
*Quality of Health Care/statistics & numerical data
Alzheimer Disease
Dementia
*Homes for the Aged/standards/statistics & numerical data
Female

@article {pmid41912523,
year = {2026},
author = {Yu, P and Liu, J and Xu, W and Peng, L and Li, Y and Shao, S and Wang, Y and Qiu, Z and Yang, H},
title = {Synaptic rescue in an Alzheimer's mouse model: low-temperature steam-derived black ginseng oligosaccharides remodel protein S-nitrosylation-NADPH oxidase axis.},
journal = {NPJ science of food},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41538-026-00812-9},
pmid = {41912523},
issn = {2396-8370},
support = {no. 20240305022YY//Science and Technology Development Planning Project of Jilin Province/ ; no. 2025ccyc01//Changchun Talents Technology Innovation Project/ ; },
abstract = {Synaptic loss and aberrant protein S-nitrosylation (SNO) are strongly linked to cognitive decline in both patients and animal models of Alzheimer's disease (AD). Our recent work in an AD mouse model has shed light on the role of oligosaccharides extracted from black ginseng (OSBG) in ameliorating cognitive impairment. However, the precise molecular mechanisms responsible for therapeutic efficacy of OSBG in AD are not well understood. In the present study, we employed an innovative SNOTRAP-based proteomic approach to quantify SNO proteins in the brain of APP/PS1 mice following OSBG intervention. The results revealed that differentially expressed SNO proteins, such as SNO-NOX1 and SNO- NOX5, confirmed by Western blot (WB), are significantly enriched in pathways related to oxidative stress, such as "Oxidative_stress activation of NADPH oxidase" and "Synaptic target recognition". OSBG treatment significantly alleviated oxidative stress via inhibition of NADPH oxidase activity in APP/PS1 mouse and PC12 cells by WB immunofluorescence (IF) assays. More importantly, upregulation of PSD-95 and SYN1 was detected in the hippocampal tissue of APP/PS1 mice after OSBG intervention, which was further validated by the corresponding mRNA expression levels. Consistently, histopathological analysis revealed the restoration of hippocampal cellular structure. Overall, our findings highlight the synapse-protective effect of OSBG in an AD model through regulating protein SNO levels and inhibiting NADPH oxidase activity, revealing a novel mechanism by which OSBG alleviated oxidative stress injury.},
}

@article {pmid41731612,
year = {2026},
author = {Bice, PJ and Nho, K and Ertekin-Taner, N and Saykin, AJ},
title = {Systems biology of Alzheimer's Disease: a scoping review of key pathways and mechanisms.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {41731612},
issn = {1750-1326},
support = {P30 AG072976/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; P30 AG010133/NH/NIH HHS/United States ; U01 AG072177/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; P30 AG010133/NH/NIH HHS/United States ; },
abstract = {UNLABELLED: Alzheimer’s Disease (AD) is a progressive and ultimately fatal neurodegenerative disorder, representing the most common form of dementia and affecting nearly 7 million people in the United States. For over a century, research has centered on hallmark AD pathologies—extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau (pTau). While these mechanisms remain central to our understanding of the Disease, the underlying molecular events and broader biological pathways driving AD are still not fully understood. Precision medicine for AD and related dementias (ADRD) requires a comprehensive understanding of neurodegenerative Disease through pathophysiologic biomarkers for early detection, prediction of progression, and for evaluating response to treatment. Systems biology provides a powerful framework for this effort, leveraging multi-omics for biomarker discovery and elucidation of critical Disease pathways. The purpose of this scoping review is to identify and inform the field on key pathways being intensively investigated in AD/ADRD, including hallmark pathology, proteostasis, inflammation, oxidative stress, glucose metabolism, lipid dysregulation, neurotransmitter systems, synaptic integrity, neurogenesis, co-pathology- and sex-related pathways. Finally emerging biomarkers, tools and strategies for discovery and analysis are discussed, emphasizing advances related to the emerging precision medicine for AD.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-026-00934-4.},
}

@article {pmid41832369,
year = {2026},
author = {Udaiyappan, JP and Balakrishnan, R and Tamilarasan, MM and Balasubramanian, B and Abass, KS},
title = {Selective Inhibition of Tumor Necrosis Factor for Attenuating Alzheimer's Disease: Strategies Targeting Neuroinflammation.},
journal = {Inflammation},
volume = {49},
number = {1},
pages = {},
pmid = {41832369},
issn = {1573-2576},
abstract = {Neuroinflammation is increasingly recognized as a key feature in the development of Alzheimer’s disease (AD), with tumor necrosis factor-alpha (TNF-α) playing a crucial role in initiating inflammatory responses. Continuous activation of TNF-α leads to synaptic dysfunction, neuronal loss, and worsening of amyloid and tau pathology. Specifically, the upregulation of the pro-inflammatory cytokine TNF-α in the brain activates its receptors (TNFR1 & TNFR2). Targeting TNF-α through selective inhibition presents a promising therapeutic strategy for regulating neuroinflammatory responses without compromising systemic immunity. This review discusses current insights into TNF-α signaling in AD progression and examines the effectiveness of selective TNF-α inhibitors in preclinical and clinical studies. We also highlighted specific TNF-α inhibitors, including small molecules and gene therapy approaches, for chronic inflammatory conditions and discussed the limitations and future directions of the current review. Targeted TNF-α inhibition could serve as a novel, disease-modifying treatment for AD, especially when combined with multi-targeted approaches addressing amyloid burden, tau pathology, oxidative stress, and neuroinflammation.},
}

@article {pmid41901221,
year = {2026},
author = {Watt, G and Olaya, J and Muench, G and Garner, B and Karl, T},
title = {Effects of Chronic 100 mg/kg Cannabidiol Treatment in Male Double Transgenic APPSwe/PS1∆E9 Mice.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {3},
pages = {},
pmid = {41901221},
issn = {1424-8247},
support = {n.a.//Alzheimer's Australia Dementia Research/ ; #1102012, #1141789, and #1095215//National Health and Medical Research Council/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a neurodegenerative disease for which there are no highly effective treatments, which highlights the need for novel therapeutics. Cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory and neuroprotective properties. Chronic CBD treatment (20 mg/kg and 50 mg/kg) reverses social recognition memory deficits of APPSwe/PS1∆E9 (APP/PS1) transgenic mice; however, it does not produce effects on AD-relevant brain pathology. Methods: Here, we investigated whether chronic high-dose CBD treatment (i.e., 100 mg/kg intraperitoneally) in early symptomatic 7.5-month-old APP/PS1 males would reverse cognitive deficits while also influencing neuropathological markers relevant to AD. Mice were assessed for anxiety, recognition memory, and social and aggressive behaviours before carrying out neuropathological analyses of collected brain tissue. Results: Vehicle-treated APP/PS1 transgenic males demonstrated reduced aggressive behaviour and increased socio-positive behaviour. A moderate deficit in social recognition memory was restored by CBD. APP/PS1 mice also exhibited elevated cortical proBDNF levels under vehicle treatment, and hippocampal levels of TNF-α and IL-1β were reduced in all APP/PS1 mice. AD transgenic mice exhibited no changes in soluble or insoluble Aβ42 levels or PPARγ isoforms. Conclusions: This study found that high-dose CBD restored a moderate social recognition memory deficit. However, CBD did not have marked effects on AD-relevant neuropathological markers assessed, most likely because the AD transgenic mice were evaluated at a disease stage too early to detect significant pathological changes. Thus, the underlying mechanisms for CBD's effect on social recognition memory require further investigation.},
}

@article {pmid41903051,
year = {2026},
author = {Jiang, C and Krivinko, J and Yu, Z and Sweet, RA and Zeng, L and Wang, H and Ding, Y and Zeng, Z and Kofler, J and Wang, L},
title = {Comparative Mortality Risk of Aripiprazole, Olanzapine, Quetiapine, and Risperidone in Alzheimer's Disease: A Real‑World Retrospective Cohort Study with Treatment Effect Heterogeneity Analysis.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {41903051},
issn = {1179-1934},
support = {R01 MH116046/MH/NIMH NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Second-generation antipsychotics (SGAs) are frequently used off-label to manage behavioral symptoms in Alzheimer's disease (AD), despite ongoing concerns about their safety. Comparative evidence on mortality risk across specific SGAs remains limited. In this study, we aim to compare all-cause mortality among patients with AD treated with one of the commonly prescribed SGAs and to explore treatment effect heterogeneity using causal machine learning.

METHODS: We conducted a retrospective cohort study using deidentified electronic health records from the Truveta platform. Patients with incident AD initiating treatment with aripiprazole, risperidone, quetiapine, or olanzapine were identified using a new-user design. Exposure was modeled as a time-varying covariate in Cox proportional hazards models, with propensity score matching applied to control for confounding. Causal tree and targeted maximum likelihood estimation were used to identify subgroups with heterogeneous treatment effects.

RESULTS: Among 17,004 patients with AD, aripiprazole was associated with significantly lower mortality than olanzapine (adjusted hazard ratio [AHR] 0.667, 95% confidence interval [CI] 0.472-0.941) and quetiapine (AHR 0.677, 95% CI 0.462-0.990). Quetiapine was also associated with lower mortality than olanzapine (AHR 0.833, 95% CI 0.702-0.990) and risperidone (AHR 0.830, 95% CI 0.705-0.978). Causal tree analysis revealed treatment effect heterogeneity by clinical characteristics, particularly among patients using type 2 diabetes mellitus (T2DM) medications. In subgroup analyses, aripiprazole remained protective in T2DM users (AHR = 0.604 versus the combined group of quetiapine and risperidone, p = 0.002).

CONCLUSIONS: Mortality risks vary substantially across SGAs in patients with AD with single-medication usage. Aripiprazole and quetiapine were associated with lower mortality compared with olanzapine and risperidone. Treatment effect heterogeneity suggests the need for individualized prescribing based on patient characteristics such as comorbid T2DM.},
}

@article {pmid41903678,
year = {2026},
author = {Yee Lee, AL and Ang, CW and Yeong, KY},
title = {Antibiotic repurposing as alternative therapeutic strategies for cancer and Alzheimer's disease: A solution or conundrum?.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104651},
doi = {10.1016/j.drudis.2026.104651},
pmid = {41903678},
issn = {1878-5832},
abstract = {Traditionally, drugs targeting mammalian systems have been repurposed as antibacterials to combat antimicrobial resistance. This review highlights the reverse perspective - exploring the emerging potential of antibiotics in the treatment and management of cancer and Alzheimer's disease. Because antibiotics are fast losing their efficacy due to resistance, repurposing clinically approved antibiotics for other diseases presents an attractive strategy, offering a new avenue for antibiotic applications rather than allowing valuable research efforts to go to waste. This review provides an overview on antibiotic repurposing for crucial diseases such as cancer and Alzheimer's disease, while also exploring the challenges and limitations associated with this approach. Future prospects of antibiotic repurposing are also discussed.},
}

@article {pmid41903830,
year = {2026},
author = {He, S and Lin, Z and Zhou, X and Wang, Q and Fang, C and Jin, Q and Guan, L},
title = {The novel therapeutic strategy of myricetin/chitooligosaccharide/astaxanthin, as potent multi-target-directed ligands for the potential treatment of Alzheimer's disease with comorbid depression.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178806},
doi = {10.1016/j.ejphar.2026.178806},
pmid = {41903830},
issn = {1879-0712},
abstract = {OBJECTIVE: The mixed particles of Myricetin (MYR)/Chitooligosaccharide (COS)/Astaxanthin (AST) had not study to therapeutic effects on Alzheimer's disease (AD) combined with depression. In this study, the mixed particles of MYR/COS/AST were investigate the inhibitory activities against cholinesterase (ChE) and monoamine oxidase (MAO), possessing good activity were further assayed to inhibit β-amyloid1-42 (Aβ1-42) aggregation, beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), the neuroprotective activity and cytotoxicity.

MATERIALS AND METHODS: ChE and MAO inhibitory activities by Ellman and Holts method. Aβ aggregation were evaluated by thioflavin T assay, BACE1 inhibition used the fluorescence resonance energy transfer (FRET)- based. The protective effect were tested by against L-Glutamate (L-Glu)-induced HT22 cell damage, Cu[2+]- and Fe[3+]-induced neuronal damage, the cytotoxicity were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- tetrazolium bromide (MTT) test. The antidepressant activities were measured by the forced swimming test (FST).

RESULTS: The results showed that the mass ratio of the mixed particles MYR/COS/AST was 10:10:3, which exhibited the best inhibitory activities on AChE, MAO, also exhibited inhibition against Aβ1-42 aggregation, BACE-1, Aβ1-42 disaggregation, exerted protective effects L-Glu-induced HT22 cell damage and on the cells against Cu[2+] and Fe[3+]-induced damage in BV-2 cells. In the FST, the mixed particles of MYR/COS/AST (10:10:1) exhibited good antidepressant effect. None of three substances showed cytotoxicity against L929 cells. The molecular docking revealed important interactions between the active three substances and amino acid residues.

CONCLUSIONS: These studies provide the technical data for ensuring potential treatment of AD combined with depression of the mixed particles of MYR/COS/AST (10:10:3).},
}

@article {pmid41903861,
year = {2026},
author = {Salas, YM and Kemper, KM and Shanmughapriya, S and Langford, D and Natarajaseenivasan, K},
title = {Lipid Metabolism and Neurodegeneration: Mechanistic Insights and Therapeutic Targets.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103114},
doi = {10.1016/j.arr.2026.103114},
pmid = {41903861},
issn = {1872-9649},
abstract = {Lipid metabolism plays a crucial role in maintaining brain homeostasis, affecting energy balance, membrane structure, and signaling pathways essential for neuronal and glial health. Disruption of lipid pathways is linked to neuroinflammation and the progression of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as aging. Changes in cholesterol trafficking, sphingolipid and ceramide metabolism, and phospholipid remodeling can compromise synaptic membrane integrity and signaling, thereby increasing oxidative stress and inflammatory responses. Advanced techniques such as single-cell RNA sequencing (scRNA-seq) and single-nucleus transcriptomics have revealed specific alterations in lipid metabolism across different cell types, indicating a metabolic shift that enhances microglial activation and astrocytic reactivity. This lipid dysregulation contributes to a cycle that heightens neuronal vulnerability. Lipid rafts also facilitate receptor-mediated signaling, tying lipid imbalances to immune activation. Consequently, therapeutic strategies targeting lipid pathways are gaining traction, including modulating apolipoprotein E, inhibiting ceramide synthesis, and supplementing fatty acids to enhance membrane fluidity. Moreover, lipidomics helps identify unique lipid signatures that could serve as biomarkers for early diagnosis and treatment monitoring. Understanding the connection between lipid metabolism, neuroinflammation, and neurodegeneration offers valuable insights for developing targeted interventions in neurodegenerative diseases.},
}

@article {pmid41904014,
year = {2026},
author = {Sahu, S and Rangappa, N and Chinnathambi, S and Mishra, M},
title = {Tau-Cytoskeleton and their interaction with other neurodegenerative proteins.},
journal = {Advances in protein chemistry and structural biology},
volume = {150},
number = {},
pages = {489-517},
doi = {10.1016/bs.apcsb.2025.10.032},
pmid = {41904014},
issn = {1876-1631},
mesh = {Humans ; *tau Proteins/metabolism ; *Tauopathies/metabolism/pathology ; Animals ; *Cytoskeleton/metabolism/pathology ; alpha-Synuclein/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Parkinson Disease/metabolism/pathology ; Huntingtin Protein/metabolism ; Brain/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {A wide range of neurological conditions known as Tauopathies are distinguished by a peculiar accumulation of Tau protein and its effect on the central nervous system (CNS) and beyond. In Tauopathies, Tau aggregation has a primary role in the neurodegenerative process. Clinically, individuals exhibit various symptoms, such as cognitive or behavioural anomalies, mobility issues, memory loss, and language problems. The major Tau isoforms (3R, 4R, or an equal 3R:4R ratio) identified in the inclusion bodies of the brain are used to classify Tauopathies pathologically. We address various Tauopathies, differentiating between primary and secondary forms, the involvement of Tau isoforms, the affected brain areas, and the corresponding neuropathological features. This review emphasizes the pathological and physiological role of Tau protein, providing a comprehensive analysis of the molecular processes enabling Tau aggregation and its subsequent effect on neuronal structure and function. Additionally, the review highlights the complex interactions that exist between Tau and other neurodegenerative proteins, including amyloid-beta in Alzheimer's disease, alpha-synuclein in Parkinson's disease, huntingtin protein in Huntington's disease, and how these relationships worsen Tau pathology and advance neurodegeneration. The organ-specific impact of Tauopathy, including the brain and other peripheral organs, has been discussed. The significance of these findings for future treatment techniques aiming at addressing Tau disease and mitigating its organ-specific repercussions.},
}

Humans
*tau Proteins/metabolism
*Tauopathies/metabolism/pathology
Animals
*Cytoskeleton/metabolism/pathology
alpha-Synuclein/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Alzheimer Disease/metabolism/pathology
Parkinson Disease/metabolism/pathology
Huntingtin Protein/metabolism
Brain/metabolism/pathology
Amyloid beta-Peptides/metabolism

@article {pmid41904723,
year = {2026},
author = {Yang, Q and Ren, X and Jia, R and Zheng, L and Ou, R and Xu, Y and Luo, Y and Yang, G and Wang, X},
title = {Programmed cell death: a promising management for Alzheimer's disease.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {4},
pages = {},
pmid = {41904723},
issn = {1573-675X},
support = {ZRY2022J007//Seed Foundation of Zhejiang Provincial People's Hospital/ ; 82302918//National Natural Science Foundation of China/ ; 2024KY758//Medical and Health Research Project of Zhejiang province/ ; 2025HY0772//Medical and Health Research Project of Zhejiang province/ ; 2025HY0770//Medical and Health Research Project of Zhejiang province/ ; LQ24H160044//Natural Science Foundation of Zhejiang Province/ ; QN26H160024//Natural Science Foundation of Zhejiang Province/ ; 2024WJC187//Hangzhou Biomedical and Health Industry Development Support Science and Technology Special/ ; 2022WJC232//Hangzhou Biomedical and Health Industry Development Support Science and Technology Special/ ; 2024WJC072//Hangzhou Biomedical and Health Industry Development Support Science and Technology Special/ ; 2026ZL0638//Zhejiang Province Traditional Chinese Medicine Science and Technology Project/ ; LHZQN26H160006//Hangzhou Joint Fund of Zhejiang Provincial Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism/genetics/therapy ; Humans ; *Apoptosis/genetics ; Autophagy/genetics ; Animals ; Biomarkers/metabolism ; Necroptosis ; Ferroptosis ; },
abstract = {Epidemiological investigations have indicated that Alzheimer's disease (AD) has emerged as a predominant health challenge among older adults, with its mortality rate rising sharply each year. Nevertheless, measures capable of delaying or halting its clinical progression have remained largely unattained until recent years. Programmed cell death (PCD), defined as a genetically regulated and orderly mode of cellular demise, is pervasive throughout organismal development and essential for maintaining life homeostasis. As research on PCD in AD has expanded, accumulating evidence has shown that autophagy, ferroptosis, cuproptosis, pyroptosis, necroptosis, parthanatos, NETosis, disulfidptosis, and oxeiptosis are intimately linked to the onset, progression, and prognosis of AD. This review synthesizes recent advances regarding the application of PCD in biomarker identification and therapeutic innovation to enhance AD diagnosis and management. Additionally, challenges and emerging opportunities in employing PCD as novel management strategies are examined, with the overarching aim of transitioning from treatment toward prevention.},
}

*Alzheimer Disease/pathology/metabolism/genetics/therapy
Humans
*Apoptosis/genetics
Autophagy/genetics
Animals
Biomarkers/metabolism
Necroptosis
Ferroptosis

@article {pmid41905544,
year = {2026},
author = {Simpson, D and Morrone, CD and Wear, D and Khani, A and Liu, F and Gutierrez, J and Yu, WH},
title = {Neurovascular large artery dilatation increases the risk for Alzheimer's disease pathology.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107368},
doi = {10.1016/j.nbd.2026.107368},
pmid = {41905544},
issn = {1095-953X},
abstract = {Alzheimer's disease and related dementias are increasing globally, highlighting the urgent need to clarify disease mechanisms to improve diagnosis and treatment. Vascular alterations are a major pathological feature of Alzheimer's disease. Beyond the established contributions of small vessel disease and large artery atherosclerosis, our group has shown that dilatation of large cerebral arteries is associated with an increased risk of dementia and Alzheimer's pathology. The most severe manifestation of this non-atherosclerotic vascular phenotype is dolichoectasia, characterized by abnormal enlargement of large blood vessels. Despite consistent epidemiological evidence, the mechanisms linking arterial dilatation to Alzheimer's disease pathology remain poorly understood. To address this gap, we induced large artery dilatation in homozygous App[NL-G-F] mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. Mice were euthanized at 9 months and brains were analyzed using biochemical and immunohistochemical approaches. Elastase-treated mice showed a significant increase in amyloid plaque burden in the hippocampus and cortex compared with vehicle-treated controls. Neuronal loss was observed in the CA1 region of the hippocampus, with a similar trend in CA3. Markers of impaired autophagic-lysosomal clearance were elevated in both hippocampal and cortical regions, while neuroinflammation and astrogliosis were unchanged. In contrast, matrix metalloproteinase-9 (MMP-9) levels were significantly increased. Overall, this study establishes a novel mixed vascular-neurodegenerative pathology model by inducing large artery dilatation in an amyloid mouse model. Our findings demonstrate that vascular dilatation accelerates Alzheimer's disease-related pathology and provide a platform to investigate underlying mechanisms and potential therapeutic targets for mixed dementia.},
}

@article {pmid41905660,
year = {2026},
author = {VanGilder, JL and Hooyman, A and Hakhu, S and Schilling, KG and Hu, LS and Zhou, Y and Caselli, RJ and Baxter, LC and Beeman, SC},
title = {Using diffusion MRI to relate hippocampal subfield microstructure to delayed verbal memory in cognitively intact individuals at genetic risk for developing Alzheimer's disease.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113112},
doi = {10.1016/j.exger.2026.113112},
pmid = {41905660},
issn = {1873-6815},
abstract = {Intervention to delay the onset of Alzheimer's disease (AD) is an important treatment strategy but detecting at-risk individuals before significant disease progression remains challenging. This study evaluates the relationship between hippocampal microstructure and verbal cognition in cognitively intact older adults, focusing on the differences between APOΕ ε4 allele carriers and noncarriers. Participants (n = 41 noncarriers, 33 carriers) over 60 years old (mean ± SD: carriers 71 ± 6.6; noncarriers 71 ± 6.4 years) underwent diffusion-weighted magnetic resonance imaging (dMRI) and volumetric assessments. We assessed hippocampal structure, including microstructure, using Neurite Orientation Dispersion and Density Imaging (NODDI), diffusion tensor imaging (DTI), and volumetric measures. Regression analyses examined the relationship between these hippocampal measures and verbal and visuospatial cognition, as evaluated by the Rey delayed recall tests, i.e., the Auditory Verbal Learning Test (AVLT) and Complex Figure Test (CFT), respectively. Results indicated that while volumetric data showed no significant findings, microstructural measures, particularly orientation dispersion (ODI) in the left subiculum, were positively associated with verbal recall in APOΕ ε4 carriers (p = 0.0011; Bonferroni-corrected alpha = 0.005). These findings suggest that hippocampal microstructure, rather than volume, may provide insights into cognitive decline in individuals at genetic risk for AD.},
}

@article {pmid41896046,
year = {2026},
author = {Fisher, DW and Mehta, R and Morrow, CB and Kerr, KF and Jayadev, S and Domoto-Reilly, K and Schrift, MJ and Darvas, M},
title = {Clinical Associations and Possible Risk Factors for Affective Neuropsychiatric Symptoms in Older Adults With and Without Cognitive Impairment.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.02.015},
pmid = {41896046},
issn = {1545-7214},
abstract = {OBJECTIVE: Affective neuropsychiatric symptoms (NPS)-depression, anxiety, and apathy-are frequent in older adults. Understanding which clinical characteristics might be associated with which affective NPS may guide future treatment and prevention strategies.

DESIGN: The National Alzheimer's Coordinating Center dataset, a large case series of more than 170,000 clinical visits.

SETTING: Multiple Alzheimer's Disease Research Centers throughout the United States.

PARTICIPANTS: Adults 60 years and older with and without cognitive impairment.

MEASUREMENTS: The authors associated the odds of depression, anxiety, and apathy with clinical variables, including common and cardiovascular comorbidities, vital signs, medication classes, APOE status, race and ethnicity, and marital status across three cognitive groups: Cognitively Normal, Mild Cognitive Impairment, and Dementia.

RESULTS: Hearing loss and sleep abnormalities were robustly associated with all affective NPS at all cognitive stages. Cardiovascular diseases were not consistently associated with depression but were associated with greater apathy odds in cognitively normal participants. Nearly all odds ratios for all three affective NPS tended to attenuate to 1 as cognition worsened, potentially suggesting that neurodegeneration may drive affective NPS beyond other risk factors. Other associations with angina, osteoarthritis, blood pressure, heart rate, tobacco use, and race were noted.

CONCLUSIONS: Clinical associations often vary by NPS metric choice. Hearing and sleep deficits may be important therapeutic targets to increase quality of life by reducing affective NPS in older adults. Further research into the specific biological mechanisms whereby neurodegeneration can cause affective NPS presentation may be warranted, separate from other risk factors for affective NPS in older adults.},
}

@article {pmid41897462,
year = {2026},
author = {Zhang, M and Zhu, L and Wang, Y and Chen, W and He, Z},
title = {A Nasal Taxifolin Hydrogel Targets the TLR4/NF-κB/HIF-1α Axis to Suppress Ferroptosis in Alzheimer's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030316},
pmid = {41897462},
issn = {2076-3921},
support = {YDZJ202502CXJD077//Construction of Jilin Province International Science and Tech-nology Cooperation Key Laboratory: Jilin Province Sika Deer Efficient Breeding and Product De-velopment International Cooperation Key Laboratory/ ; 2025ZDYFNS06//Changchun Key Research and Development Program: Research and Application Promotion of Sika Deer Full Industry Chain Technology/ ; },
abstract = {In order to further explore new therapeutic targets for Alzheimer's disease (AD), this study, under the guidance of network pharmacology and molecular docking analysis, focused on the TLR4/NF-κB/HIF-1α signal axis and ferroptosis and verified the mechanism of a nasal taxifolin thermosensitive hydrogel (TF-Gel). In the Okada acid (OA)-induced AD mouse model, intranasal administration of TF-Gel significantly improved cognitive dysfunction and reduced neuroinflammation and oxidative stress. Mechanism studies have shown that TF-Gel effectively reduces the accumulation of reactive oxygen species in the hippocampus, enhances mitochondrial membrane potential, and improves mitochondrial ultrastructure by specifically inhibiting the TLR4/NF-κB/HIF-1α pathway, thereby effectively inhibiting neuronal ferroptosis. Western blot analysis confirmed the regulation of ferroptosis, synaptic function, and apoptosis-related proteins by TF-Gel. Of particular importance, the therapeutic benefits of TF-Gel were completely abolished by co-administration of the ferroptosis inducer Erastin, directly confirming that ferroptosis inhibition is the core link in its neuroprotective effect. This study reveals for the first time that TF-Gel exerts a multi-target neuroprotective effect by precisely regulating the TLR4/NF-κB/HIF-1α axis ferroptosis pathway, providing a new perspective for research into the mechanism and treatment of AD.},
}

@article {pmid41898257,
year = {2026},
author = {Chen, X and Deng, W and Chen, X and Yu, Y},
title = {Magnesium Transporter SLC41A1 Links Magnesium Homeostasis to NMDA Receptor-Related Synaptic Dysfunction: A Transdiagnostic Therapeutic Target for Neuropsychiatric Disorders.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030610},
pmid = {41898257},
issn = {2227-9059},
support = {2021A1515011322//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {Background: Neuropsychiatric disorders such as Alzheimer's disease (AD), bipolar disorder (BD), and depression exhibit shared glutamatergic abnormalities, although their upstream molecular mechanisms remain poorly defined. Magnesium (Mg[2+]) serves as a key regulator of N-methyl-D-aspartate (NMDA) receptor function; however, the role of Mg[2+] transporters, particularly SLC41A1, has not been systematically investigated. As NMDA receptor dysregulation contributes to emotional and cognitive impairments, elucidating Mg[2+]-NMDA signaling may enable the development of novel therapeutic strategies. Methods: We integrated Mendelian randomization, locus colocalization, human brain transcriptomics, functional enrichment, and co-expression analyses to determine whether SLC41A1 functions as a cross-disorder molecular driver. In addition, in vitro electrophysiological experiments using field potential recordings in hippocampal Schaffer-CA1 synapses were conducted to validate its functional role in NMDA receptor-mediated synaptic transmission. Results: Genetically elevated SLC41A1 expression increased the risk of AD, BD, depression, and alcohol dependence, with strong colocalization analyses supporting shared causal variants. Transcriptomic profiling revealed SLC41A1 upregulation in AD and BD, with enrichment in magnesium transport, mitochondrial function, and synaptic signaling pathways. Co-expression networks across GTEx brain regions demonstrated strong correlations with NMDA-related genes (e.g., GRINA, CAMK2G, GRIN2C). Under NMDAR-selective recording conditions, both imipramine treatment and SLC41A1 knockdown significantly reduced NMDAR-mediated fEPSP amplitudes, supporting a role for SLC41A1 in regulating NMDA receptor-dependent synaptic responses. Conclusions: This study identifies SLC41A1 as a magnesium-centered, transdiagnostic therapeutic target that links Mg[2+] homeostasis to NMDA-dependent synaptic dysfunction. These findings provide a mechanistic foundation for developing SLC41A1-modulating or magnesium-based therapeutic approaches for mood and cognitive disorders.},
}

@article {pmid41898539,
year = {2026},
author = {Lee, SH and Son, Y and Jang, H and Kim, HY and Kim, KS and Lee, HS and Lee, HJ},
title = {Fluoxetine Repurposing Mitigates Alzheimer's Disease Pathology via the GSK3β-CREB-ADAM10 Axis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062676},
pmid = {41898539},
issn = {1422-0067},
support = {RS-2025-24873145//National Research Foundation of Korea/ ; },
mesh = {*Fluoxetine/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Glycogen Synthase Kinase 3 beta/metabolism ; Mice ; Humans ; *Drug Repositioning ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Amyloid Precursor Protein Secretases/metabolism ; *ADAM10 Protein/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Signal Transduction/drug effects ; Phosphorylation/drug effects ; Male ; Selective Serotonin Reuptake Inhibitors/pharmacology ; Cell Line, Tumor ; *Membrane Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the aging population. Drug repurposing provides a cost-effective strategy to identify novel therapeutics that may mitigate age-associated pathologies. Here, we report the therapeutic potential of fluoxetine, a selective serotonin reuptake inhibitor commonly used as an antidepressant, in alleviating cognitive impairment and AD-like pathology in 5xFAD mice, a transgenic model of familial AD. Chronic fluoxetine administration significantly ameliorated anxiety-like behavior and cognitive deficits in 5xFAD mice, as assessed by open field, Y-maze, and novel object recognition tests. Fluoxetine treatment was associated with reduced amyloid plaque deposition in the hippocampus and cortex, attenuation of microglial activation, and decreased expression of inflammatory cytokines. At the molecular level, fluoxetine increased phosphorylation of GSK3β at Ser9, which was associated with enhanced CREB phosphorylation and upregulation of the α-secretase ADAM10. These effects were further examined in SH-SY5Y neuronal cells, where CREB phosphorylation and ADAM10 expression were significantly modulated by GSK3β inhibition, whereas CaMKII inhibition had no detectable effect under our experimental conditions. Our findings suggest that fluoxetine modulates amyloid-associated signaling pathways in the 5xFAD model, in part through regulation of the GSK3β-CREB signaling framework. These results provide mechanistic insight into how fluoxetine may influence APP processing in an amyloid-driven pathological context, although further studies are required to clarify its translational implications in human AD.},
}

*Fluoxetine/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
Animals
*Glycogen Synthase Kinase 3 beta/metabolism
Mice
Humans
*Drug Repositioning
*Cyclic AMP Response Element-Binding Protein/metabolism
*Amyloid Precursor Protein Secretases/metabolism
*ADAM10 Protein/metabolism
Mice, Transgenic
Disease Models, Animal
Signal Transduction/drug effects
Phosphorylation/drug effects
Male
Selective Serotonin Reuptake Inhibitors/pharmacology
Cell Line, Tumor
*Membrane Proteins/metabolism

@article {pmid41898669,
year = {2026},
author = {Promprom, W and Chatan, W and Homwutthiwong, K and Apaijit, K and Cheepsunthorn, P and Mairuae, N},
title = {Anti-Inflammatory and Antioxidant Properties of Bauhinia thailandica Leaf Extract in Microglial Cells.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062809},
pmid = {41898669},
issn = {1422-0067},
support = {//Thailand Science Research and Innovation and Faculty of Medicine, Mahasarakham University./ ; },
mesh = {*Plant Extracts/pharmacology/chemistry ; *Microglia/drug effects/metabolism ; *Plant Leaves/chemistry ; *Antioxidants/pharmacology/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Bauhinia/chemistry ; Animals ; Mice ; Lipopolysaccharides ; Reactive Oxygen Species/metabolism ; Cell Line ; Nitric Oxide/metabolism ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; },
abstract = {Neuroinflammation is pivotal in the development of numerous neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Microglial cells, the principal immune cells of the central nervous system (CNS), are essential mediators of this process. Upon exposure to pathogenic stimuli such as lipopolysaccharide (LPS), microglia activate and release pro-inflammatory mediators, leading to heightened oxidative stress and neuronal damage. Therefore, targeting microglial activation is a promising therapeutic approach to prevent or slow neurodegeneration. This study aimed to investigate the antioxidant and anti-inflammatory effects of the leaf extract of the newly identified species Bauhinia thailandica on LPS-activated BV2 microglia. The phytochemical compound of the B. thailandica leaf extract was also investigated. BV2 cells were treated with LPS (1 μg/mL) for 24 h in the presence or absence of B. thailandica leaf extract (12.5 and 25 µg/mL). The levels of reactive oxygen species (ROS), nitric oxide (NO), and interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha (TNF-α) were quantified with CM-H2DCFDA, Griess reagent assay, and ELISA, respectively. Treatment with LPS resulted in significant increases in ROS, NO, IL-6, IL-1, and TNF levels compared to untreated cells (p < 0.01). However, co-treatment with B. thailandica leaf extract significantly suppressed the production of these inflammatory markers (p < 0.01 for 25 µg/mL across all parameters, except TNF-α; p < 0.05). The results also showed that B. thailandica leaf extract possessed significant levels of total phenolic content (TPC; 70.55 mg GAE/g dry extract), total flavonoid content (TFC; 249.47 mg QE/g dry extract), and tannins (397.50 mg TAE/g dry extract). Phytochemical screening also revealed the presence of saponins and cardiac glycosides in the extract. In conclusion, the leaf extract of B. thailandica is a potent source of phytochemicals exhibiting antioxidant capabilities and has shown both antioxidant and anti-inflammatory actions in LPS-activated BV2 microglial cells. The findings indicate that B. thailandica leaf extract shows significant promise as a novel herbal treatment for neuroinflammatory disorders mediated by microglia. Further research is necessary to clarify the underlying mechanisms of action and to investigate the active substances responsible for these effects.},
}

*Plant Extracts/pharmacology/chemistry
*Microglia/drug effects/metabolism
*Plant Leaves/chemistry
*Antioxidants/pharmacology/chemistry
*Anti-Inflammatory Agents/pharmacology/chemistry
*Bauhinia/chemistry
Animals
Mice
Lipopolysaccharides
Reactive Oxygen Species/metabolism
Cell Line
Nitric Oxide/metabolism
Oxidative Stress/drug effects
Cell Survival/drug effects

@article {pmid41898672,
year = {2026},
author = {Davis, A and Casmedes, IY and Burton, MD},
title = {Radical Revelations: The Interplay of Nitrosative Stress, the Endocannabinoid System, and Treatment of Age-Related Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062813},
pmid = {41898672},
issn = {1422-0067},
support = {GM147094//National Institute of Health/ ; DK130015//National Institute of Health/ ; },
mesh = {Humans ; *Endocannabinoids/metabolism ; *Nitrosative Stress/drug effects ; Animals ; *Reactive Nitrogen Species/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Aging/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Parkinson Disease/metabolism/drug therapy ; Signal Transduction ; },
abstract = {The crosstalk between the endocannabinoid system (ECS) and reactive nitrogen species (RNS) has emerged as an important area of investigation in recent years. Although many aspects of this interaction remain elusive, accumulating evidence demonstrates that the ECS plays a critical role in regulating RNS-mediated signaling under physiological conditions. This modulation can be either inhibitory or stimulatory, depending on the specific receptor subtype, cell type, and tissue location involved. While ECS-RNS interactions support normal cellular homeostasis, their dysregulation contributes to various disease states, particularly neurodegenerative disorders. Studies in both rodent models and human subjects show that ECS modulation can reduce anxiety, attenuate neuroinflammatory responses, and slow disease progression in neurodegenerative conditions. This review examines how cannabinoid-based interventions modulate nitrosative stress and neuroinflammation in Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting their potential as targeted therapeutics that address multiple pathological mechanisms simultaneously and may offer advantages over conventional treatment approaches.},
}

Humans
*Endocannabinoids/metabolism
*Nitrosative Stress/drug effects
Animals
*Reactive Nitrogen Species/metabolism
*Alzheimer Disease/metabolism/drug therapy
*Aging/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy
*Parkinson Disease/metabolism/drug therapy
Signal Transduction

@article {pmid41898738,
year = {2026},
author = {Sun, F and Liu, K and Xi, E and Zhao, Y and Gao, N},
title = {Constructing Curcumin-Based Biological Metal-Organic Frameworks (MOFs) for the Treatment of Alzheimer's Disease Through the Pyroptosis Pathway.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062871},
pmid = {41898738},
issn = {1422-0067},
support = {2022YFB3805902//National Key R&D Program of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//the "111" project/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Metal-Organic Frameworks/chemistry/pharmacology ; *Pyroptosis/drug effects ; *Curcumin/chemistry/pharmacology ; Mice ; Mice, Transgenic ; Quercetin/analogs & derivatives/chemistry/pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; Disease Models, Animal ; Antioxidants/pharmacology/chemistry ; },
abstract = {Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder that presents as neuronal cell death caused by the pyroptosis pathway. Currently, curcumin is widely reported in the treatment of AD due to its dual inhibitory effects on NLRP3-associated inflammasome activation, but it suffers from poor bioavailability. Therefore, in this study, a highly stable curcumin-based Zn-organic framework (medi-MOF-1) loaded with taxifolin (TAX@medi-MOF-1) was presented to overcome the defect with a specific surface area of 2530.652 m[2] g[-1]. The loaded TAX could further enhance the anti-inflammatory and antioxidant properties. In 5×FAD transgenic mice, TAX@medi-MOF-1 significantly improved cognitive and motor functions, reduced Aβ plaque deposition, and downregulated key pyroptosis proteins (NLRP3, caspase-1, and GSDMD-N). The dual-drug system exhibited synergistic effects, offering a promising multi-target therapeutic strategy for AD.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Animals
*Metal-Organic Frameworks/chemistry/pharmacology
*Pyroptosis/drug effects
*Curcumin/chemistry/pharmacology
Mice
Mice, Transgenic
Quercetin/analogs & derivatives/chemistry/pharmacology
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Humans
Disease Models, Animal
Antioxidants/pharmacology/chemistry

@article {pmid41899281,
year = {2026},
author = {Takahashi, T and Muguruma, K},
title = {Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.},
journal = {Journal of clinical medicine},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/jcm15062357},
pmid = {41899281},
issn = {2077-0383},
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia and can be conceptualized as a tauopathy initiated by the accumulation of amyloid-β (Aβ) in the brain. The clinical introduction of anti-Aβ antibody therapies has marked the beginning of a new era in disease-modifying treatment for dementia. While the deleterious effects of Aβ on postsynaptic spines and axonal microtubules have been increasingly clarified, recent studies have shifted attention beyond extracellular Aβ deposition as senile plaques to the pathogenic significance of intracellular Aβ. In particular, accumulating evidence highlights lysosomes as critical sites of intracellular Aβ toxicity. Interactions between Aβ and gangliosides, v-ATPase-dependent lysosomal acidification, and lysosomal membrane integrity are the key determinants of disease progression. In parallel, additional molecular players, including components of the complement cascade and asparaginyl endopeptidase, have been implicated in linking Aβ pathology to tau dysregulation and neurodegeneration. As therapeutic strategies targeting Aβ enter clinical practice, these emerging pathways represent promising targets for the next generation of AD treatment. Here, we summarize current insights and ongoing therapeutic developments centered on these mechanisms.},
}

@article {pmid41899485,
year = {2026},
author = {Ramírez-Expósito, MJ and Cueto-Ureña, C and Martínez-Martos, JM},
title = {Neurotransmitter Systems in Alzheimer's Disease.},
journal = {Current issues in molecular biology},
volume = {48},
number = {3},
pages = {},
doi = {10.3390/cimb48030334},
pmid = {41899485},
issn = {1467-3045},
abstract = {Alzheimer's disease (AD), the leading cause of global dementia, is a multifactorial process that goes beyond the accumulation of β-amyloid (Aβ) plaques and tau protein tangles, including glia cell-mediated neuroinflammation, vascular dysfunction, metabolic alterations, and synaptic loss. Its complex etiology also involves oxidative stress and mitochondrial dysfunction. Multiple neurotransmitter systems involved in the pathogenesis and the various cognitive and non-cognitive symptoms of AD are thus altered. The cholinergic system, historically the first to be associated with AD, suffers early degeneration and loss of neurons/receptors, correlating with cognitive impairment. The glutamatergic system, the main excitatory system, exhibits excitotoxicity due to increased extracellular glutamate and alterations in NMDA/AMPA receptor distribution, exacerbating neuronal damage. The GABAergic system, the main inhibitor, shows alterations in parvalbumin-positive interneurons, leading to hyperexcitability and dysfunction of neuronal networks. Monoaminergic systems (serotonergic, dopaminergic and noradrenergic) undergo early degeneration in key nuclei such as the raphe and locus coeruleus, contributing to the apathy, depression and sleep disturbances characteristic of AD. Other less explored systems, such as histaminergic and purinergic, are also crucial in cognitive modulation and neuroinflammation. The endocannabinoid system acts as a master modulator with neuroprotective and anti-inflammatory effects. These systems do not operate in isolation; their complex interactions generate pathological circuits that amplify neuronal dysfunction. The limited efficacy of current therapies, which are primarily symptomatic, highlights the need for multimodal approaches that may transform AD treatment toward personalized and more effective interventions.},
}

@article {pmid41900050,
year = {2026},
author = {Lopes, LES and Oliveira, MR and Neto, RVB and Santos, TB and De Conto, JF and Oliveira, MBPP and Gomes, MZ and Santos, KS},
title = {Preclinical Evaluation of Tradescantia spathacea Phenolic Extract-Loaded Silica in a Parkinson's Disease Model.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {6},
pages = {},
doi = {10.3390/molecules31060950},
pmid = {41900050},
issn = {1420-3049},
support = {CNPq/MCTI Universal Project (Process No. 407015/2023-0, Call No. 10/2023 - UNIVERSAL)//National Council for Scientific and Technological Development/ ; UID/50006//the PT national funds (FCT/MECI) - Laboratório Associado para a Química Verde - Tecnologias e Processos Limpos/ ; },
mesh = {Animals ; *Plant Extracts/chemistry/pharmacology ; *Silicon Dioxide/chemistry ; Rats ; *Parkinson Disease/drug therapy ; Disease Models, Animal ; *Phenols/chemistry/pharmacology ; Rats, Wistar ; *Neuroprotective Agents/pharmacology/chemistry ; Male ; *Thymelaeaceae/chemistry ; },
abstract = {The current limitations in Parkinson's Disease (PD) treatments necessitate innovative approaches. To this end, phenolic compounds from Tradescantia spathacea (T. spathacea) and bioactive silica demonstrate potential therapeutic efficacy in the prevention or treatment of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Hence, this study explores the neuroprotective potential of silica loaded with T. spathacea extract (SiO2-TS) in a preclinical model of PD. The aqueous extract of T. spathacea (AETS) was prepared via infusion and characterized in terms of overall yield (21.9 ± 0.4%), total phenolic compounds (25.51 ± 2.39 mg GAE/g), and total flavonoid content (6.10 ± 0.16 mg RE/g). Silica loaded with AETS was synthesized and tested in adult Wistar rats (PD-like symptoms). The rats were treated with daily intranasal administration of SiO2-TS (10 or 30 mg/kg) for 15 days. Quantitative behavioral analysis showed significant motor improvement and reduced anxiety-like behavior in the 30 mg/kg SiO2-TS group compared to the 6-OHDA (6-hydroxydopamine) control. Immunohistochemistry revealed preserved dopaminergic neurons and reduced astrogliosis (GFAP expression) in the same SiO2-TS group. These results suggest SiO2-TS has significant neuroprotective effects and warrants further study for Parkinson's disease treatment.},
}

Animals
*Plant Extracts/chemistry/pharmacology
*Silicon Dioxide/chemistry
Rats
*Parkinson Disease/drug therapy
Disease Models, Animal
*Phenols/chemistry/pharmacology
Rats, Wistar
*Neuroprotective Agents/pharmacology/chemistry
Male
*Thymelaeaceae/chemistry

@article {pmid41900916,
year = {2026},
author = {Papaliagkas, V and Kalinderi, K and Moschou, M and Arnaoutoglou, M and Koutsouraki, E and Kimiskidis, VK},
title = {The Role of Transcranial Magnetic Stimulation for the Treatment of Alzheimer's Disease: A Narrative Review.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/life16030397},
pmid = {41900916},
issn = {2075-1729},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease that accounts for 60-80% of all dementia cases and affects millions of people worldwide. At present, standard drug therapies provide only limited symptomatic relief. Therefore, the exploration of novel therapeutic approaches is crucial for improving patient outcomes. Transcranial magnetic stimulation (TMS) has emerged as a promising non-invasive neuromodulation technique that may provide benefit in AD management. This review discusses the pathophysiological mechanisms by which TMS operates, evaluates its clinical efficacy in AD patients, assesses its safety profile, and suggests future directions for research.},
}

@article {pmid41901082,
year = {2026},
author = {Kumari, A and Zeng, XA},
title = {Dietary Bioactives in Alzheimer's Disease: A Critical Appraisal of Clinical Trials and Future Nutritional Strategies.},
journal = {Nutrients},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/nu18060907},
pmid = {41901082},
issn = {2072-6643},
support = {32172348//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease ; Humans ; *Dietary Supplements ; *Phytochemicals/therapeutic use/administration & dosage ; Clinical Trials as Topic ; Cognition/drug effects ; *Diet ; Biomarkers ; },
abstract = {Background: Alzheimer's disease (AD) remains a major public health challenge. Observational associations between dietary patterns and reduced dementia risk have prompted investigations of dietary bioactives (DBs) as cognitive nutraceuticals. Methods: This critical narrative review examines interventional trials for nine prominent DBs relevant to AD: docosahexaenoic acid (DHA), curcumin, resveratrol, epigallocatechin gallate (EGCG), nicotinamide riboside (NR), tricaprilin, vitamin E (α-tocopherol), cannabinoids, and NIC5-15 (D-pinitol). Trials were identified through ClinicalTrials.gov (search date: December 2024) and supplemented by PubMed searches for published results. Data were extracted on trial phase, design, cognitive/functional endpoints, biomarker outcomes, and development status. Findings are synthesized qualitatively; no formal meta-analysis or risk of bias assessment was conducted. Results: None of the nine bioactives demonstrated consistent cognitive efficacy in AD. Phase III trials of DHA, curcumin, and tricaprilin did not meet primary cognitive endpoints. Resveratrol reduced CSF Aβ40 without cognitive benefit. Cannabinoids improved behavioral symptoms but showed no measurable cognitive effects. High-dose vitamin E slowed functional decline, while cognition remained unchanged. In contrast, trials in preclinical or at-risk populations reported preliminary cognitive signals for EGCG and biomarker engagement for NR, suggesting potential for early intervention. Conclusions: Current clinical evidence does not support high-dose DBs supplementation as an effective treatment for AD. Predominantly negative late-phase findings highlight limitations, with potential contributors including limited bioavailability, late intervention, insufficient target engagement, and biological heterogeneity. Future research may benefit from early biomarker-defined populations, optimized formulations, multi-nutrient or dietary approaches, and precision nutrition strategies considering genetic risk and baseline nutrient status. DBs may be better positioned for prevention or early-stage intervention rather than late-stage therapy.},
}

*Alzheimer Disease
Humans
*Dietary Supplements
*Phytochemicals/therapeutic use/administration & dosage
Clinical Trials as Topic
Cognition/drug effects
*Diet
Biomarkers

@article {pmid41886893,
year = {2026},
author = {Wang, M and Zhang, B and Guo, R and Wang, H and Wu, D and Peng, X and Guo, H and Duan, J and Yang, W and Ren, P and Zhang, S},
title = {Restoration of autophagy-lysosomal function via transcranial focused ultrasound stimulation ameliorates β-amyloid pathology and cognitive deficits in an Alzheimer's disease model.},
journal = {Ultrasonics},
volume = {165},
number = {},
pages = {108075},
doi = {10.1016/j.ultras.2026.108075},
pmid = {41886893},
issn = {1874-9968},
abstract = {Transcranial focused ultrasound (FUS) is a non-invasive neuromodulation technique that regulates intracellular functions and treats brain disorders. In Alzheimer's disease (AD), impaired autophagy-lysosomal pathway (ALP) function leads to the accumulation of β-amyloid (Aβ). However, the potential of FUS alone to alleviate AD pathology by restoring ALP function remains unexplored. In this study, sixteen male transgenic mice with five familial Alzheimer's disease mutations (5×FAD) received bilateral FUS targeting the hippocampus and were compared with sixteen age-matched untreated male 5×FAD mice. Cognitive function was evaluated using behavioral tests, and Aβ pathology was analyzed by immunofluorescence. RNA sequencing, western blotting, and electron microscopy were employed to assess the effects of FUS on the ALP. The results indicated that FUS reduced Aβ deposition and ameliorated cognitive deficits. Compared with the AD group, FUS treatment significantly reduced escape latency by 40.9% (p = 0.010), increased the novel object recognition index by 38.2% (p = 0.016), and increased spontaneous alternation by 18.2% (p = 0.009). Critically, FUS enhanced lysosomal biogenesis and improved autophagosome-lysosome fusion, increasing colocalization efficiency from 28.07 ± 3.73% to 53.22 ± 4.85% in the cortex (p = 0.009) and from 31.95 ± 3.65% to 48.00 ± 2.18% in the hippocampus (p = 0.026). It also promoted the nuclear translocation of transcription factor EB (TFEB). Moreover, the ALP antagonist chloroquine (CQ) suppressed the beneficial effects of FUS, indicating that FUS exerts therapeutic effects in an ALP-dependent manner. Our findings demonstrate that restoring ALP via FUS is a crucial mechanism for mitigating Aβ pathology.},
}

@article {pmid41889233,
year = {2026},
author = {Santos, LRC and de Almeida, JNB and Frias, CC and Almeida, WP and Maistro, EL},
title = {Evaluation of DNA/Chromosome Integrity and Cell Death in Human Metabolically Noncompetent and Competent Cells Exposed to N'-(3,5-Difluorobenzylidene)Pyridine-4-Carbohydrazide.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70171},
pmid = {41889233},
issn = {1099-1263},
support = {Finance code 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 303604/2021-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Universidade Estadual Paulista/ ; },
abstract = {The N-acylhydrazone scaffold is recognized as a privileged structure for the design of bioactive substances with increasing applications in medicinal chemistry research. Ensuring the safety of newly developed molecules is a critical step for both human health and environmental protection. Accordingly, this study aimed to evaluate the cytotoxic and genotoxic properties of N'-(3,5-difluorobenzylidene)pyridine-4-carbohydrazide in two cellular models: nonmetabolizing leukocytes and metabolically active hepatic cells (HepG2/C3A). The resazurin-based cytotoxicity analysis, performed with concentrations between 1 and 600 μg/mL, indicated that only the uppermost concentration caused a marked decrease in viability of both cell populations after 48 h of incubation. Regarding genotoxicity at 50, 100, and 200 μg/mL concentrations, no DNA damage was detected in the comet assay, but in the micronucleus test, a significant increase in chromosome alterations in leukocytes at 200 μg/mL concentration was detected, with a decrease in cell proliferation in both cell types. The data indicate that, at the concentrations where the biological effects of acylhydrazone were previously observed, the substance appeared to be safe, but at higher concentrations and/or during chronic exposure, caution and further studies are needed.},
}

@article {pmid41889929,
year = {2026},
author = {Shi, Y and Rozen, SD and Swint, JT and McRoberts, WA and McCurry, SN and Salinas, R and Moffett, EG and Pollock, CM and Goldstein, LR and Katzev, SS and Carter, ME and Bloom, GS and Güler, AD},
title = {LiFE, a multimodal circadian intervention, improves sleep, glycemic control, and recognition memory.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711428},
pmid = {41889929},
issn = {2692-8205},
abstract = {In mammals, sleep is regulated by the central circadian system, which responds to environmental timing cues including light, exercise and availability of food. In this study, we developed a light-, food-, and exercise-based daily lifestyle intervention (LiFE) that combines the effects of multiple circadian entrainment cues on central clock function, ultimately strengthening central clock rhythms. In wild-type (WT) mice, LiFE consolidated nocturnal activity, enhanced suprachiasmatic nucleus rhythmicity, and increased sleep time. Despite comparable caloric intake to control conditions, LiFE lowered baseline blood glucose, reduced glycemic variability, and improved glucose tolerance. We found long-term LiFE treatment improved recognition memory in WT mice. Sleep and circadian disruption are commonly observed in patients with Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. We applied long-term LiFE treatment in two AD mouse models (5xFAD and 5xFAD/PS19). Alongside a subtle reduction in AD histopathology, LiFE produced near-significant trends toward improved motor performance and recognition memory. Together, these findings support multimodal circadian chronotherapy as a non-pharmacological approach in which integrated light, feeding, and exercise entrainment promotes sleep and metabolic health.},
}

@article {pmid41890202,
year = {2026},
author = {Zhu, T and Cai, L and Hu, L and Yang, D and Li, M and Quan, F and Lu, C and Liu, S and Cui, J},
title = {Cognitive improvement by non-pharmacological electrical stimulation modalities in mild cognitive impairment: a protocol for systematic review and network meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1752516},
pmid = {41890202},
issn = {1663-4365},
abstract = {OBJECTIVE: Mild cognitive impairment, characterized by progressive cognitive decline, represents a prevalent transitional state among the global aging population and demonstrates high conversion rates to Alzheimer's disease, establishing itself as a critical window for preventive interventions against AD. Although growing evidence supports the efficacy of various non-pharmacological therapies in enhancing cognitive function, their comparative effectiveness remains insufficiently elucidated. This study aims to analyze the efficacy and safety of different electrical stimulation modalities in treating MCI patients, quantitatively compare the therapeutic benefits across multiple interventions, and provide evidence-based recommendations to facilitate informed clinical decision-making.

METHODS: We will systematically search 13 databases. All relevant studies published from inception until November 1, 2025, will be retrieved. Two reviewers will independently assess the risk of bias for all included studies using the revised Cochrane Risk of Bias tool (RoB 2). The primary outcome will be the Montreal Cognitive Assessment score to evaluate changes in cognitive function. Secondary outcomes will include neuropsychological assessments related to cognition, such as the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), as well as the modified Barthel Index for activities of daily living and the patient-reported Pittsburgh Sleep Quality Index. Data synthesis will be performed using Stata software, employing a random-effects network meta-analysis model to compare the efficacy and safety of non-pharmacological electrical stimulation therapies. The surface under the cumulative ranking curve (SUCRA) will be used to estimate the probability of intervention hierarchies. The strength of evidence will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations framework.

CONCLUSION: This study will synthesize evidence from multiple studies on various electrical stimulation therapies for improving cognitive function in patients with mild cognitive impairment, thereby providing a diverse body of evidence to support clinical decision-making by physicians and optimization of treatment strategies for patients.

STUDY PROTOCOLS REGISTRATION: [https://www.crd.york.ac.uk/prospero/], identifier [CRD420251184505].},
}

@article {pmid41891120,
year = {2026},
author = {Grande, I and Schmidt, SN and Reines, E and Christensen, MC},
title = {Vortioxetine in Subgroups of Patients with Major Depressive Disorder and Early-Stage Dementia: Further Results from the MEMORY Study.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {549106},
pmid = {41891120},
issn = {1176-6328},
abstract = {BACKGROUND: Depression and dementia are common in older adults; however, many antidepressants have limited effectiveness in patients with major depressive disorder (MDD) comorbid with dementia. In the MEMORY study (NCT04294654), significant improvements in depressive symptom severity, cognitive performance, overall functioning, and health-related quality of life were seen in patients with MDD and early-stage dementia during treatment with vortioxetine. This subgroup analysis was undertaken to further explore the effectiveness of vortioxetine in this patient population.

METHODS: MEMORY was a multinational, open-label, Phase IV study. Patients (n = 82) aged 55-85 years with MDD and early-stage dementia were treated with vortioxetine (5-20 mg/day) for 12 weeks. This was a post-hoc analysis for four key subgroups of patients in this study: (i) those with Alzheimer's disease (n = 35), (ii) those with mixed-type dementia (n = 22), (iii) those receiving concomitant drugs for dementia (n = 34), and (iv) those with severe depression (Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≥30) at baseline (n = 42).

RESULTS: Significant improvement in depressive symptom severity was seen in all patient subgroups from week 1 onwards (P < 0.05). At week 12, the mean change from baseline ranged from approximately -12 to -14 for MADRS total score (P < 0.0001), -6 to -8 for MADRS anhedonia subscore (P < 0.0001), and +3 to +6 for Digit Symbol Substitution Test score (P < 0.05). Improvements in verbal memory, ability to perform activities of daily living, health-related quality of life, and overall disease severity were also observed in all patient subgroups.

CONCLUSION: Our findings provide further support for the effectiveness and tolerability of vortioxetine in patients with MDD and early-stage dementia. Clinically significant improvement in depressive symptoms, cognitive performance, and health-related quality of life during treatment with vortioxetine was observed in patients with Alzheimer's disease, those with mixed-type dementia, patients receiving concomitant treatment with drugs for dementia, and those with severe depression.},
}