@article {pmid42307825,
year = {2026},
author = {Li, Y and He, X},
title = {Single-cell Transcriptomics Reveals that the SORBS1/FBXO22/BAG3 Axis Drives Astrocyte Senescence via Calcium Signaling and Affects Alzheimer's Disease-Related Neuronal Damage.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42307825},
issn = {1559-1174},
mesh = {*Astrocytes/pathology/metabolism/physiology ; *Alzheimer Disease/pathology/metabolism/genetics ; *Cellular Senescence/genetics ; Humans ; *Neurons/pathology ; *Calcium Signaling/physiology/genetics ; *Adaptor Proteins, Signal Transducing/physiology/genetics ; Amyloid beta-Peptides/pharmacology/toxicity ; *Inhibitor of Apoptosis Proteins/physiology/genetics ; Animals ; Single-Cell Analysis ; Coculture Techniques ; Senescence-Associated Secretory Phenotype/genetics ; Single-Cell Gene Expression Analysis ; Cells, Cultured ; *Nerve Tissue Proteins/physiology/genetics ; Ubiquitination ; Transcriptome ; },
abstract = {In Alzheimer's disease (AD), senescent astrocytes fuel neuroinflammation and neuronal damage via the senescence-associated secretory phenotype (SASP). Calcium signaling plays a crucial role in this process, but the underlying molecular mechanisms remain elusive. We retrieved scRNA-seq data from the Gene Expression Omnibus (GEO) for AD and control brains. After cell-type annotation, we resolved astrocyte sub-clusters. Pseudotime trajectory and differential-expression analyses identified SORBS1 as a key senescence-related gene, which we followed with gene-set enrichment analysis. Next, we established an in vitro AD model by treating astrocytes with amyloid-β (Aβ). We evaluated astrocyte senescence using SA-β-gal staining, qRT-PCR, Western blot (WB) for senescence markers, and ELISA for SASP cytokines. We measured concentration of Ca[2+] with Fluo-4 AM probes. Subsequently, bioinformatic screening predicted FBXO22 as an interactor of SORBS1 and BAG3 as a ubiquitination substrate of FBXO22. We validated these interactions using Co-IP and in vitro ubiquitination assays. Finally, we constructed an astrocyte-neuron co-culture model. We detected neuronal cell viability, AChE activity, AD phenotype-related protein expression, apoptosis, and levels of inflammatory factors using MTT assay, specific kits, WB, flow cytometry, and ELISA, respectively, to assess neuronal damage. ScRNA-seq analysis revealed a marked reduction in astrocyte expression in AD brains, which may result from cellular senescence. The SASP gene SORBS1 was selectively up-regulated in astrocytes and significantly enriched in calcium-signaling pathways. Functional assays confirmed that SORBS1 accelerated astrocyte senescence. Mechanistically, SORBS1 interacted with FBXO22 to promote the ubiquitin-dependent degradation of BAG3, thereby amplifying calcium signaling, accelerating astrocyte senescence, and contributing to AD-related neuronal damage. We uncover a novel mechanism by which the SORBS1/FBXO22/BAG3 axis drives astrocyte senescence through the regulation of calcium signaling, thereby influencing AD-related neuronal damage. This finding provides a potential therapeutic target for AD treatment by targeting astrocyte senescence.},
}

*Astrocytes/pathology/metabolism/physiology
*Alzheimer Disease/pathology/metabolism/genetics
*Cellular Senescence/genetics
Humans
*Neurons/pathology
*Calcium Signaling/physiology/genetics
*Adaptor Proteins, Signal Transducing/physiology/genetics
Amyloid beta-Peptides/pharmacology/toxicity
*Inhibitor of Apoptosis Proteins/physiology/genetics
Animals
Single-Cell Analysis
Coculture Techniques
Senescence-Associated Secretory Phenotype/genetics
Single-Cell Gene Expression Analysis
Cells, Cultured
*Nerve Tissue Proteins/physiology/genetics
Ubiquitination
Transcriptome

@article {pmid42307826,
year = {2026},
author = {Soni, S and Sarkar, S and Tripathi, P and Maurya, S and Kaur, G and Haque, S},
title = {Neuroinflammation mediated repurposing of clemastine for Alzheimer's disease through network pharmacology, molecular dynamics, and experimental validation studies.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42307826},
issn = {1568-5608},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with significant involvement of neuroinflammation, for which the current interventions are limited in efficacy. Certain antihistamines such as clemastine have neuroprotective properties beyond H1 receptor antagonism, including anti-inflammatory, antioxidant, remyelinating effects, modulates neuroinflammatory pathways. This study aims to investigate the neuroprotective potential of clemastine via in silico and in vivo studies for repurposing against AD.

METHODOLOGY: In silico analyses involved network pharmacology, molecular docking, and 100-ns molecular dynamic simulations along with principal component analysis and binding free energy calculations. Whereas, experimental studies involved treatment of clemastine (5 mg/kg and 10 mg/Kg, p.o.) for 14 days in lipopolysaccharide-induced neuroinflammatory (250 µg/Kg, i.p.) rat. Behavioral assessment was performed using Morris water maze (MWM) test. Biochemical parameters including acetylcholinesterase (AChE) activity, oxidative stress markers (MDA, SOD, CAT, GSH), and inflammatory biomarkers (NLRP3, TNF-α, IL-1β) were evaluated. Histopathological analysis of hippocampal CA3 region was performed using Nissl's staining.

RESULTS: Network analysis identified 52 overlapped targets between clemastine and AD. Hub genes such as GSK3β, DRD1, DRD2, CHRNA4, and SLC6A4 were associated with neurotransmission and kinase signaling pathways. Enrichment analysis highlighted PI3K/Akt, MAPK, and neuroactive ligand-receptor interaction pathways. Molecular docking and molecular dynamic simulations confirmed stable binding of clemastine with GSK-3β, PI3K, and NLRP3 proteins. Animal model studies demonstrated that clemastine significantly improved cognitive performance in MWM (p < 0.001), reduced AChE level (p < 0.0001), restored antioxidant enzyme levels, suppressed inflammatory mediators (p < 0.0001), and preserved hippocampal neuronal structure.

CONCLUSION: The study provides novel integrative evidence linking its antihistaminic action with simultaneous regulation of neuroinflammation through multi-target modulation of inflammation, oxidative stress, and neuronal signaling pathways, highlighting its potential as a promising repurposed therapeutic candidate for AD.},
}

@article {pmid42307833,
year = {2026},
author = {Sood, S and Singh, S and Singh, TG},
title = {PCSK9 in bridging metabolism and neurodegeneration: a new paradigm for alzheimer's treatment.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42307833},
issn = {1573-7365},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Proprotein Convertase 9/metabolism ; Animals ; Cholesterol/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; *Nerve Degeneration/metabolism ; },
abstract = {Proprotein convertase subtilisin-kexin type 9 (PCSK9) has recently emerged as a significant mediator that links metabolic dysfunction to neurodegeneration related to Alzheimer's disease (AD). It is a well-known and crucial component involved in cholesterol homeostasis. However, its function in the central nervous system (CNS) is still in its early stages. Normally, it is engaged with the breakdown of cholesterol in the body, but within the brain, PCSK9 has been seen to disrupt the homeostasis of cholesterol and its uptake. Receptors such as LDL receptor-related protein-1 (LRP-1) and low-density lipoprotein receptor (LDLR) are crucial for the survival of neurons, as they are responsible for the clearance of amyloid-β (Aβ) and peripheral lipid control. Elevated PCSK9 activity may promote degradation of these receptors, which eventually leads to deposition of Aβ near synapses along with reduced uptake of cholesterol by neurons, which may contribute to neurotoxicity and neuronal dysfunction. This review aims to explore the effect of elevated PCSK9 levels on the development as well as exacerbation of AD via different molecular mechanisms. Along with cholesterol dyshomeostasis, PCSK9 is found to be involved in glucose dysregulation, mechanistic target of rapamycin (mTOR) dysregulation, increased oxidative stress, neuroinflammation, reduced neurogenesis, affected Wnt-β-catenin signaling, and cholinergic signaling. Together, these mechanisms may contribute to AD progression. Preclinical studies show that pharmacological therapies targeting PCSK9 can give promising results by reducing neuroinflammation, modulating lipid homeostasis, and lowering Aβ accumulation. Therefore, modulation of PCSK9 represents a promising therapeutic strategy that warrants further mechanistic and clinical investigation in AD.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Proprotein Convertase 9/metabolism
Animals
Cholesterol/metabolism
Amyloid beta-Peptides/metabolism
*Brain/metabolism
*Nerve Degeneration/metabolism

@article {pmid42308766,
year = {2026},
author = {Kam, MK and Kim, JW and Choi, JY and Koh, YH and Jo, C},
title = {HSP90 is involved in curcumin-mediated inhibition of tau aggregation.},
journal = {Biochemical and biophysical research communications},
volume = {829},
number = {},
pages = {154140},
doi = {10.1016/j.bbrc.2026.154140},
pmid = {42308766},
issn = {1090-2104},
abstract = {Tau aggregation in neurons is a pathological hallmark of Alzheimer's disease (AD). The development of therapeutic drugs that inhibit tau aggregation in tauopathies, including AD, remains challenging. Herein, we developed a tau self-interaction reporter system using split Nanoluciferase (Tau-NLuc) in which luciferase activity is restored by the self-assembly of split Nanoluciferases following self-interaction between tau proteins. Curcumin (CCM), a phenolic organic compound, significantly reduced luciferase activity in the Tau-NLuc system, including mutant tau forms such as S396/404E and P301L, which are known aggregation-prone tau forms, suggesting that CCM may act as a potential inhibitor of tau aggregation. CCM did not alter the protein levels of phosphorylated tau as well as total tau, indicating that the reduction in luciferase activity by CCM did not originate from tau degradation, but rather from tau aggregation inhibition. Of note, CCM significantly increased heat shock protein (HSP) 90 dimer. The reduced luciferase activity in the Tau-NLuc system by CCM was recovered by knockdown of the HSP90 gene using a siRNA specific for HSP90 or treatment of an inhibitor of HSP90 NCT-58, supporting the involvement of HSP90. Intriguingly, hexahydrocurcumin (HHC), a derivative of CCM, did not reduce luciferase activity, nor did it induce the formation of the HSP90 dimer, suggesting that HSP90 dimer formation may contribute to the CCM-mediated inhibition of tau aggregation. Taken together, the results demonstrate that CCM inhibits tau aggregation with the involvement of HSP90, providing novel insights into the development of therapeutic strategies for AD.},
}

@article {pmid42309020,
year = {2026},
author = {Milà-Alomà, M and Hausle, I and Petersen, KK and Thropp, P and Schindler, SE and Tosun, D and , },
title = {The time interval from amyloid to tau PET positivity varies by age, sex and APOE-ε4 status.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100622},
doi = {10.1016/j.tjpad.2026.100622},
pmid = {42309020},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials.

OBJECTIVES: To investigate how the estimated age at amyloid and tau PET positivity, and the time interval between these two key events ("amyloid-tau time interval"), relate to symptom onset and clinical progression, and to assess the effects of APOE-ε4 status and sex on these associations.

DESIGN: This analysis used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Harvard Aging Brain Study (HABS).

SETTING: The ADNI is a multicenter observational cohort conducted at 55 sites across the United States; The HABS is a longitudinal, single-center observational cohort.

PARTICIPANTS: This study included participants with at least one positive amyloid PET scan (ADNI n = 792; HABS n = 104) or at least one positive tau PET scan (ADNI n = 212; HABS n = 48). All participants had information on sex, APOE-ε4 status, and longitudinal cognitive assessments.

MEASUREMENTS: We examined the influence of APOE-ε4 status, sex, and their interaction on the estimated age at biomarker positivity and the amyloid-tau time interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset (CDR > 0) based on estimated biomarker positivity age and the amyloid-tau time interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline, as measured by CDR-SB, over five years following symptom onset according to estimated biomarker positivity age and amyloid-tau time interval. Additional models included interaction terms with sex or APOE-ε4 status.

RESULTS: The amyloid-tau time interval varied markedly between individuals and was shorter in APOE-ε4 carriers, women, and those with older age at amyloid PET positivity. APOE-ε4 carriers and women became amyloid and tau PET positive at younger ages. Following amyloid PET positivity, a shorter time to tau PET positivity predicted earlier symptom onset. After symptom onset, faster cognitive decline was observed in individuals with younger ages at amyloid or tau PET positivity. The time to symptom onset following tau PET positivity, or the rate of cognitive decline after symptom onset, were not influenced by the amyloid-tau time interval.

CONCLUSIONS: After becoming amyloid PET positive, APOE-ε4 carriers, women and older individuals may have a shorter window for detection and treatment before they become tau PET positive and develop symptoms. These findings should guide the identification of individuals at highest risk of rapid AD progression, enabling more efficient participant selection for clinical trials.},
}

@article {pmid42309609,
year = {2026},
author = {Mia, M and Dutta, A and Hossain, MM and Adhikari, J and Rahman, MM and Shibly, AZ},
title = {Exploring the neuroprotective, antioxidant, and anti-amyloid effects of Ganoderma lucidum compounds in Alzheimer's disease: insights from experimental and computational approaches.},
journal = {Journal, genetic engineering & biotechnology},
volume = {24},
number = {2},
pages = {100706},
pmid = {42309609},
issn = {2090-5920},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation and oxidative stress, with limited effective therapeutic options. This study evaluated the antioxidant, neuroprotective, and anti-amyloidogenic potential of Ganoderma lucidum, medicinal mushroom rich in bioactive compounds, including triterpenoids and sterols. Antioxidant activity was assessed using the DPPH assay, and neuroprotective effects were examined in Caenorhabditis elegans models (N2 and CL4176). The anti-Aβ potential of selected bioactive compounds was investigated through molecular docking, molecular dynamics simulations, and MM/GBSA analysis, along with ADMET predictions. The extract exhibited strong antioxidant effects, achieving 96.3% scavenging at 0.25 mg/mL. In C. elegans, treatment enhanced survival under oxidative stress by 25% at 0.5 mg/mL (p < 0.01) and delayed Aβ-induced paralysis, with 17.82% of worms remaining active at 68 h. Docking studies identified Epoxyganoderiol C (-7.8 kcal/mol), 5,6-Dihydroergosterol (-7.9 kcal/mol), and Ganoderiol A (-7.7 kcal/mol) as potent Aβ inhibitors, stabilized in molecular dynamics simulations with favorable RMSD, RMSF, Rg, and SASA profiles. MM/GBSA analysis confirmed strong binding affinities for 5,6-Dihydroergosterol, Epoxyganoderiol C, and Ganoderiol A against Aβ, with ΔG_bind values of - 71.66, -56.42, and - 45.45 kcal/mol, respectively. ADMET predictions indicated good drug-likeness, high gastrointestinal absorption, and no toxicity risks. In conclusion, G. lucidum extract demonstrated potent antioxidant and neuroprotective effects, while its bioactive key compounds-Epoxyganoderiol C, 5,6-Dihydroergosterol, and Ganoderiol A-showed favorable binding affinity and stability with Aβ, along with acceptable pharmacokinetic profiles. These findings suggest that G. lucidum and its bioactive constituents may serve as promising natural candidates for AD therapy.},
}

@article {pmid42310298,
year = {2026},
author = {Diaz Escarcega, R and M J, VK and Arizmendez, A and Tan, C and Urayama, A and Marrelli, SP and Morales, R and Wefel, JS and Zhang, C and McCullough, LD and Kim, N and Monchaud, D and Jung, SY and Tsvetkov, AS},
title = {Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08971-z},
pmid = {42310298},
issn = {2041-4889},
support = {4R01AG068292//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AFAR BIG21042//Glenn Family Foundation/ ; AFAR BIG21042//American Federation for Aging Research (American Federation for Aging Research, Inc.)/ ; },
abstract = {G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in male and female neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.},
}

@article {pmid42310327,
year = {2026},
author = {Varga, BT and Ernyey, AJ and Tajti, BT and Gáspár, A and Demeter, Z and Kollár, L and Kovács, P and Albert, M and Alpár, A and Gyertyán, I},
title = {Translational difficulties in establishing a pharmacologically induced neurovascular uncoupling model in rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58244-0},
pmid = {42310327},
issn = {2045-2322},
abstract = {Neurovascular uncoupling (NVU) contributes to neurological disorders like Alzheimer's disease. While a mouse NVU model exists, a reliable rat model critical for cognitive research remains underdeveloped. To address this methodological gap, we investigated a pharmacological approach in rats using the same drugs (N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH), L-NG-nitroarginine methyl ester (L-NAME), indomethacin) that proved to be efficacious in mice. The compounds were formulated as a cocktail solution and administered intraperitoneally for 13 days to aged, cognitively experienced Long-Evans rats. Our goal was to induce NVU while minimizing adverse systemic effects seen previously (e.g., hypertension, intestinal ulceration). The treatment induced only a modest (28%, non-significant) reduction in cerebral hyperaemia, with decreased prostaglandin E2 levels but unchanged 11,12-epoxyeicosatrienoic acid concentration in the brain. Cognitive effects were limited-transient impairment in the 5-choice task but no changes in spontaneous alternation, visual discrimination, cooperation, or motor learning. Significant adverse effects emerged: reduced food intake, weight loss, gastrointestinal malaise, and moderate renal toxicity. Our findings specifically highlight the challenges of achieving sufficient and symptomatically apparent NVU while minimizing systemic toxicity. While partial NVU occurred, this polypharmacy approach had major limitations. A reliable, industrially applicable rat NVU model remains urgently needed to accelerate antidementia drug development.},
}

@article {pmid42311340,
year = {2026},
author = {Li, G and Jiao, S and Zhou, Y and Cheng, X},
title = {Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: theoretical foundations, regulatory suspension, and translational challenges.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1849207},
pmid = {42311340},
issn = {2673-6217},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological changes in β-amyloid protein deposition, abnormal tau protein phosphorylation neurofibrillary tangles, and chronic neuroinflammation. Recent studies have shown that the glymphatic-meningeal-cervical lymphatic system pathway plays a crucial role in the clearance of intracranial metabolic waste. Dysfunction of this system may lead to a decrease in the clearance efficiency of Aβ and tau proteins. Deep cervical lymphaticovenous anastomosis (DCLVA) has been proposed as a novel surgical approach to enhance cervical lymphatic drainage, reduce Aβ/tau accumulation, and improve cognitive function in patients with AD. However, on 8 July 2025, the National Health Commission of China issued a notice prohibiting the clinical application of "deep cervical lymphaticovenous anastomosis" for the treatment of AD. This article provides a narrative review with critical appraisal of the theoretical basis, surgical mechanisms, and clinical evidence of DCLVA for AD. We objectively evaluate the strengths and limitations of current clinical studies, critically appraise the uncertainty of underlying physiology, and comprehensively analyze the potential risks, safety concerns, and translational obstacles that led to regulatory suspension. We further clarify unresolved scientific questions including pressure gradients, lymphatic contractility, reflux risk, anastomotic patency, and biomarker validation. By framing DCLVA within the context of its clinical prohibition, we provide clinicians and researchers with a balanced appraisal that acknowledges both the procedure's potential and the substantial gaps that must be addressed before widespread application can be justified.},
}

@article {pmid42299852,
year = {2026},
author = {Beh-Pajooh, A},
title = {Identification of candidate diagnostic biomarkers and gene networks for moderate stages of Alzheimer's disease in fusiform gyrus exhibiting neurofibrillary tangles.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452277},
doi = {10.1177/13872877261452277},
pmid = {42299852},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder whose incidence grows with age and its development is gradual. However, if detected earlier there is much hope to prevent further exacerbation. In this study, NGS transcriptomics data from cases and controls with Braak scores of III-IV were investigated that all possessed neurofibrillary tangles (NFTs) in their fusiform gyrus.ObjectiveThe aim of this study was to discover the underlying mechanisms at gene level which could explain cognitive impairment by considering the presence of NFTs in both groups.MethodsDifferentially expressed genes (DEGs) were determined and ROC AUC were evaluated by leave-one-out cross-validation method on the diagnostic DEGs to detect candidate gene biomarkers. WGCNA was employed to identify co-expression modules with their trait association. Finally, in silico hybridization of lncRNAs from potential biomarkers with important AD-related microRNAs was carried out.ResultsHighly ranked potential diagnostic gene biomarkers revealed assessed AUC ranges of 80-90% in which RASGRF2-AS1 demonstrated the highest value. WGCNA demonstrated upregulated genes in favor of dephosphorylation of tau, proper proteostasis and vascular health in resilient controls whereas dysfunctional proteostasis, chronic protein misfolding, heightened cellular stress and tetrahydrobiopterin deficiency were attributed to cognitive impairment in AD patients. In silico analyses predicted some lncRNAs with a high possibility of acting as sponge for AD-related microRNAs.ConclusionsThis study discovered potential diagnostic gene biomarkers and transcriptional signatures that could explain the mechanisms of cognitive decline by considering the existence of NFTs, which could provide further insight for diagnosis and treatment of the disease.},
}

@article {pmid42300138,
year = {2026},
author = {Wolf, EJ and Zhao, X and Hao, S and Lawhorn, C and Carbaugh, J and Fortier, CB and Milberg, WP and Logue, MW and Miller, MW},
title = {PTSD Severity-Related Accelerated Aging, Hippocampal Volume, and CLDN5 DNA Methylation.},
journal = {Biopsychosocial science and medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001501},
pmid = {42300138},
issn = {2998-8756},
abstract = {OBJECTIVE: The claudin-5 (CLDN5) gene is critical for blood brain barrier integrity and may link traumatic stress, accelerated aging, and neurological disease. Building on prior research showing associations between trauma exposure and PTSD with CLDN5 DNA methylation (DNAm), we tested if candidate CLDN5 DNAm loci were associated with advanced epigenetic aging in blood and brain tissue and with hippocampal volume.

METHODS: 1302 trauma-exposed individuals (Mage=44.23, SD=13.71; 76% male) underwent psychiatric diagnostic interviews and blood draws for obtaining epi/genetic information; 473 underwent magnetic resonance imaging of the brain. Data from 109 PTSD brain bank decedents with DNAm from ventromedial prefrontal cortex (vmPFC) were also examined (Mage-at-death=45.20, SD=14.21; 62% male).

RESULTS: All candidate loci were associated with metrics of epigenetic age in blood (p-adj range: .0396 to 4.5e-05) and these associations largely extended to postmortem vmPFC. There was an indirect association between PTSD severity and CLDN5 DNAm in blood at cg21872764 via GrimAge residuals (indirect β=.033, P=.040) that was diminished when the direct PTSD association was modeled. The CLDN5 probe cg17411190 in blood was negatively related to left and right hippocampal volume (p-adj=.042) and with volume of multiple hippocampal substructures. The association between PTSD severity and hippocampal volume was indirect via blood DNAm at cg17411190 (indirect β=-.011, P=.045).

CONCLUSIONS: PTSD severity-related accelerated aging may be associated with altered CLDN5 DNAm, which may signal neurodegeneration, such as reduced hippocampal volume. CLDN5 DNAm in blood may serve as a useful proxy for brain CLDN5 DNAm. Given that prior environmental enrichment and antidepressant studies show initial efficacy in altering CLDN5 expression, future studies could evaluate if PTSD treatment alters CLDN5 epigenetics and reduces risk for neurodegeneration.},
}

@article {pmid42300608,
year = {2026},
author = {Khorrami, S and Alifarsangi, A and Mohammed, LJ and Amshawee, AM and Zarrabi, A},
title = {Metal-based nanoparticles' potential in Alzheimer's disease diagnosis, therapy and theranostics.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5nr04613k},
pmid = {42300608},
issn = {2040-3372},
abstract = {Metal-based nanoparticles are emerging as a versatile platform to overcome critical challenges in the diagnosis and treatment of Alzheimer's disease (AD). This review provides a comprehensive synthesis of recent advances, structured around the three core domains of AD management: diagnostics, therapeutics, and theranostics. We discuss how the unique physicochemical properties of metals and metal oxides enable highly sensitive biosensing of amyloid and tau biomarkers, as well as high-contrast imaging modalities. The review then evaluates strategies for engineering metal-based nanoparticles to bypass the blood-brain barrier and achieve targeted accumulation, alongside their therapeutic roles in drug delivery, photothermal therapy, and modulating protein aggregation. Finally, we assess integrated theranostic systems that combine real-time imaging with targeted intervention. The key conclusion is that platforms based on metal-based nanoparticles, through their multifunctionality, offer a realistic pathway toward minimally invasive early diagnosis and targeted therapy. However, the field's future direction must prioritize rigorous standardization and advanced preclinical validation to translate these promising nanotechnologies from bench to bedside, ultimately advancing precision neurotheranostics for AD.},
}

@article {pmid42300721,
year = {2026},
author = {Song, BX and Schecter, J and Vieira, E and Gallagher, D and Diniz, BS and Fischer, CE and Flint, AJ and Herrmann, N and Kennedy, JL and Mah, L and Mulsant, B and Pollock, BG and Rajji, TK and Ma, C and Lanctôt, KL and , },
title = {Angiogenesis markers and cognitive response in a randomized trial of cognitive remediation plus transcranial direct current stimulation in older adults at risk of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457934},
doi = {10.1177/13872877261457934},
pmid = {42300721},
issn = {1875-8908},
abstract = {BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions.ObjectiveTo determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia.MethodsNineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up.ResultsIn 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment (β(SE) = 0.17(0.08), p = 0.04, padj = 0.11, f[2] = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up (χ[2]LRT(3) = 24.9, p < 0.001).ConclusionsLower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS.ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670; NCT02386670.},
}

@article {pmid42300919,
year = {2026},
author = {Peesapati, S and Chakraborty, S},
title = {Modeling the organizational heterogeneity of cholesterol-enriched microdomains in the neuronal membranes of gray and white matter of Alzheimer's brain: a computational lipidomics study.},
journal = {Soft matter},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6sm00153j},
pmid = {42300919},
issn = {1744-6848},
abstract = {Alzheimer's disease (AD) is a leading cause of death among the elderly, with no existing treatment. The development of therapies is further hindered by a limited understanding of the molecular pathogenesis and the absence of reliable early-detection biomarkers. Neuroimaging and lipidomic studies reveal structural and biochemical alterations in both gray and white matter in AD patients, including disruptions in membrane organization and neuronal signaling pathways. In the present work, we employed lipidomics-guided modeling of membranes in gray and white matter regions under healthy and diseased (AD) conditions, and used all-atom molecular dynamics (MD) simulations to examine how AD-associated alterations in lipid composition influence the structure, spatial organization, and micro-heterogeneity of neuronal plasma membranes. The data suggest that Alzheimer's disease-associated lipid alterations in gray matter (GM) and white matter (WM) impact membrane thickness and microdomain distribution, highlighting the critical role of lipid composition in maintaining neuronal membrane homeostasis and function. Higher-order cholesterol-ceramide-sphingomyelin-enriched domains are more abundant in the neuronal membranes of the GM region under diseased conditions. Under AD-mimicking conditions, lipidomic analyses demonstrate that neuronal membranes in GM experience more substantial compositional and structural remodeling than those in WM. Our results show significant changes in membrane microdomain distribution across the lipid bilayers, and, interestingly, these changes are more pronounced in the gray matter than in the white matter. This study establishes a framework for modeling the tissue-specific lipidomics data to understand how disease-driven compositional changes affect the structure, organization, and dynamics of biological membranes.},
}

@article {pmid42301522,
year = {2026},
author = {Welikovitch, LA and Oakley, DH and Bennett, RE and Serrano-Pozo, A and Zhu, H and Ruiz-Uribe, NE and Zwang, TJ and Chibnik, LB and Gomez-Isla, T and Frosch, MP and Marks, DS and Salloway, S and Bernick, C and Greeley, D and Latimer, CS and Nolan, A and Hutchison, RM and Rubel, CE and Bussiere, T and Plowey, ED and Keene, CD and Hyman, BT},
title = {Neuropathological study of the effects of aducanumab anti-Aβ immunotherapy on patients with Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42301522},
issn = {1432-0533},
support = {24AARF-1192364/ALZ/Alzheimer's Association/United States ; R01AG071567/NH/NIH HHS/United States ; UW ADRC P30 AG066509/NH/NIH HHS/United States ; P30AG062421//Massachusetts Alzheimer Disease Research Center/ ; W81XWH-21-S-TBIPH2//US Department of Defense/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/drug therapy/therapy/immunology ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; *Amyloid beta-Peptides/metabolism/immunology ; Male ; Aged ; *Brain/pathology/drug effects/metabolism ; Aged, 80 and over ; Neurofibrillary Tangles/pathology ; *Immunotherapy/methods ; Plaque, Amyloid/pathology ; tau Proteins/metabolism ; },
abstract = {Fluid and imaging biomarker data show that anti-amyloid (Aβ) antibodies promote the clearance of Aβ from the brains of patients with Alzheimer's disease (AD). We examined postmortem brain tissue of individuals who participated in aducanumab clinical trials and investigated the drug's effects on Aβ pathology and other AD phenotypes. The medial temporal lobe of six aducanumab clinical trial participants-who had extensive exposure to aducanumab and happened to die between 7 weeks and 5 years after their last antibody infusion-was compared with that of nine untreated AD patients matched for age, APOE genotype, and Braak neurofibrillary tangle stage, to determine how aducanumab impacts AD pathobiology. Patients treated with aducanumab displayed a robust reduction in Aβ burden. As observed in previous studies, Aβ was associated with non-arterial microvessels in aducanumab-treated patients, suggesting a redistribution of Aβ within the neuropil. Neuritic phospho-tau decreased in parallel with fewer Aβ plaques, but the density of PHF-1[+] and AT8[+] neurofibrillary tangles remained unchanged relative to the average untreated AD donor. Measures of microglial and astroglial reactivity were also comparable to those in untreated AD controls. These findings confirm aducanumab's potent ability to target and remove brain Aβ. On average, Aβ plaques increased in proportion to the length of time after the last dose, consistent with the idea that plaques gradually redeposit post-treatment. The selective reduction of neuritic, but not neurofibrillary tangle phospho-tau implies that Aβ-targeted antibodies such as aducanumab alleviate plaque-associated dystrophy but may not address established tangles. This study describes the long-term outcomes of anti-Aβ immunotherapy in AD.},
}

Humans
*Alzheimer Disease/pathology/drug therapy/therapy/immunology
*Antibodies, Monoclonal, Humanized/therapeutic use
Female
*Amyloid beta-Peptides/metabolism/immunology
Male
Aged
*Brain/pathology/drug effects/metabolism
Aged, 80 and over
Neurofibrillary Tangles/pathology
*Immunotherapy/methods
Plaque, Amyloid/pathology
tau Proteins/metabolism

@article {pmid42302727,
year = {2026},
author = {Kim, MS and Kang, D},
title = {Why Deep Cervical Lymphovenous Anastomosis for Alzheimer Disease Lacks Scientific Foundation.},
journal = {The Journal of craniofacial surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/SCS.0000000000013042},
pmid = {42302727},
issn = {1536-3732},
abstract = {Deep cervical lymphovenous anastomosis (DCLVA) has been rapidly adopted as a surgical treatment for Alzheimer disease (AD), based on the hypothesis that enhancing cervical lymphatic drainage may promote glymphatic clearance of neurotoxic proteins. By mid-2025, an estimated 382 hospitals in China had performed the procedure before any randomized controlled trial was completed, prompting China's National Health Commission to prohibit its clinical use on the grounds of insufficient evidence. That prohibition addressed the absence of clinical trial data but did not articulate a specific physiological objection. Following a recent critical review of lymphovenous anastomosis in the lower extremity, the senior author investigated the status of this technique in the craniofacial region and found that its dominant application is not for head and neck lymphedema but for AD. This review identifies fundamental scientific gaps in the rationale for DCLVA in AD. The target pathology-cervical lymphatic insufficiency-has never been confirmed in living patients with AD. Preclinical evidence is contradictory: modulating dural lymphatic vessels in either direction does not alter amyloid pathology in mouse models. No study has controlled for confounding anesthetic effects. No standardized surgical protocol exists. Hemodynamic conditions at the anastomotic site during supine sleep-when glymphatic clearance is most active-have never been measured. Serious adverse events have already been reported. These gaps represent deficiencies in the fundamental science that must be resolved before clinical investigation can be justified.},
}

@article {pmid42304162,
year = {2026},
author = {Madhu, LN and Attaluri, S and Kotian, S and Upadhya, R and Somayaji, Y and Rao, S and Tarale, P and Ganesh, SV and Huard, C and Kodali, M and Shuai, B and Rao, VV and Shetty, AK},
title = {Human iPSC-NSC-Derived Extracellular Vesicles Can Alleviate Alzheimer's Disease-Linked Impairments in Mitochondria, mTOR Signaling, Autophagy, and Hippocampal Neurogenesis.},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70590},
pmid = {42304162},
issn = {1474-9726},
support = {RF1AG074256/AG/NIA NIH HHS/United States ; R01AG075440/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *TOR Serine-Threonine Kinases/metabolism ; Humans ; Animals ; *Mitochondria/metabolism ; *Hippocampus/metabolism/pathology ; *Neurogenesis ; Mice ; Signal Transduction ; *Induced Pluripotent Stem Cells/metabolism ; *Autophagy ; Male ; *Extracellular Vesicles/metabolism/transplantation ; *Neural Stem Cells/metabolism ; Female ; },
abstract = {Intranasal (IN) administrations of extracellular vesicles (EVs) derived from human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSCs) have shown promise in reducing chronic neuroinflammation mediated by microglia and astrocytes in 5x familial Alzheimer's disease (5xFAD) mice, a model for early-onset Alzheimer's disease (AD). The current study rigorously investigated whether treatment with hiPSC-NSC-EVs could also alleviate several other neuropathological changes contributing to progressive cognitive decline. Three-month-old male and female 5xFAD mice received IN administrations of either hiPSC-NSC-EVs (~30 × 10[9]/week for 2 weeks) or vehicle. Two months later, the hippocampus of both male and female 5xFAD mice treated with the vehicle showed increased levels of markers of oxidative stress and mechanistic target of rapamycin (mTOR) signaling, altered expression of genes and/or proteins linked to mitochondria and autophagy, and diminished neurogenesis. In contrast, treatment with hiPSC-NSC-EVs restored levels of oxidative stress markers and the expression of genes and/or proteins linked to various mitochondrial complexes, mitochondrial biogenesis, fission, fusion, and mitophagy closer to naïve control levels, indicating alleviation of mitochondrial impairments. These improvements were accompanied by reduced phosphorylated mTOR levels and multiple autophagy markers matching those in naïve controls, suggesting a dampening of mTOR signaling and an enhancement of autophagy. Furthermore, mice treated with hiPSC-NSC-EVs showed increased hippocampal neurogenesis, associated with enhanced brain-derived neurotrophic factor signaling. Overall, the results highlight that IN administrations of hiPSC-NSC-EVs in the early stages of AD can help slow the progression of multiple neuropathological changes associated with cognitive decline in 5xFAD mice and potentially AD.},
}

*Alzheimer Disease/metabolism/pathology
*TOR Serine-Threonine Kinases/metabolism
Humans
Animals
*Mitochondria/metabolism
*Hippocampus/metabolism/pathology
*Neurogenesis
Mice
Signal Transduction
*Induced Pluripotent Stem Cells/metabolism
*Autophagy
Male
*Extracellular Vesicles/metabolism/transplantation
*Neural Stem Cells/metabolism
Female

@article {pmid42304897,
year = {2026},
author = {Kim, S and Park, SK},
title = {Fucoxanthin Promotes Longevity and Neuroprotection in Caenorhabditis elegans via DAF-16 and Autophagy Pathways.},
journal = {Rejuvenation research},
volume = {},
number = {},
pages = {15491684261460844},
doi = {10.1177/15491684261460844},
pmid = {42304897},
issn = {1557-8577},
abstract = {Identification of natural compounds that delay aging and prevent age-related neurodegeneration is a key goal in gerontology. Fucoxanthin, a marine-derived xanthophyll, exhibits potent antioxidant properties, yet its effects on organismal aging and specific molecular mechanisms remain underexplored. Here, we investigated the pro-longevity and neuroprotective effects of fucoxanthin using Caenorhabditis elegans. Fucoxanthin supplementation significantly extended the mean lifespan of wild-type nematodes by 12.1% and improved health span, as evidenced by delayed age-related motility decline and enhanced resistance to oxidative stress. Notably, this lifespan extension occurred without compromising reproductive fitness. Genetic analysis revealed that the beneficial effects of fucoxanthin require the FOXO transcription factor DAF-16 and the autophagy-essential gene bec-1. Furthermore, fucoxanthin treatment increased autophagic flux and upregulated the expression of SKN-1/Nrf2-dependent detoxification genes, hsp-16.2 and gst-4. In nematode models of Alzheimer's and Parkinson's disease, fucoxanthin significantly ameliorated Aβ-induced paralysis and protected against dopaminergic neurodegeneration and α-synuclein accumulation in a DAF-16-dependent manner. Collectively, our findings demonstrate that fucoxanthin acts as a multitarget geroprotector that promotes healthy aging through the coordinated activation of DAF-16 and autophagy, suggesting its potential as a therapeutic intervention for age-related decline.},
}

@article {pmid42304917,
year = {2026},
author = {Sinha, S and Gupta, S and Tiwari, P},
title = {Therapeutic Potential of Natural Chalcones Against Alzheimer's Disease: A Mechanistic Insight.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454130260605061515},
pmid = {42304917},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, amyloid-beta (Aβ) plaque deposition, tau hyperphosphorylation, oxidative stress, and chronic neuroinflammation. Therapeutic strategies are at present mainly symptomatic and do not modify the course of the disorder. Natural chalcones, precursors of flavonoids, are emerging as multi-target agents for neuroprotection since they have the ability to protect neurons and exert anti-inflammatory and antioxidant activities.

METHODS: A systematic literature search was performed in PubMed, Scopus, Web of Science, and Google Scholar utilizing keywords that associate chalcones with Alzheimer's disease. Studies were included if they reported in silico docking, in vitro assays, or mechanistic insights on AD-related targets (AChE, BACE1, GSK-3β, NF-κB). Data extraction included information about the compound's identity, structural changes, docking scores, enzyme inhibition, oxidative stress, and cytokine modulation. The findings were synthesized both qualitatively and quantitatively, with structure-activity relationship (SAR) analysis emphasizing patterns of hydroxylation and methoxylation. These helped in the rational design of chalcone derivatives, which showed potential as multi-target agents against AD pathology.

RESULTS: Several chalcones exhibited potent inhibition against AChE and BACE1, besides reducing reactive oxygen species (ROS) generation and preventing the release of pro-inflammatory cytokines. These findings demonstrate their potential to mitigate cholinergic deficits and neuroinflammatory signaling. SAR studies revealed a significant enhancement in bioactivity for certain hydroxylation and methoxylation substituents. This provides insights into the rational design of improved chalcone derivatives.

DISCUSSION: Chalcones display multifunctional properties and are able to modulate several AD pathological signatures, suggesting potential application in the prevention of AD symptoms. Their therapeutic importance is emphasized by their combined ability to target cholinergic dysfunction, oxidative stress, and neuroinflammation. The SAR analysis further supports the focused development of chalcone-based derivatives with improved potency.

CONCLUSION: The present study provides insights into the mechanistic basis of the neuroprotective activity of chalcones and paves the way for subsequent preclinical evaluation. The chalconebased strategy holds promise for the development of potential drug candidates for the treatment of neurodegenerative diseases such as Alzheimer's disease by addressing the multi-target nature of this complex disease.},
}

@article {pmid42305190,
year = {2026},
author = {Sedlacek Miskerikova, M and Houfkova, A and Benkova, M and Andrys, R and Janousek, J and Soukup, O and Musilek, K and Benek, O},
title = {Development of Novel 17β-HSD10 Inhibitors and Their Evaluation in an In Vitro Model of Alzheimer's Disease.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {6},
pages = {1347-1354},
pmid = {42305190},
issn = {1948-5875},
abstract = {17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a multifunctional mitochondrial enzyme and a potential drug target for the treatment of various pathologies, including Alzheimer's disease (AD). In this study, five new benzothiazole-derived 17β-HSD10 inhibitors were developed based on structure-activity relationship (SAR) analyses of previously published compounds. To evaluate the inhibitory effects, cytotoxicity, and therapeutic potential of these new compounds, several enzyme- and cell-based methods were employed. All prepared compounds exhibited high inhibitory potential and confirmed good biomembrane permeation. Three inhibitors (9b, 9c, and 15a) showed lower IC50 values in both enzyme- and cell-based assays than the formerly published hit compounds. The compounds were also found to reduce the pathological effects associated with 17β-HSD10 overexpression, although not the combined pathological effects of 17β-HSD10 overexpression within an amyloid-β rich environment.},
}

@article {pmid42305665,
year = {2026},
author = {Vignesh Pandi, A and Malakar, V and Jeyabalan, JB and Sanjai, M and Shevate, K and Rajagopal, K and Prashantha Kumar, BR and Justin, A},
title = {Integrated computational-based design of putative dual TrkA/TrkB agonists for Alzheimer's disease: pharmacophore modelling, docking, MM/GBSA, DFT and dynamics studies.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1779769},
pmid = {42305665},
issn = {2673-7647},
abstract = {BACKGROUND: The rapid progression of Alzheimer's disease (AD) is primarily caused by compromised neurotrophin functions and decreased tropomyosin receptor kinase expression in the basal forebrain area. The two main pathogenic features of AD are cholinergic-dependent cognitive dysfunctions and amyloidogenic-induced neurodegeneration. Concurrent stimulation of major neurotrophin signalling pathways, such as tropomyosin receptor kinases receptor A and B (TrkA and TrkB), may reduce amyloid-β-mediated neurotoxicity and cholinergic denervation in the basal forebrain, improving cognitive performance and re-establishing neuronal communication. The development of new medications with dual agonist action towards TrkA and B receptors holds enormous therapeutic potential for managing the symptoms of neurodegenerative diseases.

AIM: This study aims to develop novel dual TrkA/TrkB receptor agonists for the treatment of AD by enhancing neurotrophin signalling, reducing cholinergic denervation, and mitigating amyloid-β-induced neurotoxicity.

METHODS: An in silico drug discovery pipeline was employed, involving homology and pharmacophore modelling of amitriptyline, virtual screening of ChEMBL compounds, molecular docking, ADMET, MM/GBSA analysis, DFT calculations and molecular dynamics (MD) simulations for 100 and 300 ns to assess ligand stability and binding behaviour of the ligand-protein complexes.

RESULTS: Six novel optimised quinoline analogues (OP-1 to OP-6) were identified as computationally predicted dual TrkA/TrkB agonists by molecular docking (-8.90 to -5.07 kcal/mol), MM/GBSA (-40.47 to -30.71 kcal/mol), ADMET and DFT analysis. Furthermore, OP-1, OP-2, and OP-3 exhibit stable binding interactions over 300 ns of MD simulations. The optimised compounds demonstrated favorable computational binding profiles, predicted pharmacokinetic properties, and stable receptor-ligand interactions, identifying them as promising candidates for further experimental validation as potential dual TrkA/TrkB modulators in Alzheimer's disease.},
}

@article {pmid42306035,
year = {2026},
author = {Kalpaktsi, I and Panara, A and Mavroidi, B and Niforos, GG and Kalampaliki, AD and Vlachogianni, IC and Georgiou, EA and Fragopoulou, E and Tsarbopoulos, A and Skaltsounis, AL and Pelecanou, M and Palikaras, K and Gikas, E and Kostakis, IK},
title = {Novel hydroxytyrosol esters as potential anti-amyloid and neuroprotective agents for Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42306035},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is associated with the aggregation of β-amyloid (Aβ) peptides and oxidative stress, two interconnected processes that contribute to neuronal dysfunction and cognitive decline. Natural polyphenols such as oleuropein and its metabolite hydroxytyrosol display antioxidant and anti-amyloidogenic properties, but oleuropein suffers from limited stability due to glycosidic hydrolysis. To develop more robust and potent oleuropein analogs, we synthesized a series of hydroxytyrosol-based esters in which the secoiridoid glucoside scaffold of oleuropein was replaced by lipophilic substituents designed to enhance molecular stability and interactions with Aβ peptide. The compounds were evaluated for their ability to interact with Aβ40 using ESI-MS, circular dichroism (CD), and thioflavin-T fluorescence (ThT), along with complementary antioxidant assays. Most of the compounds formed stable non-covalent complexes with Aβ40, inhibited early aggregation events, and prevented the peptide's conformational transition from random coil to β-sheet. To assess biological efficacy and safety in vivo, the most promising analog (3b) was evaluated in Caenorhabditis elegans models of amyloid-β toxicity. Treatment with 3b exhibited no detectable toxicity in wild-type animals, as evidenced by normal development, growth, and reproductive efficacy. Importantly, 3b rescued lifespan shortening and locomotor deficits in transgenic nematodes expressing human Aβ42 pan-neuronally, while having no effect on control strains lacking Aβ42 expression. These findings demonstrate that 3b confers functional protection against amyloid-induced toxicity in vivo. Overall, our results identify the newly synthesized hydroxytyrosol-derived esters as promising multifunctional scaffolds that combine potent anti-aggregation activity with strong antioxidant properties and in vivo neuroprotective efficacy, supporting their further development as anti-amyloidogenic agents for AD therapy.},
}

@article {pmid42306774,
year = {2026},
author = {Rodriguez Martinez, PJ and Yslas, AR and Inoue, Y and Parsons, TM and Baker, SK and Lu, W and Raulin, AC and Kanekiyo, T},
title = {APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.},
journal = {Frontiers in molecular biosciences},
volume = {13},
number = {},
pages = {1778856},
pmid = {42306774},
issn = {2296-889X},
abstract = {Aging and neurodegenerative disorders like Alzheimer's Disease (AD) are associated with progressive dysfunction of the blood-brain barrier (BBB) and neurovascular unit (NVU), contributing to impaired vascular integrity and neuronal vulnerability. Apolipoprotein E (APOE) is a key regulator of neurovascular function, and the rare APOE3-R136S "Christchurch" variant (APOE3Ch) confers protection against AD. Mesenchymal stromal cells (MSCs) represent a promising cell-based therapy for the treatment of neurodegenerative diseases due to their paracrine effect exerted on vascular and neural cells. To investigate how APOE3Ch influences MSC-mediated neurovascular support, we used isogenic iPSC-derived MSCs (iMSCs) with homozygous APOE3Ch or APOE3. We found that APOE3Ch iMSCs have stronger immunosuppressive effect on LPS-induced NFκB activation of THP1 cells. APOE3Ch iMSCs also enhanced endothelial barrier resistance and angiogenic capacity compared to APOE3 iMSCs when directly co-cultured with endothelial cells. In addition, conditioned medium from APOE3Ch iMSCs promoted neurite outgrowth more efficiently than that from APOE3 iMSCs. Metabolic profiling revealed differences between APOE3Ch and APOE3 iMSCs, suggesting altered metabolic resilience. Together, these findings demonstrate that iMSCs support vascular and neuronal function through paracrine mechanisms and suggest that APOE3Ch variant improves specific aspects of MSC-mediated neurovascular support. This work highlights the potential of combining MSC-based therapies with protective APOE variants to target BBB and NVU dysfunction in aging and neurodegeneration.},
}

@article {pmid42293147,
year = {2026},
author = {Pinky, and Neha, and Kaushik, M and Tiwari, P and El-Tanani, M and Rabbani, SA and Parvez, S},
title = {Propranolol reinstates mitochondrial dynamics and synaptic memory pathways through CaMKII/CREB-BDNF/ PKMζ cascades in an AD-like rat model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729046},
pmid = {42293147},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, neurofibrillary tangles, and progressive cognitive decline. Despite significant advances in understanding its pathophysiology, current therapeutic options provide limited symptomatic relief. The present study investigated the nootropic and anti-amnesic effects of propranolol (PRO) in a scopolamine (SCP)-induced AD-like rat model.

METHODS: Wistar rats received PRO (10, 30, or 50 mg/kg, p.o.) or donepezil (DPZ; 1 mg/kg) for 17 days. Cognitive deficits were induced by SCP (1 mg/kg, i.p.) administration from day 9 onward. Behavioral performance was assessed using the Novel Object Recognition (NOR) and Elevated Plus Maze (EPM) tests. Molecular and cellular analyses were conducted to evaluate synaptic plasticity markers (CaMKII, CREB, BDNF, PKMζ), mitochondrial function, oxidative stress parameters, and inflammatory markers (GFAP, TNF-α).

RESULTS: Propranolol treatment significantly improved long-term memory performance, enhanced recognition index, and attenuated anxiety-like behavior in SCP-treated rats. These behavioral effects were associated with upregulation of CaMKII-CREB-BDNF-PKMζ signaling, improvement in mitochondrial membrane potential (Δψm), reduction in reactive oxygen species (ROS) generation and Aβ1-42 accumulation, and decreased expression of GFAP and TNF-α.

CONCLUSION: The findings suggest that propranolol mitigates SCP-induced cognitive impairments, potentially through modulation of synaptic plasticity- related signaling, mitochondrial function, and neuroinflammatory responses. These results indicate the therapeutic potential of propranolol in experimental models of AD-related neurodegeneration, warranting further investigation.},
}

@article {pmid42294918,
year = {2026},
author = {Singh, M and Steinke, I and Crall, N and Tamhankar, S and Wibowo, FS and Xavier, J and Yue, Z and Pondugula, SR and Huang, CJ and Griffett, K and Smith, FT and Chowdhury, K and Suppiramaniam, V and Amin, RH},
title = {Design and Development of a Novel LXRβ/PPARδ Dual Agonist for Memory Impairment and Pathology in 3xTg-AD Animal Model of Alzheimer's Disease.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.6c00240},
pmid = {42294918},
issn = {1554-8937},
abstract = {The rising prevalence of Alzheimer's disease (AD) underscores an urgent need for neuroprotective strategies that modulate cholesterol metabolism, neuroinflammation, improve pathology, and cognitive function. While Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are validated targets for enhancing amyloid-β and tau clearance, clinical translation of first-generation LXR agonists has been hindered by LXRα-mediated hepatic steatosis and hypertriglyceridemia. Here, we report the structure-based design of AU403, a potent, isoform-selective LXRβ/PPARδ dual agonist designed to bypass LXRα-driven hepatotoxicity. Molecular modeling indicates that AU403 achieves LXRβ selectivity by engaging residues Phe329 and Leu330 while avoiding the corresponding LXRα residues Arg305 and Leu316. This structural precision translates to robust functional activity, with luciferase assays confirming potent activation of LXRβ (EC50 ≈ 45 nM) and PPARδ (EC50 ≈ 40 nM). Notably, AU403 exhibits a superior safety profile, circumventing hepatotoxicity, neutropenia, and hERG inhibition that have limited the clinical development of prior agonists. Furthermore, chronic administration of AU403 in 3xTg-AD mice significantly improved cognitive functions and reduced amyloid-β plaque burden, establishing AU403 as a promising dual-acting agonist for the treatment of Alzheimer's Disease.},
}

@article {pmid42295086,
year = {2026},
author = {Liu, Q and Lin, RR},
title = {Optimizing Antibody-Based Therapies for Alzheimer's Disease: From Clinical Limitations to Molecular Engineering Innovations.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0292},
pmid = {42295086},
issn = {2152-5250},
abstract = {Antibody-based immunotherapy represents one of the most promising disease-modifying strategies for Alzheimer's disease (AD). Recent anti-amyloid-β (Aβ) antibodies have achieved robust plaque clearance and modest cognitive benefits in early AD, establishing clinical proof of concept. However, limited efficacy and safety concerns, particularly amyloid-related imaging abnormalities (ARIA), continue to restrict their therapeutic potential. This review outlines the current clinical status of antibody therapies targeting Aβ, tau, and neuroinflammatory pathways, and summarizes key antibody optimization strategies, including aggregation-state-selective targeting, Fc engineering, brain shuttle technologies, nanobody platforms, and nanotechnology-enabled delivery. We further discuss emerging concepts from tumor immunotherapy, such as antibody-guided protein degradation and conditionally active biologics, as potential avenues for next-generation AD treatment.},
}

@article {pmid42295611,
year = {2026},
author = {Guo, Y and Chen, P and Chen, S and Xu, N and Shi, J and Li, D and Zhang, P},
title = {Circ_0092222 is Enhanced in Alzheimer's Disease and Exacerbates Aβ-induced Neurotoxicity Through Sponging miR-331-3p.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42295611},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/blood/metabolism ; *Amyloid beta-Peptides/toxicity ; *MicroRNAs/genetics/metabolism ; *RNA, Circular/genetics/metabolism ; Cell Line, Tumor ; Apoptosis/drug effects/genetics ; Female ; Male ; Cell Survival/drug effects ; Neurons/metabolism/drug effects/pathology ; *Peptide Fragments/toxicity ; RNA, Competitive Endogenous ; },
abstract = {This study aimed to explore the expression pattern of circ_0092222 in Alzheimer's disease (AD) and its role in Aβ-induced neuronal apoptosis. circ_0092222 was identified from the GEO dataset. Serum level of circ_0092222 in 95 AD patients and 100 controls was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). AD cell model was achieved by treating SH-SY5Y cells with Aβ25-35. Cell viability, cytotoxicity, apoptosis and inflammation were detected. The targeting relationship between circ_0092222 and miR-331-3p, and between miR-331-3p and SEC61A1 was verified by the dual-luciferase reporter gene assay. Pearson correlation and Logistic regression analysis were used to evaluate the relationship between variables and the risk factors for AD progression. Circ_0092222 expressions in AD patients were higher than that in the control group. Short years of education, low mini mental state examination (MMSE) score, low plasma Aβ42/40 ratio, and elevated circ_0092222 were independent risk factors for the progression of mild AD to moderate/severe. In cell experiments, the expression of circ_0092222 was upregulated. Knockdown of circ_0092222 could significantly reduce the apoptosis rate, lactate dehydrogenase (LDH) release, pro-inflammatory cytokine levels, and the expressions of Bax and cleaved caspase-3, and increase cell viability and Bcl-2 expression. Bioinformatics prediction and dual-luciferase reporter gene assay confirmed that circ_0092222 directly binds to miR-331-3p, and miR-331-3p directly targets SEC61A1. Functional rescue experiments demonstrated that circ_0092222 regulates Aβ25-35-induced neuronal injury by up-regulating SEC61A1 through sponging miR-331-3p. Inhibiting circ_0092222 can improve Aβ25-35-induced apoptosis and inflammation, suggesting that circ_0092222 may be a potential target for AD treatment.},
}

Humans
*Alzheimer Disease/genetics/pathology/blood/metabolism
*Amyloid beta-Peptides/toxicity
*MicroRNAs/genetics/metabolism
*RNA, Circular/genetics/metabolism
Cell Line, Tumor
Apoptosis/drug effects/genetics
Female
Male
Cell Survival/drug effects
Neurons/metabolism/drug effects/pathology
*Peptide Fragments/toxicity
RNA, Competitive Endogenous

@article {pmid42295692,
year = {2026},
author = {Nath, R and Chakraborty, A and Akhtar, MJ and Maity, I and Ganguly, S and Nehra, B and Ashique, S and Khan, SA and Tariq, M and Bakshi, S and Debnath, B and Yasmin, S and Khalilullah, H and Ansari, MY},
title = {Recent trends in anti-Alzheimer's potential of novel biologically active isatin analogues: synthetic strategies, structural activity relationship studies and molecular docking insights.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42295692},
issn = {1573-501X},
abstract = {Alzheimer's disease is a progressive neurodegenerative illness i.e., characterized by cognitive decline, memory impairment, cholinergic dysfunction, oxidative stress, Aβ aggregation, tau hyperphosphorylation and neuroinflammation. Due to multifactorial nature of AD, conventional single-target therapeutic approaches exhibit limited clinical success. Hence, development of multifunctional small molecules emerged as a promising strategy for management of Alzheimer's diseases i.e., capable to modulate multiple pathological pathways simultaneously. Among various heterocyclic pharmacophores, isatin (1H-indole-2,3-dione) gained considerable attention due to its structural versatility, synthetic accessibility and broad spectrum of biological effects. Recent studies demonstrated that isatin-derived molecules possess significant inhibitory activity against acetylcholinesterase, butyrylcholinesterase, monoamine oxidase-A/B, β-secretase and amyloid aggregation pathways. Furthermore, hybridization of isatin core with pharmacologically active moieties like triazoles, coumarins, tacrine, benzylamine, piperazine, quinoline, hydrazones and melatonin afford more promising multitarget-directed ligands with improved BBB permeability, antioxidant potential and improved neuroprotective properties. Also, docking, MD simulation and ADMET analyses validated favorable binding interactions and drug-likeness characteristics of many isatin analogues. This review comprehensively summarizes recent advances in design, synthesis, biological evaluation, docking investigations and SAR studies of isatin-based anti-Alzheimer agents. In addition, key emphasis is placed on SAR trends which is responsible for promoted potency and selectivity including electron-withdrawing substitutions, linker optimization, hydrophobic interactions and dual-site binding with catalytic as well as peripheral anionic sites of target enzymes. Integration of hybrid isatin scaffolds with complementary pharmacophore combined with advanced in silico modeling and preclinical evaluation may pave the way for next-generation multifunctional therapeutics with improved efficacy and safety in treatment of Alzheimer's disease.},
}

@article {pmid42297456,
year = {2026},
author = {Alghamdi, A and Balafas, S and Bos, JHJ and van Munster, BC and Rafie, K and Dolga, AM and Hak, E},
title = {Association between the use of anti-herpetic drugs and subsequent initiation of Alzheimer's disease drug treatment: Dutch population-based inception cohort study.},
journal = {BMJ open},
volume = {16},
number = {6},
pages = {e114033},
doi = {10.1136/bmjopen-2025-114033},
pmid = {42297456},
issn = {2044-6055},
mesh = {Humans ; Female ; Aged ; *Alzheimer Disease/drug therapy/epidemiology ; Netherlands/epidemiology ; *Antiviral Agents/therapeutic use ; Retrospective Studies ; Male ; Middle Aged ; Aged, 80 and over ; Valacyclovir/therapeutic use ; Acyclovir/therapeutic use ; Famciclovir/therapeutic use ; Proportional Hazards Models ; Memantine/therapeutic use ; Donepezil/therapeutic use ; },
abstract = {OBJECTIVES: To examine whether exposure to anti-herpetic drugs (AHDs: acyclovir, valacyclovir, famciclovir) is associated with reduced risk of Alzheimer's disease (AD) treatment initiation.

DESIGN: Population-based retrospective matched cohort study.

SETTING: University Groningen community pharmacy database IADB.nl, covering approximately 125 Dutch pharmacies (1994-2024).

PARTICIPANTS: 262 757 adults aged 50-80 years without prior dementia or AD treatment. Exposed individuals with antiherpetic prescriptions (n=23 887) were matched 1:10 to unexposed controls (n=238 870) by age, sex and calendar time.

INTERVENTION: AHDs: acyclovir, valacyclovir, famciclovir.

MAIN OUTCOME MEASURES: Initiation of AD drug treatment, defined as at least two prescriptions for rivastigmine, donepezil, galantamine or memantine within 1 year. Cox proportional hazards models estimated HRs with 95% CIs, adjusted for comorbidities and medications. Analyses were stratified by period (1994-2018 vs 2019-2024) and drug type.

RESULTS: During follow-up, 2495 participants initiated AD treatment. The age of the participants was 65 (SD 9), and 59% were female. Any AHD exposure was associated with 90% reduced hazard of AD treatment (HR 0.09, 95% CI 0.07 to 0.13, p<0.001). Similar association was found in both periods: HR 0.14 (95% CI 0.09 to 0.20) in period one and HR 0.05 (95% CI 0.03 to 0.10) in period 2. All three AHDs were associated with a lower likelihood of future AD drug prescription: valacyclovir HR 0.10, acyclovir HR 0.09, famciclovir HR 0.07. The incidence rate of AD treatment initiation was substantially lower among AHD users compared with unexposed individuals overall (0.69/1000 person-years (py) vs 4.96/1000 py, p<0.001), with this association evident in both period 1 (0.65/1000 py vs 3.74/1000 py, p<0.001) and period 2 (0.81/1000 py vs 8.22/1000 py, p<0.001).

CONCLUSIONS: AHD exposure was consistently associated with markedly lower risk of AD treatment initiation, with similar findings observed in recent years. These findings support the hypothesis that herpesvirus reactivation may contribute to AD pathogenesis and suggest antiviral therapy could have preventive implications. Confirmation through prospective studies and randomised trials is needed.},
}

Humans
Female
Aged
*Alzheimer Disease/drug therapy/epidemiology
Netherlands/epidemiology
*Antiviral Agents/therapeutic use
Retrospective Studies
Male
Middle Aged
Aged, 80 and over
Valacyclovir/therapeutic use
Acyclovir/therapeutic use
Famciclovir/therapeutic use
Proportional Hazards Models
Memantine/therapeutic use
Donepezil/therapeutic use

@article {pmid42298279,
year = {2026},
author = {Siengsukon, CF and Hand, LK and Nelson, E and Glaser, A and Ludwig, R and Russell, JA and Phadnis, MA and Dai, J and Bruce, J and Vidoni, ED and Drerup, M and Morris, J and Burns, JM},
title = {The impact of cognitive behavioral therapy for insomnia on cognitive performance and amyloid beta in older adults: A randomized controlled trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71591},
pmid = {42298279},
issn = {1552-5279},
support = {R01AG058530/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; T32 AG078114/AG/NIA NIH HHS/United States ; T32HL007028/NH/NIH HHS/United States ; T32HD057850//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; *Amyloid beta-Peptides/metabolism ; Female ; *Sleep Initiation and Maintenance Disorders/therapy/psychology/metabolism ; Aged ; Male ; *Cognition/physiology ; Neuropsychological Tests ; Alzheimer Disease ; Aged, 80 and over ; Executive Function ; },
abstract = {INTRODUCTION: Insomnia is associated with increased risk for Alzheimer's disease (AD). It is unknown how cognitive behavioral therapy for insomnia (CBT-I) impacts two hallmarks of AD progression, cognitive performance and beta-amyloid (Aβ) burden.

METHODS: Cognitively normal older adults with symptoms of insomnia were randomized into CBT-I treatment (n = 100) or control (n = 100) groups. Cognitive performance was assessed at baseline, 6-weeks, and 1-year (1 year). Aβ burden was assessed in a subsample (n = 50).

RESULTS: No differences were observed between groups in change in cognitive performance, including speed of information processing (mean difference, 0.017; 95% confidence interval [CI], -0.1036 to 0.1376; p = 0.78), executive function (-0.0881; 95% CI, -0.2945 to 0.1182; p = 0.40), and memory (0.4068; 95% CI, -2.3965 to 3.2101; p = 0.77). No group differences were observed in Aβ deposition.

DISCUSSION: CBT-I did not improve cognitive performance or Aβ deposition by one year. Longer follow up is needed to understand the potential impact of CBT-I on AD risk.

CLINICAL TRIAL REGISTRATION: The study was registered on clinicaltrials.gov (NCT03954210) on 5/17/2019.},
}

Humans
*Cognitive Behavioral Therapy/methods
*Amyloid beta-Peptides/metabolism
Female
*Sleep Initiation and Maintenance Disorders/therapy/psychology/metabolism
Aged
Male
*Cognition/physiology
Neuropsychological Tests
Alzheimer Disease
Aged, 80 and over
Executive Function

@article {pmid42298289,
year = {2026},
author = {Amouyel, P and Andrieu, S and Bradshaw, A and Carmona, RC and Dumont, M and Grinberg, LT and Iwatsubo, T and Hansson, O and Jack, CR and Jicha, GA and Mahinrad, S and McDade, E and Mummery, CJ and Petersen, RC and Robinson, S and Schneider, JA and Shellcross, L and Smith, AG and Snyder, HM and Tapply, B and Teunissen, C and van der Flier, WM and Vellas, B and Wallon, D and Williamson, JD and Wilcock, D and Carrillo, MC},
title = {Provider and patient perspectives on the diagnosis and treatment of Alzheimer's disease: A global perspective from the Global Alzheimer's Leadership Series (GoALS).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71536},
pmid = {42298289},
issn = {1552-5279},
mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; },
abstract = {Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world-leading experts for innovative discussions to advance Alzheimer's disease (AD) research and care. The second GoALS think tank, held in June 2024 in Paris, focused on the relationship between biological changes and clinical manifestations of AD in the context of the evolving therapeutic landscape. Discussions spanned real-world experiences of providers, patients, and their families, theoretical considerations, and health system challenges. The lived experience perspective was central to these discussions. The importance of shared decision-making, clear and transparent communication, and the need for real-world data to holistically support patients during their experiences were highlighted. This manuscript shares key insights from both the think tank meeting in Paris and a featured research session at the 2024 Alzheimer's Association International Conference that expanded the discussion themes for broader dissemination with the community.},
}

*Alzheimer Disease/diagnosis/therapy
Humans

@article {pmid42298621,
year = {2026},
author = {Gezginer, I and Karakatsani, ME and Nanda, P and Chalasani, P and Kindler, D and Storz, R and Belau, M and Ni, R and Schratt, G and Deán-Ben, XL and Razansky, D},
title = {Transcranial pulse stimulation modulates spectral signatures of Alzheimer's disease in the 3×Tg-AD mouse model.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02109-1},
pmid = {42298621},
issn = {1758-9193},
abstract = {BACKGROUND: Large-scale brain network dysfunction is increasingly recognized as an important feature of Alzheimer's disease (AD), offering insight into disease mechanisms and opportunities for targeted therapeutic intervention. The spectral features of this dysfunction remain poorly understood, and how neuromodulatory interventions interact with and reshape these frequency-resolved network signatures has yet to be explored.

METHODS: Triple-transgenic (3×Tg-AD) mice underwent resting-state functional MRI to assess functional connectivity, signal power, and variance across frequency bands after acute and longitudinal transcranial pulse stimulation (TPS), a low-intensity single-pulse neuromodulatory intervention. Novel object recognition testing was used to evaluate exploratory drive and short-term recognition memory following repeated TPS or sham treatment.

RESULTS: AD mice exhibited widespread functional connectivity loss accompanied by reduced low-frequency resting-state power and variance, together with a redistribution of spectral energy from slow-5 (0.01-0.027 Hz) to slow-4 (0.027-0.073 Hz) activity. TPS modulated these abnormalities by increasing low-frequency power, rebalancing slow-5/slow-4 fractional power, and strengthening network coherence, with the most prominent effects in cingulate, insular, piriform, and striatal regions. TPS effects showed a non-linear, region-dependent emergence across stimulation trains, with the strongest and most consistent modulation appearing after repeated stimulation. Similar spectral rebalancing was observed both after acute and longitudinal stimulation, persisting for up to 5 days. In addition, hippocampal regions that showed minimal acute responses exhibited delayed spectral changes at 24 h, with further modulation at 120 h. TPS-treated 3×Tg-AD mice did not show the decline in object exploration observed in sham-treated animals and showed an exploration-adjusted increase in novel object preference.

CONCLUSIONS: Frequency-specific neural dynamics are sensitive markers of AD-related dysfunction and may provide a useful framework for tracking disease-related network abnormalities. TPS selectively modulates low-frequency oscillatory activity and network coherence and is accompanied by preliminary behavioral changes, including preserved exploratory engagement and an exploration-adjusted increase in novel object preference in a separate behavioral cohort. This highlights the potential of combining neuromodulation with spectral network analysis to monitor disease-related network dysfunction and treatment-associated responses.},
}

@article {pmid42299007,
year = {2026},
author = {Imai, N and Yano, H and Ikegame, Y and Yasuda, S and Morishima, R and Okumura, A and Kumagai, M and Shinoda, J and Izumo, T},
title = {Cerebral Hyperperfusion with Lecanemab in Alzheimer's Disease Assessed by Amyloid PET and Arterial Spin Labeling.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050453079260226065149},
pmid = {42299007},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is characterized by cognitive decline, amyloid-β deposition, and decreased Cerebral Blood Flow (CBF). Lecanemab, a monoclonal antibody targeting amyloid-β, slows cognitive decline in AD; however, its effects on CBF remain unclear. This study aimed to characterize CBF changes following lecanemab treatment and their association with baseline amyloid burden.

METHODS: Thirty patients with AD treated with lecanemab were analyzed retrospectively. Baseline amyloid deposition was quantified using the Centiloid scale, and patients were stratified into low, middle, and high groups. CBF was analyzed at baseline and at 8, 12, and 26 weeks using arterial spin labeling (ASL). Monoclonal antibody-triggered cerebral hyperperfusion (MATCH) was defined as a >20% CBF increase at week 8.

RESULTS: Seven patients were MATCH-positive (median CBF: 133.5% [125.5-167.8] of baseline). All MATCH-positive patients exhibited a decrease in CBF at week 12 compared to week 8. MATCH occurred in 6 of 10 patients in the middle Centiloid group. The low Centiloid group showed stable CBF, while the high Centiloid group showed a decreasing trend. The MATCHpositive group showed a significant deterioration in Instrumental Activities of Daily Living scores.

DISCUSSION: A transient CBF increase was closely associated with the middle Centiloid group. These CBF responses, including MATCH, may reflect amyloid removal, hyperperfusion, amyloidrelated imaging abnormalities, or immune responses.

CONCLUSIONS: CBF changes differed according to baseline amyloid burden. Understanding these therapy-related CBF changes is crucial for elucidating AD pathology, and ASL provides a practical, non-invasive method for longitudinal CBF monitoring in routine clinical practice.},
}

@article {pmid42299502,
year = {2026},
author = {Liu, M and Hong, H and Zhang, X and Ren, J and Tang, C},
title = {Targeting the Nrf2 Signaling Pathway: A Review of Traditional Chinese Medicine for Alzheimer's Disease.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-29},
doi = {10.1142/S0192415X26500400},
pmid = {42299502},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by [Formula: see text]-amyloid (A[Formula: see text]) deposition, Tau protein hyperphosphorylation, and chronic neuroinflammation. Current pharmacological interventions demonstrate limited therapeutic efficacy. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a pivotal regulator of oxidative stress and neuroinflammation, plays a critical role in AD pathogenesis. Recent studies have revealed that traditional Chinese medicines (TCMs) and their bioactive constituents can modulate the Nrf2 signaling pathway to mitigate oxidative stress, suppress neuroinflammation, enhance A[Formula: see text] clearance, and reduce Tau protein phosphorylation. By doing so, TCMs exert multi-targeted anti-AD effects. This review systematically summarizes the mechanisms and recent advances concerning the active ingredients of Nrf2 pathway-modulating TCMs, herbal medicines, and TCM formulations for the prevention and treatment of AD. Furthermore, it critically evaluates current research limitations and prospects for future research directions to provide a theoretical foundation for the development of novel anti-AD therapeutics derived from TCMs.},
}

@article {pmid42299696,
year = {2026},
author = {Brisendine, MH and Nieves-Esparcia, DQ and Willoughby, OS and Brown, B and Brown, JR and Braxton, DS and Henry, SN and McCoin, CS and Thyfault, JP and Morris, JK and Poelzing, S and Grange, RW and Jarome, TJ and Najt, CP and Drake, JC},
title = {Age-Dependent Remodeling of the Sciatic Nerve Proteome in 5xFAD Mice Can Be Attenuated by Exercise or Donepezil Treatment to Maintain Neuromuscular Function.},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70595},
pmid = {42299696},
issn = {1474-9726},
support = {R01AG080731/AG/NIA NIH HHS/United States ; K02AG088474/AG/NIA NIH HHS/United States ; R00AG070104/AG/NIA NIH HHS/United States ; R01AG062548/AG/NIA NIH HHS/United States ; R01AG069781/AG/NIA NIH HHS/United States ; P20GM144269/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Donepezil/pharmacology/therapeutic use ; Mice ; *Proteome/metabolism ; *Sciatic Nerve/metabolism/drug effects ; *Physical Conditioning, Animal ; *Aging ; Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy ; Muscle, Skeletal/drug effects ; Male ; },
abstract = {Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline. Although AD is primarily an age-related brain pathology, increasing evidence indicates dysfunction in peripheral nerves and skeletal muscle may manifest early in the disease progression. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood. Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months, identifying proteome remodeling coincides with functional declines at 4 months particularly in pathways linked to mitochondrial turnover, calcium handling, and inflammation. We hypothesized either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates, were given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil. We assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in vivo at 4 months. Both exercise and donepezil attenuated in vivo nerve-stimulated muscle torque and CNAP dysfunction. Further, both exercise and donepezil attenuated the proteomic remodeling of the sciatic nerve through both shared and independent mechanisms that converged on mitochondria-centric pathways. Our findings in the 5xFAD model of AD support the notion that early phenotypes of AD are evident in the periphery that may have implications for timing of interventions.},
}

Animals
*Donepezil/pharmacology/therapeutic use
Mice
*Proteome/metabolism
*Sciatic Nerve/metabolism/drug effects
*Physical Conditioning, Animal
*Aging
Mice, Transgenic
*Alzheimer Disease/metabolism/drug therapy
Muscle, Skeletal/drug effects
Male

@article {pmid42299743,
year = {2026},
author = {Bélanger, E and Couch, E and Carroll, M and Gadbois, EA and Jutkowitz, E and Van Houtven, CH and Wetle, TT},
title = {Long-Term Perceptions of the Value of Amyloid PET Scans Among Cognitively Impaired Medicare Beneficiaries and Their Care Partners.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {6},
pages = {e70226},
doi = {10.1002/gps.70226},
pmid = {42299743},
issn = {1099-1166},
support = {R01AG053934/NH/NIH HHS/United States ; //American College of Radiology Imaging Network/ ; /ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Positron-Emission Tomography/psychology/economics ; Male ; Female ; Aged ; United States ; Aged, 80 and over ; Medicare ; *Alzheimer Disease/diagnostic imaging ; *Caregivers/psychology ; Qualitative Research ; *Cognitive Dysfunction/diagnostic imaging ; Amyloid ; },
abstract = {OBJECTIVES: The objective of this study was to examine the long-term perceptions of the value of receiving an amyloid PET scan, a test used to diagnose Alzheimer's disease, among Medicare beneficiaries with cognitive impairment and their care partners.

METHODS: An exploratory qualitative research design was used. A total of 100 in-depth semi-structured interviews were conducted with a purposeful sample of CARE-IDEAS participants two to three years post-scan. A team of coders applied qualitative content analysis to identify content about the value of the scan, which was then analyzed using thematic analysis, and stratified by diagnostic category (mild cognitive impairment vs. dementia) and scan results (elevated amyloid vs. not elevated).

RESULTS: A majority of amyloid PET scan recipients and their care partners emphasized major benefits of receiving the scan including increased certainty about diagnosis, the ability to prepare for the future, potentially accessing treatment or trials, the ability to contribute to research, and limited procedural risks. Some participants also reported concerns about the cost of the scan, the lack of effective treatment options and clear prognostic information, the limited impact on their lives or treatment plans, and the emotional toll of living with the results. Their views and endorsements of the scan were shaped by their health and personal circumstances (e.g., seen as less relevant among those with rapidly declining health), and by their preference for more information and involvement in decision-making.

CONCLUSION: The perspectives of persons living with cognitive impairment and their care partners about the value of amyloid PET scans differed across disease trajectories and personal circumstances. These experiences should be taken into consideration when advising symptomatic patients on the benefits and drawbacks of biomarkers for Alzheimer's disease.},
}

Humans
*Positron-Emission Tomography/psychology/economics
Male
Female
Aged
United States
Aged, 80 and over
Medicare
*Alzheimer Disease/diagnostic imaging
*Caregivers/psychology
Qualitative Research
*Cognitive Dysfunction/diagnostic imaging
Amyloid

@article {pmid40553395,
year = {2025},
author = {Xu, Z and Zhu, Y and Liu, L and Liu, C and Zhang, Z and Li, M and Yao, L and Wang, F and Dong, Z and Gao, S and Kang, L and Shi, L},
title = {An analysis of the therapeutic efficacy and underlying mechanisms of combining lycopene with dental pulp stem cells to ameliorate alzheimer's disease in rats.},
journal = {Metabolic brain disease},
volume = {40},
number = {6},
pages = {233},
doi = {10.1007/s11011-025-01661-3},
pmid = {40553395},
issn = {1573-7365},
abstract = {The choroid plexus (CP), which is responsible for forming the blood-cerebrospinal fluid barrier, contributes to the modulation of deficits in Alzheimer’s disease (AD) by enhancing neuroinflammatory and brain immune responses. Previous research has demonstrated that lycopene (LYCO) or dental pulp stem cells (DPSCs) can attenuate AD-related inflammatory responses. However, it remains unclear whether LYCO and DPSCs can synergistically ameliorate neuroinflammation in the CP. Therefore, this study aims to investigate the feasibility of combining LYCO with DPSCs to mediate immunomodulatory effects within the CP in a rat model of AD. The findings indicated that oral administration of LYCO, transplantation of DPSCs, and the combination of these two methods significantly enhanced the learning and memory capabilities of AD rats in the water maze test, including improvements in directional sense and spatial orientation abilities. Furthermore, these treatments were associated with a reduction in pro-inflammatory mediators (TNF-α and IL-1β) and an increase in anti-inflammatory mediators (IL-10 and TGF-β1) within cerebrospinal fluid and hippocampal tissue. Furthermore, treatment with LYCO, DPSCs, or their combination effectively reverses Aβ1−42-induced upregulation of Toll-like receptor 4 expression at both mRNA and protein levels, as well as the expression of NF-κB p65. This study presents novel experimental evidence supporting the combined therapeutic potential of LYCO and DPSCs in modulating immune responses within the CP, while also offering valuable insights into the pathophysiology of AD and potential mechanisms associated with CP.},
}

@article {pmid40571874,
year = {2025},
author = {Qadir, H and Hussain, SH and Ghaffar, A and Shah, FA and Ahmed, S},
title = {Targeting Fyn Kinase for Alleviation of Cognitive Impairment in Streptozocin-Induced Alzheimer's Disease in Mice by Loperamide; An Experimental and in Silico Analysis.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {212},
pmid = {40571874},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder that leads to irreversible deterioration of neuronal cells over time. It is the most frequent cause of dementia in elderly individuals globally. Current treatment drugs exhibit modest effect on AD patients. Fyn kinase is implicated in AD pathogenesis, and its interactions with both AD hallmarks Aβ and tau make it a unique therapeutic target. To explore small molecule inhibitors effective in treating AD, FDA-approved drugs were evaluated using molecular docking to determine their affinity for Fyn kinase. The findings of molecular simulations support the repurposing of loperamide for treating AD. Swiss albino mice were divided into six groups, including sham control, STZ group, donepezil-treated positive control, and three loperamide-treated groups with varying doses (2.5, 5, 10 mg/kg). Cognitive functions were assessed using Novel Object Recognition (NOR), Morris Water Maze (MWM), and Elevated plus Maze (EPM) tests. Histological analyses were performed using Congo red, haematoxylin-eosin, and nissl staining. Gene expression of AD markers including Fyn, App, tau, Dlg4, Gfap, Bdnf, Cal1, Ide, Nep, and Sv2a were evaluated using qPCR. For protein quantification, amyloid beta 42 levels were measured using ELISA, while tau phosphorylation was assessed by immunohistochemistry. Our results show that loperamide treatment significantly improved cognitive function in mice, reduced amyloid accumulation and neuronal loss, and enhanced Aβ clearance most probably by upregulating Nep and Ide. Additionally, qPCR results revealed a significant decrease in Fyn expression. Amyloid beta 42 levels were significantly reduced by loperamide treatment, accompanied by decreased phosphorylated tau immunoreactivity in the cortex, dentate gyrus, and cornu ammonis 1 region. We conclude from these investigations that loperamide may serve as a promising therapeutic agent for AD by potentially targeting Fyn kinase, suggesting that further research is needed to explore its effectiveness in treating AD.},
}

@article {pmid41212305,
year = {2026},
author = {Li, Z and Jia, L and Huai, S},
title = {Bidirectional causal association between cathepsins and neuropsychiatric disorders: univariate and multivariate Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1775-1787},
pmid = {41212305},
issn = {1433-8491},
abstract = {BACKGROUND: Neuropsychiatric disorders are among the most common diseases worldwide and are characterized by complex pathogenic mechanisms. Cathepsins (CTS) are crucially involved in the pathogenesis and treatment of numerous diseases. Increasing evidence suggests a relationship between cathepsins and neuropsychiatric disorders. However, the causal associations remain unclear. METHODS: We performed a bidirectional two-sample Mendelian randomization (MR) analysis, applying univariable (UVMR) and multivariable MR (MVMR) to evaluate the causal association between nine cathepsins and five neuropsychiatric disorders. Data for this study were derived from genome-wide association studies (GWAS). The MR analysis primarily used five methods: Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger regression, Simple mode, and Weighted mode. Additionally, sensitivity tests were employed to assess the robustness of the MR results. RESULTS: MR analyses indicated that CTSH is associated with an increased risk of Alzheimer’s disease (AD) (UVMR: OR, 1.041; 95% CI, 1.013–1.069; p = 0.004; MVMR: OR, 1.040; 95% CI, 1.014–1.066; p = 0.003; replication UVMR: OR, 1.046; 95% CI, 1.014–1.082; p = 0.011). Findings that were significant in only one MR approach, such as the putative causal effects of CTSF on AD and bipolar disorder (BIP), of CTSL2 on major depressive disorder (MDD), and of CTSH and CTSE on Parkinson’s disease (PD) should be interpreted with caution. CONCLUSION: CTSH can be considered a plasma biomarker for AD, offering new insights and potential directions for the prevention and treatment of AD. Additionally, during the treatment of BIP and PD, attention should be paid to CTSF and CTSE expression levels to maintain physiological homeostasis.},
}

@article {pmid41372737,
year = {2025},
author = {Shah, A and Doshi, G},
title = {Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41372737},
issn = {2240-2993},
abstract = {Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis are strongly influenced by persistent stress, which accelerates both their onset and progression. This review explores the intricate interplay between chronic stressors, oxidative and metabolic imbalances, protein misfolding, inflammatory responses, and psychosocial adversity, and their cumulative impact on the aging brain’s capacity for homeostasis. The loss of cellular resilience due to prolonged stress leads to maladaptive outcomes, including mitochondrial dysfunction, sustained neuroinflammation, breakdown in proteostasis, and disruption of hypothalamic-pituitary-adrenal axis signaling, all of which amplify neuronal vulnerability. The detailed molecular pathways that underlie these phenomena, the article identifies key mediators such as Reactive Oxygen species, mitochondrial regulators, heat shock proteins, and proinflammatory cytokines that drive neurodegeneration. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar up to 2025. Eligible publications included original research articles, clinical studies, and systematic reviews focusing on stress-related molecular pathways, oxidative metabolism, proteostasis, neuroinflammation, and therapeutic interventions in aging and neurodegenerative diseases. A qualitative synthesis of these studies was performed to identify key mechanisms, biomarkers, and emerging treatment strategies relevant to stress-induced neurodegeneration. Further, the review evaluates both established and emerging interventions aimed at mitigating these stress-driven processes. Lifestyle modifications such as aerobic exercise, calorie restriction, and cognitive behavioural therapies complement pharmacological agents like antioxidants, chaperone modulators, and anti-inflammatory drugs to enhance brain resilience and delay disease onset. Recent advances in the field, including integrated multi-omics profiling, biomarker discovery, and medicine approaches, promise to refine our ability to satisfy patients and deliver targeted therapies based on individual stress profiles. Additionally, the article discusses the neuroimmune-gut axis and the potential for interventions targeting microbiome-related inflammation. Early detection of stress-related biomarkers and personalized strategies holds considerable promise for improving clinical outcomes, enabling earlier diagnosis, and fostering tailored therapies that preserve cognitive function and independence in aging populations.},
}

@article {pmid41575555,
year = {2026},
author = {Yu, S and Ye, Z and Zhao, W and Yu, X and Qiu, Y and Lin, K and Lu, T and Ge, L and Sun, J and Hua, R},
title = {Genetic evidence on chemical communication between gut microbiota and neurological and psychiatric disorders: a Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1759-1773},
pmid = {41575555},
issn = {1433-8491},
support = {2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; YN2018ZD04and2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; },
abstract = {BACKGROUND: Accumulating evidence from clinical trials and preclinical studies revealed the importance of the microbiota-gut-brain axis (MGBA) in neurological and psychiatric disorders (NPDs). MGBA remains a blueprint for extended explorations. METHODS: We examine the bidirectional association between 5 NPDs (late-onset Alzheimer’s disease (AD), migraine, autism spectrum disorder (ASD), all anxiety disorder, depression) and gut microbiota (GM) via microbial-derived metabolites, neurotransmitter, and precursors including total branched-chain amino acids (BCAA), isoleucine, leucine, valine, acetate, tryptophan, kynurenine, glutamate, tyrosine, serotonin using two step Mendelian randomization. Five methods were performed, including inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. The robustness of results was supported by Cochran’s Q test, the MR-Egger regression, the MR pleiotropy residual sum and outlier, and the leave-one-out method. RESULTS: After false discovery rate correction, we found elevated isoleucine in plasma as a risk factor for AD and elevated tyrosine in plasma as a risk factor for anxiety. Conversely, AD has genetically effect on a lower level of total BCAA, isoleucine, leucine, valine, glutamate, and tyrosine in plasma. We also found that Clostridia, Clostridiales, Sutterella, and Ruminococcus torques group were positively correlated with isoleucine. Elevated Sutterella abundance was found strongly positively correlated with ASD. Desulfovibrionales and Desulfovibrionaceae were found strongly positively correlated with AD. Pathways of Clostridia/Clostridiales/Ruminococcus torques group/Sutterella- isoleucine- AD were established with mediating percentages ranging from − 54.265% to 132.908%. CONCLUSION: Our study elucidates how chemical signalling bridges communication between GM and NPDs, paving avenues for microbiota-based treatment.},
}

@article {pmid41603981,
year = {2026},
author = {Raswanthiya, SP and Fernandes, OP and Mathew, MP and Balgote, PJ and Sivaraman, J},
title = {Decoding BDNF in neurodevelopmental, neurodegenerative, and neurological disorders: mechanisms and therapeutic perspectives.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {330},
pmid = {41603981},
issn = {1573-4978},
abstract = {Brain-Derived Neurotrophic Factor (BDNF) is an essential neurotrophin involved in neuronal survival, synaptic plasticity, and neurogenesis, critical for normal brain function as well as the pathology of neurological and psychiatric disorders. It primarily functions by activating TrkB receptors, which subsequently modulate intracellular signalling pathways such as PI3K-Akt, Ras-MAPK, and PLC-γ1. The expression of BDNF is precisely controlled by genetic, epigenetic, and transcriptional mechanisms, with environmental and activity-dependent factors providing further modulation. However, it is worth noting that BDNF dysregulation has been linked to major diseases such as depression, schizophrenia, autism spectrum disorder, epilepsy, Alzheimer’s disease (AD), and Parkinson’s disease (PD), and depression, with growing evidence supporting its use as a biomarker for disease monitoring and treatment. This review provides a comprehensive overview of BDNF synthesis, regulation, and signalling mechanisms, highlighting its context-dependent roles in both health and disease. It also examines the role of BDNF in cerebellar development, specifically its effects on granule cells, Purkinje cells, and interneurons govern neuronal survival, migration, and synaptic refinement, and its disruption may predispose to neuropsychiatric vulnerability. While BDNF modulation correlates with clinical outcomes, it remains unclear whether BDNF upregulation directly contributes to therapeutic efficacy or is merely an associated response. BDNF shows promise as a diagnostic biomarker and therapeutic target, merging mechanistic and clinical insights, but requires further research for full potential in precision medicine.},
}

@article {pmid41636819,
year = {2026},
author = {Fu, H and Feng, J and Zhang, X and Tian, L and Sun, S and Bo, H and He, C and Wang, X},
title = {Memantine mitigates radiation-induced cognitive impairment by modulating AKT/GSK3β signaling.},
journal = {Radiation and environmental biophysics},
volume = {65},
number = {1},
pages = {257-269},
pmid = {41636819},
issn = {1432-2099},
support = {NO.HYZHXM02004//State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center/ ; xcxjh20230610//Foundation of the Graduate Innovation Center, Nanjing University of Aeronautics and Astronautics/ ; },
abstract = {Memantine hydrochloride (MH), primarily employed in the clinical treatment of Alzheimer’s disease (AD), has been reported to exert beneficial effects on radiation-induced cognitive impairment; however, its underlying mechanisms have not been fully elucidated. In this study, a mouse model of radiation-induced injury was established. ICR(Institute of Cancer Research) mice were divided into six groups: control, 8 Gy irradiation, prophylactic 20 mg/kg + 8 Gy, prophylactic 40 mg/kg + 8 Gy, post-irradiation 8 Gy + 20 mg/kg, and post-irradiation 8 Gy + 40 mg/kg. Behavioral assessments indicated that ionizing radiation induced spatial cognitive deficits, which were ameliorated by MH administration. Morphological analyses revealed neuronal damage, synaptic injury, and demyelination in the hippocampal dentate gyrus (DG) region, which were markedly attenuated following MH treatment. Western blot analysis demonstrated that radiation upregulated dopamine D2 receptor (D2R) and β-arrestin 2 expression, suppressed PP2A expression, promoted AKT dephosphorylation, and led to GSK3β overactivation, along with increased expression of MBP and PLP1—potential mechanisms underlying radiation-induced cognitive impairment. MH administration downregulated D2R and β-arrestin 2, enhanced PP2A-AKT interaction, reduced GSK3β activity, and upregulated MBP and PLP1 expression. Notably, prophylactic administration conferred greater neuroprotection than post-irradiation treatment. These findings provide preliminary insight into the protective mechanisms of MH against radiation-induced cognitive impairment and offer a basis for future studies in radiation neuroprotection.},
}

@article {pmid41701395,
year = {2026},
author = {Nisar, A and Akhter, N and Chauhdary, Z and Anjum, F and Saleem, F and Sana, S and Rafiq, I and Mustafa, A},
title = {Investigating the Neuroprotective Effects of Saw Palmetto Fruit Extract Against D-Galactose and Aluminum Chloride Induced Alzheimer's Disease: In Vivo Study.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {76},
pmid = {41701395},
issn = {1573-6903},
abstract = {Serenoa repens (Saw palmetto) contain 85–90% fatty acids and other constituents include sterols rich in components as carotenoids, lipases, tannin and sugars. The purpose of this study is to investigate the therapeutic potential of Saw palmetto fruit extract against Alzheimer’s disease in a mice model. Phytochemical analysis was performed by HPLC analysis after preparation of plant extract by microwave assisted extraction technique.AD induced in mice by D-galactose and aluminum chloride 100 mg/kg of each (orally), and treated with saw palmetto fruit extract 250 mg/kg, 500 mg/kg, and 800 mg/kg were administered orally for 21 days. Neurobehavioral observations were performed to determine the pharmacological manipulation on cognitive and behavioral functions. Mice were sacrificed after behavioral studies to perform biochemical, neurochemical and gene expression analysis. Neuro-active compounds detected in HPLC analysis like chlorogenic acid, p-coumaric acid, gallic acid, HB acid and salicylic acid were screened by the molecular docking and interaction analysis. SP extract treatment showed dose-dependent neuroprotective effects as manifested by neurobehavioral, histopathological analysis which showed that with 250 mg/kg moderately enhance the synaptic density and neuronal survival. Notable neurodegenerative effects were observed at 800 mg/kg, accompanied by reduced neurodegenerative histopathology at 500 mg/kg. Phytochemicals in SP extract showed most stable conformation within the active site of target protein AChE. ADMET results sustained the computational experiments by presenting significant results, further molecular dynamic analysis also confirms the perfect interaction of the target AChE protein with Quercetin, Chlorogenic acid. These five phytochemicals could be recommended for clinical testing for management of Alzheimer’s disease.},
}

@article {pmid41746530,
year = {2026},
author = {Jadhav, VP and Mohanty, PK},
title = {Neuroprotective Effects of Citropten Against Scopolamine-Induced Cognitive Impairment and Oxidative Stress in a Rat Model.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41746530},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a chronic and progressive neurological degeneration marked by cognitive impairment and memory deficits, with oxidative stress and disturbances in the cholinergic system serving as key pathological factors. The current investigation sought to evaluate the neuroprotective and cognition-enhancing properties of Citropten (5,7-dimethoxycoumarin), a bioactive compound belonging to the coumarin class, in a scopolamine-induced cognitive impairment model. Wistar rats were divided into vehicle control, scopolamine alone, standard drug, and two Citropten-treated groups (12.5 and 25 mg/kg), and treated orally once daily for 18 days. Cognitive impairments were induced by daily scopolamine administration (2 mg/kg, i.p.) from Day 8 onward. Behavioral performance was analysed with the Novel Object Recognition (NOR), Elevated Plus Maze (EPM) and Morris Water Maze (MWM). Post-behavioral testing, brain tissues were analysed for acetylcholinesterase (AChE) activity, level of malondialdehyde (MDA), reduced glutathione (GSH), and catalase (CAT) activity. Scopolamine significantly impaired spatial, and recognition memory, as well as EPM-based learning memory performance, increased AChE activity and MDA levels, and reduced GSH and CAT activity compared with vehicle control group. Citropten treatment dose-dependently improved escape latency and target quadrant time spent in the MWM, enhanced the discrimination index in NOR test, and reduced transfer latency in the EPM. Biochemically, Citropten significantly reduced AChE and MDA levels while restoring GSH and CAT activity, showing effects comparable to the standard drug, Donepezil. Our findings demonstrate that Citropten exhibits multi-targeted neuroprotective agent, with potential relevance for mitigating cognitive dysfunction associated with cholinergic and oxidative stress pathways in scopolamine-induced cognitive impairment model.},
}

@article {pmid41758263,
year = {2026},
author = {Movaffagh, S and Behzadifard, M and Moghaddasi, M and Nazarinia, D and Jafaripour, L},
title = {Kinetin mitigate neurodegenerative damage of Alzheimer induced by beta-amyloid in male rats by antioxidant and antithrombotic effects.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41758263},
issn = {1573-7365},
abstract = {Alzheimer’s disease (AD) is a neurodegenerative disease that is charactrized by impaired memory and cognitive function. Kinetin (Kn) is a drug that possesses antioxidant and antithrombotic properties. This study aimed to evaluate the effects Kn as a potential treatment for AD in a rat model. Thirty-five Wistar rats were randomly divided into five groups: sham, Aβ, Aβ + 0.5 mg/kg Kn, Aβ + 1 mg/kg Kn, and 1 mg/kg Kn. Beta-amyloid was administered via bilateral intraventricular injection of 10 µl. KN was injected intraperitoneally for two weeks. Subsequently, behavioral tests were conducted, and plasma was used for the thrombolytic test. Hippocampal tissue was analyzed for oxidative stress markers, inflammatory cytokine expression, apoptosis-related gene expression, and neuronal damage. In the Aβ group, behavioral tests demonstrated impaired memory. Levels of plasminogen activator inhibitor-1 (PAI-1), malondialdehyde (MDA), the expression of tumor necrosis factor-alpha (TNF-α) and BAX genes, and the number of degenerated neurons in the hippocampus were significantly increased compared to the sham group. Conversely, glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), plasma tissue plasminogen activator (t-PA) level, and bcl-2 gene expression were significantly decreased in the Aβ group relative to sham controls. Treatment with kinetin improved memory performance and significantly reduced plasma level of PAI-1, MDA, and TNF-α, BAX expression, and neuronal degeneration. Additionally, kinetin significantly increased GSH, SOD, CAT, t-PA levels, and bcl-2 gene expression. Our study showed that kinetin, especially at a dose of 1 mg/kg, with its antioxidant and antithrombotic properties, reduces hippocampal tissue damage following Aβ-induced Alzheimer’s disease, thereby alleviating memory and learning impairments in rats.},
}

@article {pmid41831181,
year = {2026},
author = {Jankowski, WM and Fichna, J and Tarasiuk-Zawadzka, A},
title = {Can Nutrition Modulate the Progression of Alzheimer's Disease? A Narrative Review.},
journal = {Current nutrition reports},
volume = {15},
number = {1},
pages = {},
pmid = {41831181},
issn = {2161-3311},
support = {#503/1-156-04/503-11-001//Uniwersytet Medyczny w Lodzi/ ; },
abstract = {PURPOSE OF REVIEW: Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the nervous systems, along with the accumulation of abnormal proteins in brain structures. The most common neurodegenerative disease is Alzheimer’s disease (AD), which manifests as memory loss, cognitive deficits, communication difficulties, personality changes and impaired ability to perform daily activities. The purpose of this study is to gather available information on the relationship between dietary habits and the pathogenesis of AD. RECENT FINDINGS: A growing body of scientific literature points to the important influence of diet and its nutrients on the mechanisms of AD development. Polyphenols play a key role in reducing oxidative stress and inflammation in the brain. B vitamins, as well as vitamins A, C, D and E, help protect neurons and improve cognitive function. In addition, omega-3 fatty acids, inhibit the formation of amyloid beta deposits and reduce hyperphosphorylation of tau protein. It is worth noting that the Mediterranean diet has shown beneficial effects on brain health, in contrast to the Western diet, which promotes the development of these conditions. Recent studies also emphasize the role of the gut microbiota and its metabolites, such as short-chain fatty acids, as factors involved in preventing the development of AD. A balanced diet, such as the Mediterranean diet, rich in antioxidants, anti inflammatory components and supportive of a healthy gut microbiome, can slow the progression of AD and serve as a complementary approach to its treatment.},
}

@article {pmid41854817,
year = {2026},
author = {Yang, H and Fu, R and Duan, Y and Hua, Y and Wei, T and Li, G and Gu, X and Li, M and Yu, X and Li, L and Cao, L and Wang, ZZ and Zhang, C and Lv, Y and He, M and Xiao, W},
title = {Tubuloside B Alleviates Aβ25-35 Induced PC12 Cell Injury by Attenuating Pyroptosis, Apoptosis and Excessive Autophagy.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41854817},
issn = {1476-3524},
support = {2440STCZB2614//industrial foundation reengineering and high-quality development of manufacturing industry/ ; },
abstract = {Cistanche, a traditional Chinese medicine with reported neuroprotective effects, contains multiple bioactive constituents whose specific mechanisms of action remain incompletely defined. Here, we aimed to identify a key neuroprotective component and explore its potential mechanism against Aβ-induced neurotoxicity. Fourteen commercially available Cistanche-derived compounds were screened for neuroprotection in an Aβ25-35 (Aβ fragment 25–35)-injured PC12 cell model. The most active compound, Tubuloside B (TB), was further investigated using polymerase chain reaction (PCR) array, immunoblotting, flow cytometry, immunofluorescence, and mitochondrial function assays. TB exerted concentration-dependent protective effects in the Aβ25-35-injured PC12 model. Aβ25-35 exposure was associated with marked activation of pyroptotic signaling, characterized by caspase-1 activation, GSDMD cleavage, and increased interleukin (IL)-1β/IL-18 levels. These alterations were substantially blunted in the presence of TB. Modulation of the absent in melanoma 2 (AIM2) inflammasome pathway was further supported by reduced AIM2 expression and diminished apoptosis-associated speck-like protein containing a CARD (ASC) speck formation. Mitochondrial perturbations induced by Aβ25-35, including excessive mitochondrial reactive oxygen species (ROS) generation, membrane depolarization, and cytosolic mtDNA accumulation, were concurrently ameliorated by TB. In addition, markers of apoptosis and dysregulated autophagy were partially normalized following TB treatment. These findings suggest that TB may contribute to neuroprotection in an Aβ25-35-induced PC12 cell model, potentially involving modulation of mitochondrial dysfunction–associated inflammasome activation and downstream cell death pathways. Given the in vitro design and limited sample size, these results should be considered preliminary and warrant further validation in vivo.},
}

@article {pmid41863595,
year = {2026},
author = {Ji, J and Li, Z and Xing, A and Luo, G and Zhai, X and Xu, W and Li, J and Tan, T and Jia, R and Yan, Y and Zhang, X and Wang, L and Li, J and Li, K},
title = {Causal relationships between alzheimer's disease genetics and brain connectivity alterations: a multi-modal mendelian randomization study with transcriptomic validation of 191 rs-fMRI and 635 DTI neuroimaging traits.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41863595},
issn = {1931-7565},
support = {2023XM016//Four "Batches" Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province/ ; 0033/2023/RIB2//The Science and Technology Development Funds of Macao/ ; RP/FCA-14/2023//a Grant from Macao Polytechnic University/ ; },
abstract = {Traditional observational magnetic resonance imaging (MRI) studies have revealed changes in brain connectivity in Alzheimer’s disease (AD). However, the findings have been inconsistent due to small sample sizes and potential confounding factors. The genetic effects of AD on the inherent brain activity and connectivity of patients are still not well understood. We utilized summary-level GWAS data for 223,906 Europeans from three large AD cohorts and comprehensive GWAS data for 191 rs-fMRI functional connectivity (FC) traits (n = 34,691) and 635 diffusion tensor imaging (DTI) metrics (n = 33,292) from the BIG Knowledge Portal. A bidirectional two-sample Mendelian randomization (MR) analysis with multiple MR methods was performed to evaluate the causality between AD genetics and genetically predicted whole-brain functional and structural connectivity changes. A series of sensitivity analyses were systematically conducted to assess the pleiotropy, heterogeneity, and outliers. Additionally, SNP-to-gene mapping, enrichment analysis, protein-protein interaction (PPI), single-SNP, and SNP location-based MR were performed to elucidate the molecular mechanisms. To validate our findings, we analyzed an independent cohort from ADNI (n = 30/group) and performed transcriptomic validation using RNA-seq data from 63 samples (32 AD, 31 control). Our MR analysis revealed significant causal associations between AD and specific alterations in fMRI FC, particularly involving the precuneus, occipital lobe, and default mode network. Similarly, AD was causally linked to changes in fractional anisotropy (FA) and mean diffusivity (MD) across distinct white matter fiber tracts. The molecular mechanisms underlying these MRI changes involved polygenic contributions from multiple AD-associated SNPs, primarily those mapped to non-coding regions, in addition to genic SNPs enriched in pathways regulating amyloid-beta clearance and neuroinflammation. External validation using the ADNI cohort confirmed the FC alterations identified through MR. Transcriptomic validation confirmed the significant upregulation of four genes (CTSB, SDC4, CTNND2, and FERMT2) in AD and uncovered three potential AD-associated genes (ITGB1BP1, FBXO33, and RASGEF1C). Our multi-modal MR study elucidated causal links between AD genetics and brain imaging-derived phenotypes (IDPs), with independent validation from both neuroimaging and transcriptomic analyses. These findings enhance understanding of AD etiology and identify potential MRI markers for diagnosis and treatment monitoring.},
}

@article {pmid41863703,
year = {2026},
author = {Al-Kuraishy, HM and Jabir, MS and Rafeeq, MF and Sulaiman, GM and Albuhadily, AK and Al-Gareeb, AI},
title = {Targeting of neuroinflammation, oxidative stress, and synaptic dysfunction by vinpocetine in alzheimer's disease: a comprehensive appraisal.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863703},
issn = {1573-7365},
abstract = {Alzheimer disease (AD) is a neurodegenerative disease presented with progressive memory loss and cognitive impairment. Deposition of extracellular amyloid beta (Aβ) peptide and intracellular neurofibrillary tangles (NFTs) are the hallmarks of AD neuropathology. Progressive accumulation of Aβ and NFTs results in the development of inflammation/ neuroinflammation, oxidative stress, synaptic failure, neuronal apoptosis, and the development of AD. However, no single drug is effective as disease modifying treatment for AD, as many cellular and molecular signaling pathways beyond Aβ and NFTs are involved in AD neuropathology. Mounting evidences indicated that phosphodiesterase enzymes (PDEs) mainly PDE1 are involved in AD neuropathology. PDEs are intricate in the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are reduced in AD. Consequently, this review aims to revise the role of PDEs, and PDE1 selective inhibitor vinpocetine (VPN) in AD neuropathology. VPN by its anti-inflammatory and antioxidant effects can reduce inflammatory and oxidative stress in AD correspondingly. At molecular levels, VPN by targeting peroxisome proliferator activated receptor γ coactivator 1 α (PGC1α), brain derived neurotrophic factor (BDNF) and SIRT1 can mitigate AD neuropathology. Despite of these evidences, however there is limited clinical evidence for the efficacy of VPN in AD. Therefore, large-prospective clinical studies are warranted in this regard.},
}

@article {pmid41863721,
year = {2026},
author = {Maidh, A and Kalra, P and Khan, H and Silakari, P and Grewal, AK},
title = {Circadian disruption as a driver and target in neurodegenerative diseases: from molecular mechanisms to chronotherapeutic strategies.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863721},
issn = {1573-7365},
abstract = {The Circadian System is a complex network of coordinated clocks that regulates the organism’s internal clock in synchronisation with the outside world. These rhythms are controlled by genetically controlled positive and negative transcriptional-translational feedback loops (TTFL) that generate 24-hour oscillations in the protein level and mRNA of core circadian components. Circadian disruption is recognised as a significant contributor to the molecular pathogenesis of neurodegenerative illnesses, as disease-specific alterations in clock gene expression and melatoninergic signalling have been identified as possible early-stage molecular indicators. Emerging evidence suggests a link between dysregulated circadian rhythms and neurodegenerative diseases, implying that the changes in circadian function may play a critical role in the development and progression of neurodegenerative diseases. The correlation between circadian rhythm and neurodegeneration is highly promising for developing treatment and promoting healthy lifestyle measures. This review article primarily focuses on how abnormalities in circadian rhythms may increase the risk of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Applying knowledge from pre-clinical and translational research on neurodegenerative diseases is crucial for lowering the risks of neurodegeneration and improving the symptoms and quality of life of people with neurodegenerative diseases through approaches that restore circadian rhythm in the context of precision medicine. Understanding this interaction holds promise for developing therapeutic approaches to support a healthy lifestyle.},
}

@article {pmid41910845,
year = {2026},
author = {Nekabari, MK and Ben-Azu, B and Chijioke, BS and Esuku, DT and Chidebe, EO and Friday, FB and Usin, SG and Iwhiwhu, P and Moses, AS and Diakparomre, O and Onyeukwu, OB},
title = {Lipopolysaccharide-induced Neuroimmune Alteration and Memory Decline in Aging Mice: The Role of Augmented Cellular Senescence.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41910845},
issn = {1476-3524},
abstract = {Alzheimer’s disease (AD) remains a complex neurodegenerative disorder with multifactorial etiologies, often eluding effective modeling in preclinical studies. However, whether neuroinflammation, exacerbated by accelerated cellular senescence, is central to AD pathology induced by lipopolysaccharide, an endotoxemia agent, remains unknown. This study investigated a combination of lipopolysaccharide (LPS)-induced AD-like neuroinflammation with doxycycline-induced conditioned cellular senescence in mice. Following a 21-day doxycycline (DOXY)-induced cellular senescence in mice, neuroinflammation was induced by LPS from days 15–21. AD-related cognitive decline was investigated through spatial and non-spatial memory tests, oxidative stress, molybdoenzymes, acetylcholinesterase activity, inflammation, amyloid-beta levels, hypoxia-inducible factor (HIF-α) and brain-derived neurotrophic factors (BDNF) in brain regions affected by AD pathology, such as the hippocampus and prefrontal cortex (PFC). Behavioral assessments revealed that both LPS and DOXY independently impaired spatial and non-spatial working memory, locomotor activity, social interaction, and recognition memory, with their interactive treatment exacerbating these deficits significantly. Biochemical analyses revealed synergistic increases in pro-inflammatory cytokines (IL-1β, TNF-α, but not IL-4), oxidative stress markers (malondialdehyde, nitrite), astrocyte activation (GFAP), and amyloid-beta levels, with decreases in antioxidant defenses (GSH, GST, SOD, catalase) in the hippocampus and PFC. The DOXY + LPS group showed higher serum corticosterone levels, increased sulphite-oxidase in the PFC, and increased xanthine-oxidase and acetylcholinesterase in both regions, indicating an amplified stress response and cholinergic dysfunction. Conversely, DOXY + LPS interaction lowered hippocampal-targeted BDNF and HIF-α levels. These findings validate the role of cellular senescence in enhancing LPS-induced neuroinflammation, mimicking complex AD features, and provide a model for testing disease mechanisms and therapeutics.},
}

@article {pmid41931192,
year = {2026},
author = {Du, M and Ma, S and Bai, L and Mou, X and Gao, Y and Zhang, J and Chen, Y},
title = {Olfactory Dysfunction Exacerbates Hippocampal Aβ Accumulation, Tau Phosphorylation and Memory Deficits in Mice.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41931192},
issn = {1573-6903},
support = {202401AU070130//Natural Science Foundation of Yunnan Province/ ; 202301AT070430//Natural Science Foundation of Yunnan Province/ ; 202305AS350011//innovation team of stress and disorder in nervous system in Yunnan Province/ ; 82201597//the National Natural Science Foundation of China/ ; KUST-KH2022001Y//the Joint Medical Specialization of Kunming University of Science and Technology/ ; },
abstract = {Olfactory dysfunction is a frequent feature in patients with neurodegenerative disorders such as Alzheimer’s disease (AD). However, whether olfactory impairment is the cause or consequence of AD is unknown. We previously found that olfactory dysfunction impairs learning and memory in mice in multiple experimental paradigms, but whether olfactory dysfunction increases AD-related neuropathological changes such as Aβ deposition and tau protein phosphorylation is not clear. In this study, mice were treated with bilateral intranasal zinc sulfate (ZnSO4) solution infusion, which resulted in olfactory dysfunction for about 1 month in mice. 1, 3, 6, and 9 months after that, the Y-maze learning and memory, as well as hippocampal Aβ deposition, tau and p-tau expression were tested. We found that olfactory dysfunction leads to a long period and irreversible learning and memory impairment in mice. Olfactory dysfunction also increased Aβ deposition, Aβ42 level, and increased p-tau expression in hippocampus (HPC), which were accompanied by increased beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and decreased presenilin-1 (PS1) expression. Compared with one time of ZnSO4 treatment, repetitive ZnSO4 treatment (three times, a month apart) resulted in more significant increases in tau phosphorylation in mice hippocampus. These results suggest that olfactory dysfunction lead to behavioral and pathological changes associated with AD in mice, which suggest that olfactory dysfunction can contribute to the development of AD.},
}

@article {pmid41944966,
year = {2026},
author = {Riaz, M and Qadir, H and Noman, M and Ahmed, S and Shah, FA and Malik, MU and Bashir, K and Farooq, U and Irshad, N},
title = {Mechanistic Insights into Bergapten by Modulation of Filamin A and GSK3β in STZ Induced Alzheimer's Disease: An Integrated In Silico, In Vitro and In Vivo Study.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41944966},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction and neuroinflammation. The study investigates bergapten (BGN) as a potential AD treatment. Computational analysis revealed strong binding affinity of BGN with Filamin A (FLNA) and glycogen synthase kinase-3β (GSK3β). In vitro assays demonstrated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition suggesting cholinergic modulation. In intracerebroventricular (i.c.v) streptozotocin (STZ) induced AD mice model, BGN (25 mg/kg, 50 mg/kg and 100 mg/kg i.p) was administered daily for 23 days. The blood and brain tissues samples were collected for biochemical and histopathological analysis. BGN showed dose-dependent cognitive improvements, with biochemical tests indicating renal and hepatic safety. Reduced C-reactive protein and lactate dehydrogenase levels suggested minimal systemic toxicity and neuroinflammation. Histology revealed preserved neurons, decreased amyloid deposits, and improved brain structure. Immunohistochemical analyses indicated BGN was associated with lower Tau, NF-κB, TLR4, and Caspase-3 expression and restored redox homeostasis. Critically, ELISA confirmed reduced FLNA along with Aβ and GSK-3β levels and thus highlights BGN novel modulation of this unexplored AD target. RT-PCR analysis showed downregulated expression of amyloid precursor protein, tau, discs large scaffold protein 4 and glial fibrillary acidic protein, while enhanced synaptic plasticity markers. Collectively, these findings suggest BGN as a promising multi-target neuroprotective and safer agent for AD.},
}

@article {pmid41945111,
year = {2026},
author = {Lai, Z and Zhang, B and Fu, Z and Li, R and Qian, Y and Zhang, Y and Xu, P and Du, Y},
title = {Research advances on Cordyceps sinensis and its components in relation to omics biomarkers for the neurological disorders.},
journal = {Die Naturwissenschaften},
volume = {113},
number = {3},
pages = {},
pmid = {41945111},
issn = {1432-1904},
support = {2026ZL0010//Zhejiang Traditional Chinese Medicine Science and Technology Program of China/ ; 82202605//National Natural Science Foundation of China/ ; 2023, DU YAOQIANG//Zhejiang Provincial Special Support Program for Cultivation of High-Level Innovative Health Talents of China/ ; },
abstract = {Cordyceps is a traditional medicinal fungus belonging to the species Ophiocordyceps sinensis. It grows in the alpine ecological zone of the Tibetan Plateau and exhibits dual characteristics of both insects and fungi. The primary species include Cordyceps sinensis and Cordyceps militaris. Rich in bioactive components such as cordycepin, polysaccharides, adenosine, and peptides, cordyceps demonstrates broad applications in immune regulation, anti-tumor activity, anti-inflammatory, and neuroprotection. Cordyceps sinensis and its components show great therapeutic potential in neurological diseases such as epilepsy, Alzheimer’s disease and Parkinson’s disease through multi-level and multi-target actions However, current research faces challenges including unclear mechanisms of action and insufficient clinical translation. In this review, we analyze the molecular mechanisms underlying cordyceps’ neuroprotective effects, including the regulating of apoptosis, improvement of mitochondrial function, and promoting of nerve repair. Utilizing network pharmacology, we explore the multi-targeted actions of cordyceps and predict the key pathways. Further we summarize the research progress in the integrated multi-omics analyses (genomics, transcriptomics, proteomics and metabolomics), to reveal the synergistic roles of cordyceps components in treating neurological disorders and identify potential molecular biomarkers. Additionally, we highlight the findings from preclinical experiments and animal models on cordyceps-based drugs, discussing their advantages and challenges for clinical application. Future studies should prioritize systematic exploration of standardized drug development, advanced multi-omics integration, and rigorous clinical trials. This will provide a more robust scientific foundation and practical guidance for the treatment of neurological diseases with cordyceps.},
}

@article {pmid42010038,
year = {2026},
author = {Nakatsuji, M and Shibano, M and Fujimori, K},
title = {Antioxidant Activity of Flavonoid Glabranin by Upregulating Antioxidant Gene Expression via MEK/ERK and PI3K/Akt Pathways in Human Neuroblastoma SH-SY5Y Cells.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42010038},
issn = {1573-6903},
support = {25ak0101219h0202//Japan Agency for Medical Research and Development/ ; },
abstract = {Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of Glycyrrhiza glabra (licorice), exhibits antioxidant and anti-inflammatory properties. However, the effect of glabranin on the antioxidant response and the underlying mechanism including the specific signaling pathways, remain unclear. In the current study, we investigated the protective effect of glabranin on hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. H2O2-induced death of SH-SY5Y cells was restored by glabranin in a concentration-dependent manner. The number of H2O2-increased apoptotic cells was reduced by co-treatment with glabranin. Moreover, glabranin attenuated H2O2-induced cleaved caspase-3/7 levels. In addition, glabranin decreased H2O2-induced intracellular ROS levels via promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 and upregulating the antioxidant gene expression. Furthermore, glabranin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) following H2O2 treatment. Inhibition of mitogen-activated protein kinase kinase (MEK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways abrogated glabranin-mediated elevation of antioxidant gene expression and neuroprotective effects. These findings suggest that glabranin mitigated H2O2-induced apoptosis by increasing the expression of antioxidant genes through activation of the MEK/ERK and PI3K/Akt pathways in SH-SY5Y cells. Therefore, glabranin has the potential to prevent and treat neurodegenerative diseases as an antioxidant agent.},
}

@article {pmid42050692,
year = {2026},
author = {Rahbek, MT and Kildegaard, H and Hallas, J and Ernst, MT and Lund, LC},
title = {Acetylcholinesterase inhibitors and the risk of delirium - a Danish nationwide register-based cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02060-1},
pmid = {42050692},
issn = {1758-9193},
abstract = {BACKGROUND: Delirium is frequent in people with dementia and is linked to adverse outcomes. Disturbed cholinergic neurotransmission is implicated in its pathophysiology. We examined whether continuous use of acetylcholinesterase inhibitors (AChEIs) is associated with a reduced risk of incident delirium in patients with dementia. METHODS: Using Danish nationwide registries (2005–2024), we identified individuals ≥ 50 years initiating AChEIs. Continuous users (second prescription within 90 days) were compared with early discontinuers. Follow-up started 90 days after initiation and continued for up to 3 years. The outcome was a hospital discharge diagnosis of delirium (ICD-10 F05). Confounding was addressed using high-dimensional propensity score (hdPS) fine-stratification weighting, and Cox regression yielded hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 45,651 patients, 311 delirium events occurred among continuous users and 84 among early discontinuers, corresponding to incidence rates of 66 and 112 events per 10,000 person-years, respectively. The hdPS-weighted HR for delirium was 0.72 (95% CI 0.54–0.96). Results were consistent across sensitivity analyses and in patients with Alzheimer’s disease HR 0.68 (95% CI 0.48–0.96). A negative control outcome showed no association. CONCLUSIONS: Continuous AChEI treatment was associated with a lower risk of delirium. Findings support a potential benefit of maintaining therapy in routine dementia care, and possibly even in patients with minor intolerance to acetylcholinesterase inhibitors.},
}

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

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

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

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

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

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

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

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

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

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

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

@article {pmid42284682,
year = {2026},
author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Doré, V and Laws, SM},
title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.},
journal = {EBioMedicine},
volume = {129},
number = {},
pages = {106329},
doi = {10.1016/j.ebiom.2026.106329},
pmid = {42284682},
issn = {2352-3964},
abstract = {BACKGROUND: Accumulation of brain amyloid beta (Aβ), a key pathological hallmark of Alzheimer's disease (AD), begins decades before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which Aβ exceeds a critical threshold, may enable intervention to delay or prevent onset of AD.

METHODS: Using published genome-wide association studies (GWASs), we developed polygenic scores (PGS) for AD risk (PGSrisk) and resilience (PGSresilience), and tested whether these predicted (i) if an individual is an Aβ accumulator ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ exceeds a 20 centiloid (CL) threshold ('Age at onset of Aβ'; AAO-Aβ) in 2175 participants (1158 with AAO-Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. We also performed GWASs on these traits to develop phenotype-specific PGSs.

FINDINGS: Higher genetic risk of AD predicted increased odds of Aβ accumulation (OR = 1.16; 95% CI = 1.05-1.29; p = 0.003) and younger AAO-Aβ (β = -1.32; SE = 0.31; p = 1.63 × 10[-5]). Higher genetic resilience to AD predicted later AAO-Aβ (β = 0.91; SE = 0.29; p = 0.002) but did not predict Aβ accumulation. These associations were independent of APOE ε4 status, the strongest genetic risk factor for AD. Phenotype-specific PGSs were not significantly associated with either trait.

INTERPRETATION: Polygenic scores, alongside other risk factors, may help identify individuals at risk of accumulating Aβ, and predict the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.

FUNDING: National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).},
}

@article {pmid42288063,
year = {2026},
author = {Zhao, H and Qian, S and Wang, Y and Yang, W},
title = {Information quality of Alzheimer's disease treatment videos on TikTok and related factors: A cross-sectional study.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {152},
number = {},
pages = {112144},
doi = {10.1016/j.jocn.2026.112144},
pmid = {42288063},
issn = {1532-2653},
abstract = {BACKGROUND: The increasing reliance on mobile internet for health information necessitates a critical evaluation of content quality. This study aimed to systematically assess the quality of Alzheimer's Disease (AD) treatment-related short videos on TikTok, a leading platform for health information dissemination.

METHOD: A total of 100 CE treatment videos from TikTok, retrieved on December 20, 2025, were comprehensively evaluated using established assessment tools. Specifically, the Journal of American Medical Association (JAMA) benchmark criteriaand themodified Decision-making Information Support Criteria for Evaluating the Reliability of Non-randomised Studies (mDIS) scorewere used to evaluate thereliabilityof the video content. TheGlobal Quality Score (GQS) was used to assess theoverall quality, and the Patient Education Materials Assessment Tool for Audio Visual Content (PEMAT-A/U)was used to evaluate understandability and actionability.

RESULTS: Neurologists were identified as primary contributors of high-quality content, while videos on experimental treatments like deep cervical lymphovenous anastomosis (LVA) generally exhibited lower quality. Videos from emerging first-tier cities and those uploaded by top-tier creators demonstrated superior audience engagement and often higher content quality. A significant positive correlation was found between video duration, audience engagement metrics, and content quality scores.

CONCLUSIONS: Neurologists play a crucial role in providing reliable AD treatment information on short video platforms. There is an urgent need to improve the quality of content on experimental treatments and to encourage longer, well-referenced videos. Platforms should enhance content moderation and explicitly label experimental therapies to ensure accurate and trustworthy public health education regarding AD.},
}

@article {pmid42289507,
year = {2026},
author = {Yazi, S and Ozen, B and Buldu, B and Yalcin, E and Karakose, O and Cakmak, O and Somunkiran, S and Yananli, HR and Sehirli, US and Kirazli, O},
title = {The effect of canagliflozin on hippocampal dendrite morphology in a model of Alzheimer's disease induced by intracerebroventricular injection of streptozotocin.},
journal = {Brain structure & function},
volume = {231},
number = {6},
pages = {},
pmid = {42289507},
issn = {1863-2661},
mesh = {Animals ; *Canagliflozin/pharmacology/administration & dosage ; *Alzheimer Disease/pathology/chemically induced/drug therapy ; Male ; Streptozocin/administration & dosage ; *Dendrites/drug effects/pathology ; Rats ; *Hippocampus/drug effects/pathology ; Disease Models, Animal ; Donepezil/pharmacology ; Dendritic Spines/drug effects/pathology ; Pyramidal Cells/drug effects/pathology ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Rats, Wistar ; Rats, Sprague-Dawley ; },
abstract = {Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathophysiological features. However, the effects of antidiabetic drugs on neurodegeneration are not completely known. Canagliflozin, a novel option for DM treatment, is a dual inhibitor of sodium glucose co-transporter type 2 (SGLT2) and acetylcholinesterase. The aim of this study is to examine the morphological features of dendrites and dendritic spines of pyramidal neurons in hippocampus of AD model treated with canagliflozin. The model of AD was obtained by intracerebroventricular injection of streptozotocin. Then, the rats were divided into 3 groups: vehicle, donepezil, and canagliflozin. The injections were i.c.v. administered for 7 days. Behavioral tests were performed to evaluate memory, anxiety, and motor functions. Brain tissues were processed by Golgi impregnation method. Pyramidal neurons in the CA1 region were examined using Neurolucida software. Dendritic branching, total dendrite length, dendritic spine density, and dendritic spine types were analyzed. Compared to the vehicle group, the donepezil group and the canagliflozin group exhibited significantly higher dendritic branches (p = 0.0273, p = 0.0195) and total dendrite length (p = 0.0171, p = 0.0360), respectively. The total dendritic spine density (p < 0.0001) and the mushroom-type dendritic spine density (p = 0.0001) were significantly low in the donepezil group compared to the vehicle group. However, canagliflozin did not induce any significant alterations in the dendritic spine density. Canagliflozin treatment was as effective as donepezil treatment on hippocampal dendrite morphology. This morphological framework, indicating dendritic plasticity and remodeling, serve to better understand the cellular effects of canagliflozin. Therefore, our study may contribute to the development of novel strategies for therapy of AD.},
}

Animals
*Canagliflozin/pharmacology/administration & dosage
*Alzheimer Disease/pathology/chemically induced/drug therapy
Male
Streptozocin/administration & dosage
*Dendrites/drug effects/pathology
Rats
*Hippocampus/drug effects/pathology
Disease Models, Animal
Donepezil/pharmacology
Dendritic Spines/drug effects/pathology
Pyramidal Cells/drug effects/pathology
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
Rats, Wistar
Rats, Sprague-Dawley

@article {pmid42291413,
year = {2026},
author = {Sha, Y and Fu, H and Lu, K and Wang, G and Wang, Y},
title = {The role of YKL-40 in Alzheimer's disease pathology and drug targeting.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21361},
pmid = {42291413},
issn = {2167-8359},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Chitinase-3-Like Protein 1/metabolism/antagonists & inhibitors ; Animals ; Biomarkers/metabolism ; Apoptosis ; Disease Progression ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques, hyperphosphorylated tau tangles, and significant neuronal loss. Recent studies have implicated YKL-40, a glycoprotein commonly associated with inflammation and neural apoptosis, in the pathogenesis of AD.

METHODS: We conducted extensive searches across major scientific databases, including PubMed, Web of Science, and Embase. We selected peer-reviewed articles, review articles, and clinical studies focusing on YKL-40 in AD.

RESULTS: This review comprehensively analyses the multifaceted role of YKL-40 in AD, covering its cellular localization, biomarker associations, and pathological mechanisms. We also summarize the mechanistic pathways by which YKL-40 contributes to disease progression, highlighting its role in neuroinflammation, neural apoptosis, and disruption of the circadian regulation of immune responses. Moreover, the development of drugs that target YKL-40, such as humanized anti-YKL-40 antibodies and small molecules, offers promising strategies for blocking AD progression.

CONCLUSION: This review highlights the potential of YKL-40 as a novel drug target and its implications for enhancing diagnostic precision and treatment strategies in combating Alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Chitinase-3-Like Protein 1/metabolism/antagonists & inhibitors
Animals
Biomarkers/metabolism
Apoptosis
Disease Progression

@article {pmid42292330,
year = {2026},
author = {Mukhopadhyay, D and Das, P and Angom, RS and Dutta, S and Li, Z and Castanedes-Casey, M and Kulkarni, T and Chakravarty, T and Wang, E and Dickson, D and Rachamala, HK},
title = {Vascular endothelial growth factor receptor-1 (VEGFR-1) knock-down is protective against hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril -induced neuronal cell death: implications in AD pathogenesis.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1799391},
pmid = {42292330},
issn = {1662-4548},
abstract = {INTRODUCTION: Recent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor-1 (VEGFR-1/FLT1) and in AD brain. Increased expression of VEGFR1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between increased VEGFR-1 expression in AD pathogenesis. In this study, we explored the potential role of VEGFR-1 expression in neurons on AD pathology.

METHODS: To confirm VEGFR1 expression in AD brains, we first performed immunostaining in AD brain sections (AD - Braak stage V-VI, and normal controls - Braak 0-II). And to determine a potential detrimental role of neuronal VEGFR1 expression on AD associated pathologies, we exposed SH-SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O2) or 5 μ Aβ1-42 oligomers or fibrils for 24, 28 and 72hrs.

RESULTS: In this study, we found preferential staining of VEGFR-1 in the neuropil and neuronal cell bodies both in AD and Control hippocampus and increased VEGFR-1 immunoreactivity in dystrophic neuritic processes in the vicinity of Thio-S positive amyloid plaques in AD brains. And treatment of SH-SY5Y human neuroblastoma cell line and mouse primary neurons, with either hypoxia conditions or Aβ1-42 oligomers, resulted in increased VEGFR-1 expression and cleaved caspase 3 activation, leading to neuronal toxicities/cell death. Similarly, treatment with Aβ1-42 fibrils also increased VEGFR-1 and cleaved caspase 3 protein levels in the SH-SY5Y cells whereas treatment with Aβ1-42 monomers had no effect on VEGFR-1 expression. In addition, we show that over-expression of VEGFR-1 intracellular domains in SH-SY5Y cells directly induced neuronal toxicities and importantly, siRNA-mediated knockdown of VEGFR-1 in neurons prevented the hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced toxicities and cell death phenotypes. Treatment with either hypoxia or Aβ1-42 oligomers also reduced expression of cell survival genes including VEGFR-2 and Hippo pathway YAP1 and siRNA-mediated VEGFR-1 knockdown in the neurons normalized expression of both VEGFR-2 and YAP1. Using differential gene expression analysis, we demonstrated upregulation of several inflammatory/interferon-stimulated genes (ISGs) as well as increased expression of genes involved in activation of oxidative stress and cell death pathways in response to Aβ1-42 oligomers treatment in mouse primary neurons. And siRNA-mediated VEGFR-1 knockdown in the mouse primary neurons, reduced gene expression of both the ISGs and oxidative stress/cell death pathways in response to Aβ1-42 oligomer treatment.

DISCUSSION: In summary, these results show that siRNA-mediated knockdown of VEGFR-1 in neurons significantly prevented hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced cellular toxicities and cell death phenotypes, indicating a potential detrimental role of aberrant VEGFR-1 expression and signaling in response to AD associated pathologies.},
}

@article {pmid42292846,
year = {2026},
author = {Lindemann, L and Lambotte, J and Rothe, J and Messer, J and Diener, C and Pichereau, S and Cantrill, C and Mueggler, T and Honer, M and Beck, J and Steinbrecher, T and Tortelli, R and Gerlach, I and Ratni, H and Rodriguez Sarmiento, RM and Baumann, K},
title = {Pharmacology of nivegacetor (RG6289), a potent and selective gamma secretase modulator in clinical development for the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1783414},
pmid = {42292846},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder which involves a complex pathobiology driven by amyloid-beta (Aβ) and tau pathologies, among other factors. Aβ peptides are generated via β-secretase (BACE1) and γ-secretase cleavage of amyloid precursor protein (APP). While long isoforms like Aβ42 are neurotoxic and aggregation-prone, shorter isoforms (Aβ38, Aβ37) are non-amyloidogenic. γ-secretase modulators (GSMs) shift production from longer to shorter peptides which is expected to slow down or halt (prevent) amyloid accumulation and its downstream effects.

METHODS: The novel GSM nivegacetor was evaluated in vitro using cell lines overexpressing human wild-type APP, or human APP with the Swedish mutation K670N/M671L (APPSwe). The in vitro selectivity of nivegacetor was tested on Notch-1, a representative gamma secretase substrate other than APP. Additionally, nivegacetor was profiled for its selectivity on a range of pharmacological targets. In vivo studies tested a dose-response and a time course of nivegacetor on soluble Aβ levels in brain tissue of APPSwe transgenic mice. Furthermore, the impact of two ADAD mutations, PSEN1 E280A (Columbian) and PSEN2 N141I (Volga German), on nivegacetor's potency was tested. Moreover, nivegacetor was tested for possible effects on [[3]H]florbetaben binding to Aβ plaque pathology in human AD brain tissue sections.

RESULTS: Nivegacetor lowered the production of Aβ42 and Aβ40 and concomitantly increased levels of Aβ37 and Aβ38 in vitro and in vivo in mice. Nivegacetor did not inhibit Notch-1 and showed a favorable selectivity profile on a broad range of targets. When tested on two ADAD mutations, nivegacetor was equipotent on the PSEN1 E280A mutation and significantly less potent on the PSEN2 N141I mutation compared to wild-type gamma secretase. Nivegacetor did not interfere with the detection of amyloid plaques by [[3]H]florbetaben in human AD brain tissue, which is an important prerequisite for the use of florbetaben as a PET tracer in clinical trials.

CONCLUSION: Nivegacetor is a potent, orally bioavailable GSM with favorable properties and is currently under investigation as a clinical candidate in a Phase 2A clinical trial in individuals with prodromal and early sporadic AD, and in a Phase 2 clinical trial in individuals carrying the PSEN1 E280A ADAD mutation.},
}

@article {pmid42274866,
year = {2026},
author = {Lefcourt, S and Kim, A and Huang, P and Weiss, C and , and Jones, C},
title = {Multi-scale Radiomic Fingerprint: Quantifying Spatial Changes in Biology.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02041-8},
pmid = {42274866},
issn = {2948-2933},
support = {HT9425-23-1-0032//U.S. Department of Defense/ ; },
abstract = {Traditional radiomic studies build texture matrices using single-voxel increments. However, useful information may emerge when radiomic features are instead evaluated across multiple spatial scales. Moreover, basing these scales on physical units may produce results that are more interpretable to clinicians. We propose a multi-scale radiomic approach that defines texture distances in millimeter-based units to capture a more inclusive range of texture information, promote reproducibility, and improve clinician interpretability. We examine the variance in quantified radiomics across multiple spatial scales and diseases, including venous malformations, gliomas, Alzheimer's disease, brain metastases, and multiple sclerosis. We subsequently generated anisotropic counterparts to originally isotropic datasets to compare their performance in clinical predictive modeling. Finally, we evaluate differences between radiomic features captured at millimeter and voxel units. We discovered that the radiomic features captured at different millimeter scales were almost always statistically different (p < 0.05) across five diseases. Predictive modeling revealed that models trained on radiomics extracted from multiple millimeter scales consistently had a higher mean F1 across folds compared to those built from voxel scales. Roughly 93%, 90%, and 88% of texture metrics were statistically different between millimeter and voxel scales for venous malformations, Alzheimer's, and gliomas, respectively, suggesting that variations in spatial scale may capture differences in biology. We demonstrate that a multi-scale, millimeter-based alternative to fixed-distance voxel-based radiomics captures previously unacquired textural information while remaining clinically interpretable. This approach may have broad implications in all applications of clinical radiomic analysis, including disease diagnosis, monitoring, and treatment evaluation.},
}

@article {pmid42274906,
year = {2026},
author = {He, Y and Yi, T and Min, M and Xu, K and Lin, H and Xu, R and Deng, D and Xiao, X},
title = {Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42274906},
issn = {1995-8218},
abstract = {This review illustrates how environmental stressors disrupt glutamate homeostasis via specific mechanisms: lead-induced thiol modification, manganese mediated yin yang 1 (YY1)-histone deacetylases (HDAC) repression, PM2.5-triggered microglia-astrocyte crosstalk, and advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-nuclear factor kappa-B (NF-κB) signaling from high-sugar diets. Together with genetic susceptibility and pigment epithelium-derived factor (PEDF), these factors impair astrocytic glutamate uptake, promoting synaptic glutamate accumulation. Subsequent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor overactivation triggers calcium overload, mitochondrial dysfunction, oxidative stress, and neuroinflammation-termed "degenerative excitotoxicity". Excitotoxicity manifests in Alzheimer's disease (amyloid-beta-excitatory amino acid transporter 2 (EAAT2) interplay), Parkinson's disease (subthalamic nucleus-driven excitatory storm), and amyotrophic lateral sclerosis (astrocytic failure versus neuronal cell-autonomous mechanisms). Future interventions need multi-target strategies, emerging technologies, and lifestyle modifications. This convergent framework offers a unified understanding linking environmental exposure to neurodegeneration and charts a roadmap toward mechanism-based prevention and treatment.},
}

@article {pmid42275797,
year = {2026},
author = {Lahiri, D and Kathir, S and Punjwani, Z and Liu, A and Pasvanis, S and Seixas-Lima, B and Roncero, CT and Chertkow, H and , },
title = {Application of a clinical scale for predicting Aβ-positivity in a multicentre Canadian dementia cohort: A necessity in the era of amyloid targeting treatment.},
journal = {Journal of the neurological sciences},
volume = {488},
number = {},
pages = {126047},
doi = {10.1016/j.jns.2026.126047},
pmid = {42275797},
issn = {1878-5883},
abstract = {BACKGROUND: Clinical Amyloid positivity Prediction Score (CAPS) is a clinical tool developed on a small Canadian cohort with clinical Alzheimer's Disease (AD) to help predict amyloid-beta (Aβ) positivity. The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study is a national Canadian observational study of participants clinically diagnosed with various neurodegenerative disorders, including Alzheimer's syndrome, making it an ideal platform to validate CAPS on an independent but similar cohort of participants.

METHODS: Participants from the COMPASS-ND cohort with Subjective Cognitive Impairment (SCI), Mild Cognitive Impairment (MCI) or dementia due to AD, and a known Aβ status were included. CAPS was assigned to the individuals as follows: cognitive decline of >2 points/year on the Mini-Mental State Examination (MMSE) = 1-point, Neuropsychiatric Inventory Questionnaire (NPI-Q) ≥2 = 2 points, and low Fazekas score (0 or 1) = 1 points. A total CAP score ≥ 2 was considered indicative of Aβ positivity.

RESULTS: Total 86 participants fulfilled the inclusion criteria. Aβ + individuals had higher NPI-Q scores (2 vs 0.5, p = 0.005) and a lower baseline MMSE score (26.5 vs 28.0, p = 0.009). High WMH on brain MRI was reported more frequently in the Aβ- subgroup (50.0% vs 33.8%, p < 0.001). The frequency of people with a CAPS score of ≥2 is significantly higher in the Aβ + subgroup (75% vs 50%, p < 0.001). CAPS demonstrated a reasonable predictive value in this cohort, with 67% accuracy, and 73% sensitivity.

CONCLUSION: This validation study in a larger Canadian cohort showed that CAPS demonstrated reasonable accuracy in distinguishing between Aβ + and Aβ- subgroups.},
}

@article {pmid42276063,
year = {2026},
author = {Ishikawa, KI and Shiga, T and Hirose, T and Kuzumaki, N and Miyoshi, S and Yamaguchi, A and Tamune, H and Sarkar, AK and Nakai, K and Baba, K and Okabe, S and Hattori, N and Okano, H and Akamatsu, W},
title = {Suppression of ATM kinase signaling accelerates cellular senescence.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102956},
doi = {10.1016/j.stemcr.2026.102956},
pmid = {42276063},
issn = {2213-6711},
abstract = {Cells derived from rejuvenated human induced pluripotent stem cells (hiPSCs) require extended culture periods to achieve functional maturation, and it remains difficult to recapitulate cellular senescence in these cells in vitro. This limitation hinders the accurate and efficient modeling of age-related neurodegenerative diseases. Here, we aimed to establish a simple approach to promote neuronal maturation and improve the efficiency of hiPSC-based disease modeling. Using a small-molecule inhibitor library, we identified an ATM kinase inhibitor, KU60019, that promotes both maturation-associated features and senescence-associated phenotypes in hiPSC-derived neurons and fibroblasts. KU60019 treatment promoted the manifestation of disease-relevant phenotypes in hiPSC models of age-related neurodegenerative diseases. Furthermore, senolytic analyses suggested that KU60019-induced senescent cells depend on pro-survival pathways, including HSP90-associated signaling. These findings suggest that KU60019 provides a simple and useful tool for accelerating phenotypic recapitulation in hiPSC models of age-related neurodegenerative diseases.},
}

@article {pmid42276200,
year = {2026},
author = {Alruwaili, NS and Al-Kuraishy, HM and Al-Gareeb, AI and Shokr, MM and Bogari, NM and Alhelfawi, S and Alruwaili, M and Batiha, GE},
title = {Beyond categorical boundaries: Common molecular and cellular pathways in autism spectrum disorder and schizophrenia.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111774},
doi = {10.1016/j.pnpbp.2026.111774},
pmid = {42276200},
issn = {1878-4216},
abstract = {Historically, ASD and schizophrenia have been classified as two distinct disorders, one being a neurodevelopmental disorder and the other a psychotic disorder. Recent studies, however, suggest that there may be substantial overlap between these disorders. Here, we will discuss some of the biological mechanisms involved in the development of these diseases that show similarities. These include dysregulation of the dopaminergic, serotonergic, glutamatergic, GABAergic, and acetylcholinergic systems; changes in BDNF signaling; histamine dysregulation; microglial activation; neuroinflammation; complement-mediated synapse elimination; gut-brain axis signaling; and endocannabinoid system dysfunction. It is important to note that the aforementioned biological mechanisms are present in several CNS disorders, such as major depressive disorder, Alzheimer's disease, and multiple sclerosis. While it is true that other CNS disorders share the same biological mechanisms as ASD and schizophrenia, the similarity between these disorders stands out for a particular reason. First, the biological mechanisms present in ASD and schizophrenia are significantly similar; second, their heritability is highly consistent; third, they have similar developmental trajectories; fourth, they exhibit similar circuit-level pathology; fifth, they share bidirectional epidemiological risks; and sixth, they follow a neurodevelopmental continuum. Recognizing this overlap has potential implications for early detection, biomarker development, and transdiagnostic treatment strategies, including repurposing medications such as memantine, α7-nicotinic agonists, and anti-inflammatory agents. However, longitudinal studies are needed to determine whether early targeting of shared pathways modifies long-term psychosis risk in ASD.},
}

@article {pmid42276536,
year = {2026},
author = {Kshirsagar, S and Reddy, AP and Reddy, PH},
title = {Restoration of mitochondrial dynamics and synaptic function by mitophagy enhancers in a tauopathy cell model.},
journal = {Mitochondrion},
volume = {},
number = {},
pages = {102184},
doi = {10.1016/j.mito.2026.102184},
pmid = {42276536},
issn = {1872-8278},
abstract = {OBJECTIVES: To evaluate whether mitophagy enhancers-including urolithin A, actinonin, tomatidine, and nicotinamide riboside-can counteract mitochondrial dysfunction and synaptic damage induced by phosphorylated Tau in Alzheimer's disease.

METHODS: We Used immortalized mouse hippocampal primary HT22 neurons expressing mutant Tau (mTau-HT22). We treated cells with mitophagy enhancers and measured gene and protein levels of mitochondrial dynamics, biogenesis, mitophagy, synaptic markers, assessed cell viability, mitochondrial respiration, and examined mitochondrial morphology via transmission electron microscopy.

RESULTS: Compared to controls, mTau-HT22 cells exhibited increased mitochondrial fission and reduced fusion, diminished mitochondrial biogenesis, impaired mitophagy and synaptic gene expression, reduced cell survival, lower respiration, and fragmented mitochondria. Treatment with all mitophagy-enhancing compounds improved mitochondrial dynamics-, biogenesis-, and mitophagy-related marker expression together with mitochondrial functional outcomes, with urolithin A showing the strongest effects. Notably, a combined treatment of urolithin A with EGCG further enhanced respiratory function beyond single-agent treatments.

CONCLUSIONS: Mitophagy enhancers, particularly urolithin A alone or in combination with EGCG, restore mitochondrial and synaptic health in Tau-induced toxicity models. These findings position mitophagy enhancement as a potential therapeutic approach requiring further validation in Alzheimer's disease.},
}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid42046101,
year = {2026},
author = {Andrews, D and Golchi, S and Collins, DL and , },
title = {A digital twin methodology using retrospective patient data for sample size reduction in Alzheimer's disease clinical trials.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42046101},
issn = {1758-9193},
support = {FRN 165921/CAPMC/CIHR/Canada ; RGPIN-2015-03633//Natural Sciences and Engineering Research Council of Canada/ ; FRN 165921/CAPMC/CIHR/Canada ; },
abstract = {BACKGROUND: Recruitment for Alzheimer’s disease randomized controlled trials (RCTs) is difficult and expensive. To reduce RCT sample sizes while maintaining high statistical power, our Digital Twin Trial (DTT) methodology combines an interpretable cognitive decline prediction model with prediction-powered inference. Unlike RCT sample size reduction techniques that maintain power by recruiting only patients likely to decline, prediction-powered inference is used within the data analysis stage of the trial and does not impose additional restrictions on participant eligibility.

METHODS: For DTT participants, our model identifies similar individuals (“Digital Twins”) from a retrospective trial-matched database and uses their cognitive scores to predict decline. Predictions adjust observed scores, reducing variance within treatment groups. We simulated 18-month DTTs and standard RCTs using mixed effects models of decline in Alzheimer’s Disease Neuroimaging Initiative subjects meeting lecanemab’s Phase 3 inclusion criteria.

RESULTS: Predicted and observed change in Clinical Dementia Rating Sum-of-Boxes correlated at r = 0.437. DTTs required 9.5–19.0% fewer subjects than standard RCTs to detect a simulated 25% decline-slowing drug effect at 0.9 power. DTT Type 1 error was consistent with 0.05.

CONCLUSIONS: DTTs could reduce clinical trial recruitment and cost burdens without imposing additional inclusion criteria, enabling efficient testing of new treatments in all populations who might benefit. Model interpretability will foster clinician and regulator trust in individualized prognoses. This transparency could help smooth the model’s translation to real trials and eventually the clinic, where it could help make prognoses and better evaluate treatment effects in individual patients.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02024-5.},
}

@article {pmid42266508,
year = {2026},
author = {Khajuria, P and Kour, D and Sharma, K and Singh, L and Banoo, R and Manhas, D and Ramajayan, P and Nandi, U and B Bharate, S and Ahmed, Z and Kumar, A},
title = {AMPK-mediated autophagy induction by bisdemethoxycurcumin attenuates senescence and amyloid pathology in 3xTg-AD mice.},
journal = {Autophagy reports},
volume = {5},
number = {1},
pages = {2675164},
pmid = {42266508},
issn = {2769-4127},
abstract = {Alzheimer disease (AD) pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in Curcuma longa, stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed the senescent phenotype by ameliorating the impaired autophagy. Interestingly, the senescent phenotype persisted when autophagy was downregulated by knockdown of AMPK. Additionally, BDMC-induced autophagy aided in the removal of amyloid beta (Aβ) that was administered externally to the astrocytes. Further, to validate these results in a mouse model of AD, we confirmed that BDMC significantly penetrates the blood-brain barrier (BBB) in mice. Therefore, we administered 50 and 100 mg/kg b.w. of BDMC to transgenic 3xTg-AD mice for two months. In their hippocampus, the Control 3xTg-AD animals showed more senescent cells and lower autophagy levels. In contrast, autophagic proteins were significantly upregulated while senescence indicators, such as senescence-associated secretory phenotype (SASP) proteins, were sharply downregulated in the brain of treated animals. We discovered that the hippocampus of treated mice had a significantly lower Aβ load. These molecular changes in the brain were ultimately reflected in the improved working memory and neuromuscular coordination behavior of mice treated with BDMC. This study warrants further evaluation of BDMC for the management of AD.},
}

@article {pmid42266879,
year = {2026},
author = {Amuthan, S and Senthilkumar, NC},
title = {Ensemble Deep Learning Denoising (EDLD) model and optimized OTSU segmentation for Alzheimer's disease diagnosis using MRI images.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1743818},
pmid = {42266879},
issn = {2624-8212},
abstract = {Diagnosing Alzheimer's disease (AD) is necessary to determine treatment options. AD categorization using machine learning (ML) relies on difficult, manually specified features. The most important stage in AD diagnosis is denoising to restore image stability and quality. An ensemble image denoising technique that combines Attention Guided Convolutional Neural Network (AGCNN), Adaptive Denoising Autoencoder (ADAE), and Gaussian Deep Belief Network (GDBN) improves image denoising performance. The hybrid AGCNN reduces noise and aligns along the global route by combining global and local characteristics. In ADAE, the encoder learns picture representations using convolutional layers (CLs) while the decoder uses deconvolutional layers. In addition, the GDBN extends the standard Deep Belief Network (DBN) to Gaussian Restricted Boltzmann Machines (RBMs). Ensemble learning selects the approach with the greatest Peak Signal-to-Noise Ratio (PSNR) to integrate learning outcomes. After separating the background from the foreground by calculating the variances within the two groups, OTSU determines the threshold that minimizes the weighted sum of the variances. Levy Grasshopper Optimization Algorithm (LGOA) optimizes threshold selection by mimicking grasshopper swarming. VGG16, the DCNN model, is pre-trained for Alzheimer's datasets. The results are Sensitivity (SEN -95.86%), specificity (SPC - 94.93%), precision (PPV - 94.55%), F1-score (F1 - 95.21%), accuracy (ACC -95.87%), and Area Under the Receiver Operating Characteristic Curve (AUC - 96.45%) assess system and method performance.},
}

@article {pmid42267529,
year = {2026},
author = {Lohnes, BJ and Myskova, A and Tyagi, A and Hartwig, UF and Poddar, NK},
title = {Rewiring mTOR signaling in Alzheimer's disease: emerging mTOR modulators beyond oncology.},
journal = {Bioscience reports},
volume = {46},
number = {6},
pages = {},
doi = {10.1042/BSR20260203},
pmid = {42267529},
issn = {1573-4935},
mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology/enzymology/metabolism ; *TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; Signal Transduction/drug effects ; Animals ; *MTOR Inhibitors/therapeutic use ; },
abstract = {While Alzheimer's disease (AD) is the most common cause of dementia, curative treatments remain unavailable. Despite distinct pathologies between AD and cancer, shared dysregulation of the PI3K-AKT-mTOR signaling pathway promotes both disease states. mTOR activity significantly contributes to AD hallmarks, including amyloid-beta production, tau hyperphosphorylation, and altered metabolism and autophagy through mTOR-mediated signaling and downstream targets such as BACE-1, GSK-3β, and AChE. Consequently, mTOR-modulating compounds, demonstrating promising results in oncology, present a viable strategy to potentially halt or reverse AD progression. This review discusses the potential application of 37 mTOR pathway-modulating compounds, many originally developed for cancer treatment, given their shared molecular targets. We systematically classified the compounds based on their origin as marine, plant-derived, structural analogs, and synthetic compounds. This framework reveals a fundamental trade-off, as the structural novelty and pleiotropic effects of natural products are often counterbalanced by poor pharmacokinetics, whereas the pharmacological precision of synthetic compounds is frequently limited by compensatory feedback loops. Furthermore, we analyze translational challenges, including balancing efficacy with toxicity, limitations in blood-brain barrier penetration, and the need for patient stratification using robust biomarkers. We conclude that the most promising therapeutic approach for AD involves synergistically combining natural products with rational synthetic design. Leveraging natural products as a source of novel chemical scaffolds and employing targeted synthetic engineering to overcome their pharmacokinetic limitations, this strategy moves beyond blunt pathway inhibition. Ultimately, this enables a highly nuanced modulation of the mTOR network, providing the basis for future preclinical and clinical drug development in AD.},
}

Humans
*Alzheimer Disease/drug therapy/pathology/enzymology/metabolism
*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors
Signal Transduction/drug effects
Animals
*MTOR Inhibitors/therapeutic use

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

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

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

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

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

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

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

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

@article {pmid42268602,
year = {2026},
author = {Moore, GJ and Bose, N and Henter, ID and Manji, HK},
title = {The 25-Year Evolution of Lithium as a Disease-Modifying Agent in Dementia: A Narrative Review.},
journal = {JAMA psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamapsychiatry.2026.1296},
pmid = {42268602},
issn = {2168-6238},
abstract = {IMPORTANCE: Lithium, a long-established cornerstone therapy for bipolar disorder, is a biologically plausible disease-modifying agent for neurodegenerative disorders, including mild cognitive impairment (MCI) and Alzheimer disease (AD).

OBSERVATIONS: Rather than targeting a single pathology like amyloid or tau, lithium acts across multiple cellular resilience pathways. Chronic lithium exposure induces the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), enhances brain-derived neurotrophic factor (BDNF) signaling, inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes mitochondrial function, and reduces oxidative stress. These convergent mechanisms promote neuronal survival and synaptic integrity. In humans, proton magnetic resonance spectroscopy studies found that lithium increased N-acetylaspartate levels, consistent with improved neuronal viability, and structural magnetic resonance imaging (MRI) studies found that lithium preserved gray matter and/or reversed illness-related atrophy in hippocampal and corticolimbic regions. In addition, extensive evidence demonstrates that low-dose lithium (approximately 0.3mM)-significantly lower than traditional psychiatric doses (0.6-1.0mM)-exerts robust neurotrophic and neuroprotective effects. Preclinical models have found that these concentrations stimulate hippocampal neurogenesis, promote structural plasticity, and protect against proteotoxic injury. Furthermore, epidemiological studies have associated cumulative lithium exposure with reduced dementia risk, and early randomized clinical trials in MCI suggest cognitive stabilization and favorable tau biomarker changes at low, well-tolerated doses. The recent repletion hypothesis suggests that lithium may also function as a physiological trace element, but these findings await independent replication.

CONCLUSIONS AND RELEVANCE: These convergent data support a prospective clinical trial of low-dose lithium orotate to slow disease progression in MCI. Such an approach would prioritize established neuroprotective mechanisms while potentially mitigating the kidney and thyroid risks associated with higher-dose carbonate formulations. If low-dose lithium can indeed meaningfully alter disease trajectory, it would represent a much-needed, accessible, and inexpensive treatment that may be especially relevant in low- and middle-income countries.},
}

@article {pmid42269217,
year = {2026},
author = {Chae, HJ and Kwon, H and Son, SR and Moon, S and Park, AY and Bae, HJ and Jang, DS and Kim, DH},
title = {Fukinolic acid facilitates toxic amyloid-β oligomerization and exacerbates synaptic dysfunction.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119619},
doi = {10.1016/j.biopha.2026.119619},
pmid = {42269217},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) aggregates that induce synaptic dysfunction and neuronal loss. Among the various Aβ species, soluble oligomers are considered the most neurotoxic forms and play a critical role in AD progression. Fukinolic acid (FA), a polyphenolic compound isolated from medicinal plants, has been reported to possess antioxidant and anti-inflammatory activities; however, its effects on Aβ aggregation have not been investigated. In the present study, we investigated whether FA modulates Aβ aggregation and synaptic dysfunction. Molecular docking analysis suggested that FA directly interacts with Aβ monomers at aggregation-prone regions. Consistent with this prediction, FA facilitated the formation of toxic Aβ oligomers and enhanced Aβ-induced neuronal cytotoxicity. The potentiation of Aβ toxicity by FA was abolished by an N-methyl-D-aspartate (NMDA) receptor antagonist, indicating the involvement of NMDA receptor-dependent signaling. Electrophysiological recordings showed that FA exacerbated Aβ-induced long-term potentiation (LTP) impairment in hippocampal slices without affecting basal synaptic transmission. In addition, FA administration increased Aβ deposition and reduced neuronal viability in the hippocampus of 5XFAD mice. FA treatment showed non-significant trends toward reduced hippocampal LTP and spontaneous alternation in the Y-maze test, indicating that further studies are required to determine whether FA affects synaptic and cognitive function in vivo. These findings suggest that FA promotes toxic Aβ oligomer formation and may aggravate Aβ-associated synaptic impairment through NMDA receptor-dependent mechanisms, highlighting the importance of evaluating the effects of natural compounds on Aβ pathology in AD.},
}

@article {pmid42270143,
year = {2026},
author = {Semiz, M and Millien, E and Simoes Loureiro, I},
title = {Comparing approaches to treating anomia in early Alzheimer's disease: Network model-based method vs. embodied cognition method.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-29},
doi = {10.1080/09602011.2026.2685294},
pmid = {42270143},
issn = {1464-0694},
abstract = {Semantic memory is affected early on in Alzheimer's disease (AD), leading to language difficulties such as anomia. Defined as the inability to find words during speech, anomia constitutes a real obstacle to the quality of life of AD patients. The aim of this research is to study the benefits of two treatment methods: the ESFA (Elaborated Semantic Feature Analysis) method, based on abstractive network models of semantic memory, and the TERM (Treatment by Embodied Reactivation of Memory) method, a new sensorimotor stimulations therapy based on the theory of embodied cognition. 19 patients with early-stage AD (MMSE ≥20/30) were distributed into two groups: ESFA group (N = 10, 7 women and 3 men; mean age = 82.7, SD = 4.52) and TERM group (N = 9, 8 women and 1 man; mean age = 81.78, SD = 7.26). Groups were equal, and comparisons were possible. While the ESFA method allows a broad improvement in both trained (W = -2.809; p = .005) and untrained (W = -2.194; p = .028) items, the TERM method seems to lead to an item-centered effect (W = -2.668; p = .008). Moreover, only with the TERM method, the benefits seem to be maintained (W = -1.715; p = .086). Further studies are still needed to further investigate the benefits of these two interesting methods.},
}

@article {pmid42271174,
year = {2026},
author = {Sdougkou, K and Rekka, E and Papagiannopoulou, D},
title = {Synthesis and Evaluation of Novel Cinnamic Acid Hybrids With Antiacetylcholinesterase, Antioxidant, and Anti-Inflammatory Properties.},
journal = {ChemMedChem},
volume = {21},
number = {11},
pages = {e70343},
doi = {10.1002/cmdc.70343},
pmid = {42271174},
issn = {1860-7187},
abstract = {Alzheimer's disease, one of the most widespread neurodegenerative disorders, is known for its multifactorial nature that makes it challenging to treat. In the present work, hybrid molecules were designed and synthesized combining the anti-acetylcholinesterase (AChE) activity of donepezil with the antioxidant and/or anti-inflammatory activity of selected cinnamic acids. In particular, the new derivatives were conjugated by Steglich esterification or amidation of suitable benzylpiperazine/piperidine moieties with ferulic, sinapic, 3,4-dimethoxycinnamic acids. All new molecules were evaluated for their activity in terms of AChE inhibition, while molecules that carried a phenolic group were also evaluated for their ability to inhibit lipid peroxidation. A representative group of compounds were studied in vivo for their anti-inflammatory activity with very encouraging results in paw-induced edema in mice. The 3,4-dimethoxycinnamic and sinapic acid esters with a two-carbon linker exhibited the strongest inhibition of AChE with nanomolar values of IC50. In addition, the sinapic esters demonstrated the highest antioxidant and anti-inflammatory activity. Thus, the above results indicate that the new sinapic acid derivatives based on donepezil combine anti-AChE, anti-inflammatory, and antioxidant activities, which warrant their further evaluation as new lead compounds in the treatment of related neurodegenerative diseases.},
}

@article {pmid42272624,
year = {2026},
author = {Pham, D and O'Brien, C and Florez-Bhandari, J and Faulstich, N and Ojo, T and Aloi, S and Goodwin, R and Roley, L and Nathaniel, SI and Nathaniel, TI},
title = {Risk factors associated with cancer and metabolic encephalopathy in Alzheimer's disease patients.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1810937},
pmid = {42272624},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) frequently coexists with risk factors that modify its clinical course. The combined presence of cancer and metabolic encephalopathy (ME) in AD represents a particularly vulnerable and understudied phenotype. We investigated whether cancer-associated risk profiles differ between AD patients with and without metabolic encephalopathy.

METHODS: We used multivariate logistic regression to identify clinical, vascular, pulmonary, neurocognitive, psychiatric, and treatment-related factors distinguishing (i) AD patients with metabolic encephalopathy with and without cancer (AD + ME ± C) and (ii) AD patients without metabolic encephalopathy with and without cancer (AD - ME ± C). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were used to identify risk factors and phenotype-specific associations.

RESULTS: Of the total cohort, 10,516 patients had metabolic encephalopathy, and 118,253 did not. Cancer coexistence was present in 146 AD + ME patients and 1,167 AD - ME patients. Among AD + ME patients, cancer was strongly associated with cerebrovascular accident (OR = 3.47, 95% CI 2.16-5.59), secondary dementia (OR = 9.89, 95% CI 3.26-29.98), mild cognitive impairment (OR = 5.20, 95% CI 1.98-13.27), chronic obstructive pulmonary disease (OR = 7.66, 95% CI 5.20-11.29), and SSRI use (OR = 3.27, 95% CI 2.21-4.87). In contrast, memantine, buspirone, and valproate were associated with AD + ME without cancer. Among AD-ME patients, cancer was associated with dyslipidemia, peripheral vascular disease, congestive heart failure, arteriosclerosis, COPD, and cutaneous ulcers, reflecting chronic systemic illness.

CONCLUSION: Metabolic encephalopathy was associated with a different clinical profile in cancer-associated AD. Patients with ME exhibited increased systemic and neurologic vulnerability (e.g., vascular comorbidity and frailty indicators) rather than differences in baseline cognitive severity alone.},
}