@article {pmid42743871,
year = {2026},
author = {Guin, S and Jangli, A and Dandekar, MP},
title = {Dimethyl fumarate ameliorates amyloid-beta generated cognitive deficits by inhibiting RIPK1/RIPK3/MLKL necroptosis signalling in rats.},
journal = {International immunopharmacology},
volume = {189},
number = {},
pages = {117407},
doi = {10.1016/j.intimp.2026.117407},
pmid = {42743871},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive dysfunction. Necroptosis plays a pertinent role in the neurobiology of AD, which is governed by receptor-interacting protein kinases (RIPK) and mixed lineage kinase domain-like protein (MLKL). Dimethyl fumarate (DMF), a disease-modifying drug used to treat multiple sclerosis, is also known to inhibit necroptosis pathway. Herein, we examined the effect of DMF in C6 cell line and Aβ1-42-induced AD model. DMF treatment reversed the C6 cell viability and expression of RIPK1, RIPK3, and MLKL in lipopolysaccharide model. Intracerebroventricular injection of Aβ1-42 in rats developed the cognitive deficits. Administration of DMF, at 25 and 50 mg/kg doses via peroral route for 14 days, showed a decrease in escape latency and increased exploration of target quadrant Morris water maze test. DMF-recipient rats also displayed exploration of novel object in novel object recognition test, while locomotor activity remained unchanged in open field test. DMF reduced oxidative processes by decreasing lipid peroxidation and increasing catalase and glutathione. Moreover, DMF treatment decreased the levels of IL-6, TNF-α, and CRP cytokines in frontal cortex. A significant downregulation of RIPK1, RIPK3, and MLKL gene expression and protein expression of p-MLKL were observed in the hippocampus following DMF treatment. DMF was also able to improve synaptic plasticity by increasing the expression of synaptophysin, BDNF, MBP, and PSD95, which were determined by using immunoblot. Our results indicate the cognitive improvement and neuroprotective effects of DMF in Aβ1-42 CE model by modulating the necroptosis signalling. We suggest that the selective targeting of necroptosis process may open new treatment avenues for AD.},
}

@article {pmid42743907,
year = {2026},
author = {Coskun, EP and Barber, J and Bojarski, L and McLouth, CJ and Abner, EL and Van Eldik, LJ and Nelson, PT and Jicha, GA},
title = {Autopsy findings in Alzheimer's disease clinical trial participants demonstrate a high frequency of off-target coexisting pathologic features.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100669},
doi = {10.1016/j.tjpad.2026.100669},
pmid = {42743907},
issn = {2426-0266},
abstract = {BACKGROUND: Having multiple comorbid neuropathologic features may confound the results of interventional trials that were designed to target a specific pathophysiologic mechanism in Alzheimer's disease (AD) and or related dementias (ADRD). However, it is unknown what percentage of individuals undergoing AD/ADRD interventional studies have mixed pathologies.

OBJECTIVE: To characterize the spectrum of coexisting neuropathologies in brains of AD/ADRD clinical trial participants to inform trial design and therapeutic strategies METHODS: Autopsied participants from the University of Kentucky Alzheimer Disease Research Center (UK-ADRC) community-based cohort who died between January 2005, and February 2024 were included and queried retrospectively for participation in therapeutic interventional trials. Of a total of 614 autopsied cases, 67had been enrolled in one of the following types of clinical trials: cognitively normal participants in prevention trials for AD/ADRD (designated group P; n = 21); interventions for mild cognitive impairment or early dementia (MCI/D; n = 26); and, interventions for vascular cognitive impairment (V; n = 20). The trial-engaged groups were compared to the trial-naïve group in terms of their demographic, clinical, and genetic characteristics. Pathological features (amyloid-β, tau, α-synuclein, TDP-43, and cerebrovascular disease) were assessed using consensus-based neuropathologic methods.

RESULTS: All interventions were designed to target only a single pathologic feature. The trial-engaged group did not differ significantly from those who were trial-naïve with respect to demographic, genetic (APOE), or clinical characteristics, except for a marginally higher level of education among trial participants (p=0.04). Pure on-target pathology (i.e., only one isolated pathology was found at autopsy that was the signature pathology targeted by the intervention) was only seen in 10, 23, and 29 % of the engaged participants of V, MCI/D and P trials respectively. Comorbid pathologies were common in all three groups. On average, the trial-engaged groups altogether had a mean of 2.54 pathologic features/person, whereas the MCI/D trial-engaged group had a mean of 3.2 pathologic features/person.

CONCLUSION: Multi-etiology dementia was the norm rather than the exception for AD/ADRD trial participants. Recognizing the heterogeneity of multiple pathologies in clinical trial participants may enable the development of improved inclusion/exclusion criteria, as well as the rational use of antemortem biomarkers to stratify the likelihood of mixed comorbid pathologies that may be undesirable for single-target interventional studies. Further, multitargeted treatment strategies may be required in future trials of disease-modifying agents.},
}

@article {pmid42744009,
year = {2026},
author = {Chen, X and Fu, P and Kang, C and Wu, Y and Wu, Y and Luo, X and Chen, L and Liu, H and Ouyang, J and Zhang, M and Yin, X and Chen, Z},
title = {The mechanism of cerebellar involvement in cognitive disorders and therapeutic prospects.},
journal = {Experimental gerontology},
volume = {225},
number = {},
pages = {113324},
doi = {10.1016/j.exger.2026.113324},
pmid = {42744009},
issn = {1873-6815},
abstract = {The cerebellum has traditionally been regarded as a brain region primarily involved in motor coordination and balance. However, increasing evidence suggests that the cerebellum plays a significant role in multiple higher-order cognitive functions. This review explores the mechanisms underlying cerebellar involvement in cognitive impairment, focusing on four prevalent cognitive disorders: Alzheimer's disease, vascular cognitive impairment, Parkinson's disease dementia, and frontotemporal dementia. Analysis of existing neuroimaging, neuropathological, and clinical studies indicates that cerebellar structural and functional abnormalities constitute a common pathological feature of cognitive dysfunction in these conditions. Deepening our understanding of cerebellar-cerebral interactions offers new perspectives for early diagnosis, disease monitoring, and therapeutic interventions in cognitive disorders. This review also summarizes research on the cerebellum as a potential target for non-invasive brain stimulation therapy, which holds promise for opening up new avenues for intervention in cognitive disorders and ultimately leading to better treatment outcomes and quality of life for patients.},
}

@article {pmid42744302,
year = {2026},
author = {Reskiawan A Kadir, R and Bons, J and Vega Hormazabal, G and Vadhana Ashok Kumaar, P and Gerónimo-Olvera, C and Tshilenge, KT and Pihán, P and Galicia Aguirre, C and Schneider, K and Roberts, A and Ambrose, BD and Lerner, C and Devanney, NA and Sandholm, AM and Hady, M and Alderfer, S and Hetz, C and Furman, D and Gerencser, AA and Verdin, E and Schilling, B and Ellerby, LM},
title = {The longevity gene APOE2 enhances pericyte function and reduces lipid droplets.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag311},
pmid = {42744302},
issn = {1460-2156},
abstract = {Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer's disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity. To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation. Using unbiased proteomic profiling to understand these cellular phenotypes, we found significant alterations in lipid metabolism-related proteins. Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet (LD) accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated LD accumulation in APOE3 and APOE4 pericytes. Collectively, these findings demonstrate that APOE2 expression supports pericyte functionality through increased lipid processing, providing mechanistic insight into the cerebrovascular protective effects of APOE2 in pericytes. These findings could be translated into novel therapies aimed at enhancing pericyte function and lipid metabolism, particularly in individuals at risk for neurodegenerative diseases.},
}

@article {pmid42745524,
year = {2026},
author = {Chandrasekaran, A and Paget-Blanc, A and Decourt, B and Sabbagh, MN},
title = {Investigating oral blarcamesine for treatment of early Alzheimer's disease.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14656566.2026.2732056},
pmid = {42745524},
issn = {1744-7666},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative dementia affecting millions globally. Therapies primarily consist of symptomatic management and progression limitation. Further advances in treatments include disease-modifying therapies, many of which have unfavorable safety profiles and modest improvements in cognitive function. The need for novel disease-modifying therapies continues to grow as the burden of AD in the population increases.

AREAS COVERED: We outline approved disease-modifying therapies including the mechanisms of autophagy restoration through SIGMAR1 activation and its impact on neuronal homeostasis, and how oral blarcamesine, a SIGMAR1 agonist, demonstrates promise for early onset AD management. We then describe the Phase IIa and IIb/III clinical trials supporting the efficacy of blarcamesine in AD patients and other neurodegenerative diseases. Additionally, we discuss recent preclinical evidence supporting a preventive role for blarcamesine in AD. A Pubmed search was conducted for relevant literature regarding this topic using keywords including, but not limited to, 'blarcamesine,' 'disease-modifying therapy,' 'precision medicine,' 'sigma-1 receptor,' and 'SIGMAR1 agonist.'

EXPERT OPINION: Blarcamesine is a potential oral disease-modifying therapeutic candidate for early-stage AD that acts upstream of amyloid-beta pathogenesis and could prevent AD progression very early on, with emerging preclinical evidence also supporting its potential for disease prevention.},
}

@article {pmid42745714,
year = {2026},
author = {Ikeda, M},
title = {[How to Proceed with Diagnosing Memory Loss].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {9},
pages = {1003-1014},
doi = {10.11477/mf.188160960780091003},
pmid = {42745714},
issn = {1881-6096},
mesh = {Humans ; *Memory Disorders/diagnosis ; Diagnosis, Differential ; Alzheimer Disease/diagnosis ; *Dementia/diagnosis ; Cognitive Dysfunction/diagnosis ; },
abstract = {When diagnosing dementia disorders, obtaining a detailed medical history and identifying relevant findings on physical and neurological examinations are fundamental. It is essential to assess cognitive function, neurological symptoms and signs, and dementia severity; conduct additional tests; and establish a differential diagnosis. With the widespread use of anti-amyloid antibody therapies, mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and early-stage AD must not be overlooked. When evaluating patients with dementia who present with diverse symptoms, clinicians must consider neurological signs, findings from diagnostic tests, and the clinical course to establish an accurate diagnosis and guide appropriate treatment.},
}

Humans
*Memory Disorders/diagnosis
Diagnosis, Differential
Alzheimer Disease/diagnosis
*Dementia/diagnosis
Cognitive Dysfunction/diagnosis

@article {pmid42746101,
year = {2026},
author = {Ray, WJ and Lightfoot, YL and Trinh, RT and Fawver-Kahle, J and Cooper, S and Tsai, LH and Bortz, J and Trujillo-Gonzalez, I and Zhang, T and Wu, H and Iv, GJO and Schulz, PE},
title = {Effect of choline supplementation in presymptomatic APOE ε4 carriers: a pilot study.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70323},
pmid = {42746101},
issn = {2352-8737},
abstract = {INTRODUCTION: With the advent of early detection biomarkers, it is possible to envision testing preventive strategies that delay the onset of Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (APOE ε4) is the strongest genetic risk factor for late-onset AD; approximately 50% of all patients are APOE ε4-positive.[1] APOE is the major central nervous system (CNS) lipoprotein, and studies have linked APOE4-dependent deficits in lipid metabolism to disease-relevant processes.[2-6] Choline, the precursor for phosphatidylcholine (PC), normalizes APOE ε4-mediated lipid dysfunction in human model systems,[6] and low dietary choline intake correlates with increased disease risk or progression in mouse models and humans.[7-17] We therefore tested whether biomarkers and omics provided early evidence of choline CNS target engagement in an at-risk population.

METHODS: In a 6-month open-label phase 1 study (NCT05880849), asymptomatic APOE ε4 carriers (n = 13; age 70 ± 5.5 years) received 2200 mg/day oral choline, with plasma and cerebrospinal fluid (CSF) collected before and after treatment.

RESULTS: Choline was well tolerated with no serious adverse events. Treatment increased plasma and CSF choline and betaine, indicating systemic and CNS exposure. Exploratory lipidomics identified changes in plasma PC species and, in CSF, increases in ceramides and cholesterol esters. Although this study was not powered to assess biomarker efficacy, CSF neurofilament light (NfL) was lower at the end of treatment, and CSF phosphoserine-181 tau (pTau181)/amyloid beta (Aβ)42 and plasma pTau217 showed directionally similar trends.

DISCUSSION: These findings support randomized placebo-controlled trials of choline in at-risk populations and illustrate how fluid biomarkers and omics can de-risk AD prevention studies.},
}

@article {pmid42734057,
year = {2026},
author = {Jang, S and Chen, J},
title = {Hospital Artificial Intelligence Tools and Inpatient Utilization and Costs in Older Adults with Alzheimer's Disease and Related Dementias.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70704},
pmid = {42734057},
issn = {1532-5415},
support = {P30AG097158/AG/NIA NIH HHS/United States ; RF1AG083175/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Hospitals are increasingly adopting artificial intelligence and machine learning (AI/ML) tools to support clinical decision making and care management. However, evidence on how hospital AI/ML adoption relates to inpatient utilization and spending among clinically complex populations remains limited. Older adults with Alzheimer's disease and related dementias (ADRD) experience higher rates of readmissions and potentially avoidable hospitalizations.

METHODS: Cross-sectional study was conducted using 2023 inpatient claims linked to the Medicare Beneficiary Summary File and the American Hospital Association Annual Survey Information Technology Supplement to examine associations between hospital adoption of patient-related AI/ML tools and inpatient utilization and spending among Medicare fee-for-service (FFS) beneficiaries with ADRD. The study included 340,509 FFS beneficiaries aged 65 years or older with ADRD who experienced at least one inpatient hospitalization in 2023. Hospital adoption of patient-related AI/ML tools was measured using four indicators reflecting AI/ML use to predict inpatient health risks, identify high-risk outpatients, monitor patient health, and recommend treatments. Outcomes included frequent hospitalization, 30-day readmission, preventable acute and chronic hospitalizations, total Medicare payments, and beneficiary out-of-pocket (OOP) spending. Multivariable regression models adjusted for beneficiary and hospital characteristics.

RESULTS: Greater hospital adoption of patient-related AI/ML tools was associated with lower odds of frequent hospitalizations, 30-day readmissions, and preventable acute hospitalizations. Inpatient risk prediction and high-risk outpatient identification tools were consistently associated with lower inpatient utilization. Inpatient risk prediction was associated with lower total Medicare spending, while high-risk outpatient identification was associated with higher Medicare spending. Treatment recommendation tools were associated with higher beneficiary OOP spending.

CONCLUSIONS: Among Medicare FFS beneficiaries with ADRD, hospital adoption of patient-related AI/ML tools, particularly those focused on risk prediction and high-risk patient identification, was associated with lower inpatient utilization without increasing overall spending. Heterogeneity across AI/ML tool types suggests the importance of evaluating AI/ML tools based on their specific clinical functions.},
}

@article {pmid42735882,
year = {2026},
author = {Ma, X and Li, W and Ma, Y and Ma, W and Han, Z},
title = {Triptolide preserves cognitive function and reduces hippocampal inflammation in a mouse model of Alzheimer's disease.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104126},
doi = {10.1016/j.mcn.2026.104126},
pmid = {42735882},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that affects an estimated 50 million people worldwide. This remains a significant medical challenge. Despite the availability of numerous therapeutic agents, they are often only partially effective, highlighting the urgent need for the development of more effective next-generation drugs. Triptolide (T10), a key bioactive compound found in traditional Chinese medicine, is renowned for its wide range of pharmacological properties, including promising neuroprotective effects observed in vitro. However, its therapeutic effects and underlying mechanisms in the 5xFAD mouse model, particularly regarding microglial-mediated neuroinflammation, remain incompletely characterized. This study explored the impact of peripherally administered T10 on AD-associated behaviors and neuroinflammation in 5xFAD mice. The findings indicate that a 45-day T10 regimen significantly improved cognitive impairment in mice. Immunohistochemical analyses further demonstrated that T10 treatment markedly decreased Iba1-positive cell density in the CA1 region of the hippocampus and reduced immune and inflammatory responses in this region. Transcriptomic profiling suggests that T10 modulates cognitive function in 5xFAD mice via inflammatory signaling pathways. Taken together, these results suggest that T10 improves learning and cognitive performance and reduces hippocampal inflammatory responses in 5xFAD mice, supporting its further investigation as a potential therapeutic intervention for AD.},
}

@article {pmid42736378,
year = {2026},
author = {Thomassen, JQ and Leonard, H and Ulms, B and Grenier-Boley, B and Heikkinen, S and Garcia-González, P and Castillo-Morales, A and Kikuchi, M and Gim, J and Cao, H and Küçükali, F and Amin, N and Yoon, D and de Rojas, I and Alvarez Jerez, P and Alvarez, V and Arosio, B and Bellenguez, C and Bergh, S and Billingsley, K and Blauwendraat, C and Boada, M and Borroni, B and Bossù, P and Bullido, MJ and Daniele, A and Carracedo, Á and de Mendonça, A and Cookson, M and Deckert, J and Dichgans, M and Djurovic, S and Dols-Icardo, O and Dufouil, C and Düzel, E and Escott-Price, V and Fladby, T and Fratiglioni, L and Fu, AKY and Galimberti, D and García-Alberca, JM and Giedraitis, V and Garcia-Ribas, G and Graff, C and Grimmer, T and Grünblatt, E and Hanon, O and Hausner, L and Heilmann-Heimbach, S and Hort, J and Jessen, F and Jensen, K and Jonson, C and Kim, Y and Kuznetsov, N and Leinonen, V and Lipponen, A and Luo, J and Makarious, M and Martiskainen, H and Masullo, C and Mecocci, P and Mehrabian, S and Mir, P and Miyashita, A and Moebus, S and Mok, KY and Molina Porcel, L and Moreno, F and Nacmias, B and Parnetti, L and Pastor, P and Pérez-Tur, J and Peters, O and Pijnenburg, YAL and Piñol-Ripoll, G and Popp, J and Rainero, I and Real, LM and Riedel-Heller, S and Rodriguez-Rodriguez, E and Rongve, A and Rossi, G and Royo, JL and Rujescu, D and Saltvedt, I and Sáez, ME and Sánchez-Valle, R and Sanchez-Garcia, F and Sandau, N and Scarmeas, N and Scheffler, K and Scherbaum, N and Schneider, A and Selbæk, G and Seripa, D and Solfrizzi, V and Spallazzi, M and Squassina, A and Stordal, E and Tesi, N and Tremolizzo, L and Tripathi, KP and van der Flier, WM and Williams, J and Wiltfang, J and Aarsland, D and Singleton, AB and Amouyel, P and Debette, S and Tsolaki, M and Nicolas, G and van der Lee, S and Holstege, H and Fernandez, MV and Kehoe, PG and Sleegers, K and Ingelsson, M and Ghidoni, R and Andreassen, OA and Holmans, PA and Sánchez-Juan, P and Sims, R and Ip, NY and Lee, KH and Ikeuchi, T and Ramirez, A and Ruiz, A and Hiltunen, M and Lambert, JC and van Duijn, C and Nalls, M and Frikke-Schmidt, R},
title = {APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42736378},
issn = {1546-1718},
abstract = {Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies[1-10]. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers[11-13], hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.},
}

@article {pmid42736653,
year = {2026},
author = {Yadav, R and Sinha, J and Deeksha, K},
title = {Beyond the Single-Target Approach: Polypharmacology and Multi-Target Therapeutics in Alzheimer's Disease.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249497051260829094309},
pmid = {42736653},
issn = {1875-6166},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-beta aggregation, tau pathology, oxidative stress, neuroinflammation, mitochondrial dysfunction, and synaptic degeneration. The limited clinical success of traditional single-target therapeutic approaches has highlighted the need for more comprehensive treatment strategies. Polypharmacology has emerged as a promising paradigm that seeks to simultaneously modulate multiple pathological pathways involved in disease progression. In particular, multi-target-directed ligands (MTDLs) have gained considerable attention due to their ability to integrate multiple pharmacological activities within a single molecular entity. This review summarizes current advances in polypharmacology-based approaches for Alzheimer's disease, including rational drug design, ligand-based and network pharmacology strategies, artificial intelligence-assisted drug discovery, and emerging multi-target therapeutics. Representative synthetic and natural-productderived MTDLs are critically evaluated with respect to their mechanisms of action, pharmacokinetic limitations, blood-brain barrier penetration, and clinical development status. Finally, major translational challenges and future opportunities are discussed. Collectively, polypharmacology represents a promising framework for developing next-generation disease-modifying therapies for Alzheimer's disease, although significant challenges remain before widespread clinical implementation can be achieved.},
}

@article {pmid42736672,
year = {2026},
author = {Nadeem, MS and Rahman, S and Murtaza, BN and Al-Zharani, M and Afzal, M and Nasr, FA and Iftikhar, S and Chaieb, K and Alzarea, SI and Kazmi, I},
title = {The Microbiome-Gut-Brain Axis: Decoding the Molecular Dialogue for Next-Generation Neurotherapeutics.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X491341260902051725},
pmid = {42736672},
issn = {1875-6190},
abstract = {The human brain has traditionally been considered an isolated organ until the establishment of the microbiome-gut-brain axis (MGBA) overturned that concept. Based on recent reports, the present review provides confirmatory evidence that there is a complex communication in the MGBA that links the central nervous system with the resident microbial community of the gastrointestinal tract. A complex, highly sophisticated molecular dialogue involving immune and neuroinflammatory molecules, signaling via the vagus nerve and neural pathways, and key metabolic and endocrine routes facilitates cross-talk between the brain and the gut microbiome. Crucial microbial metabolites, such as bile acids and short-chain fatty acids (SCFAs), neurotransmitter release, and modulation of systemic inflammation are highlighted as primary mediators of gut-brain interactions. In recent times, research has shifted from establishing associations to elucidating precise mechanisms between brain physiology and the composition of the gut microbial community. Recent studies have emphasized linking specific bacterial taxa to neurological outcomes in Alzheimer's disease (AD), Parkinson's disease (PD), and autism spectrum disorder (ASD). Emerging therapeutic modalities such as engineered live biotherapeutics, next-generation psychobiotics, precision nutrition, and fecal microbiota transplantation are promising avenues for next-generation neurotherapeutics. However, the path to clinical translation is fraught with challenges, including methodological heterogeneity and reproducibility, establishing causality, and confounding host factors. This review concludes with a forward-looking roadmap that emphasizes multi-omics integration, standardization, human-relevant disease models, and personalized therapeutic strategies to decode the MGBA and exploit its full potential, which could revolutionize the treatment of brain disorders.},
}

@article {pmid42739229,
year = {2026},
author = {Rahmani, AH and Sarwar, T},
title = {Artificial Intelligence and Digital Biomarkers for Early Detection and Monitoring of Neurological Disorders: A Narrative Review.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {17},
pages = {},
pmid = {42739229},
issn = {2075-4418},
abstract = {Neurological disorders like Alzheimer's disease, Parkinson's disease, and epilepsy are becoming major causes of disability and mortality worldwide, and their prevalence is expected to rapidly increase with the aging of the population. These diseases develop silently, with irreversible neuronal damage often occurring decades before any clinical signs of illness are noticed, making early diagnosis and treatment difficult. The presymptomatic period greatly restricts the effectiveness of therapeutic interventions and reduces the possibility of disease-modifying interventions. Traditional diagnostic methods based on clinical assessment, neuroimaging, and invasive biomarkers are not sensitive enough to identify the disease at an early stage and are expensive to the healthcare system. The latest artificial intelligence (AI) technology and machine learning (ML) approaches, together with digital biomarkers obtained from eye tracking, facial expressions, speech analysis, motor dynamics, electrophysiology, wearable devices, and passive sensing, offer promising non-invasive alternatives for early detection of diseases. However, most reported performance metrics are derived from retrospective or pre-validated datasets, and prospective external validation remains limited. This narrative review synthesizes current evidence on AI-driven digital biomarkers for early detection of neurological diseases, examining disease-specific applications, methodological approaches, and challenges in clinical practices. We emphasize that clinical utility is task specific and dependent on disease stage, validation design, clinical endpoints, cost, workflow integration, and availability of disease-modifying therapies. We also note that much of the evidence summarized here derives from retrospective, case-control, or internally validated datasets and that prospective, patient-independent, and external validation with clinically meaningful endpoints remains limited. Reported performance figures should be read as proof-of-concept evidence rather than as evidence of demonstrated clinical readiness. We highlight promising future directions, including federated learning, explainable AI, and precision neurology approaches, while acknowledging that most applications remain investigational and require prospective validation before broad clinical deployment.},
}

@article {pmid42739787,
year = {2026},
author = {Kalampokini, S and Keramidiotis, I and Frontistis, A and Zuchi, F and Michmizos, D and Papaliagkas, V and Koutsouraki, E},
title = {Anti-Amyloid Antibodies in the Treatment of Alzheimer's Disease: An Umbrella Review.},
journal = {Journal of clinical medicine},
volume = {15},
number = {17},
pages = {},
pmid = {42739787},
issn = {2077-0383},
abstract = {Background: Over the last decade, numerous studies have investigated the administration of monoclonal anti-amyloid antibodies (AAAs) as a therapeutic approach in Alzheimer's disease (AD). The purpose of this umbrella review is to summarize current knowledge concerning the efficacy and safety of FDA- and EMA-approved AAAs for AD, namely, lecanemab and donanemab. Methods: We conducted a literature search in the PubMed, Scopus, and Web of Science databases in English, focusing on systematic reviews and/or meta-analyses, assessed by AMSTAR 2, concerning clinical and imaging efficacy, i.e., cognitive improvement and reduction of beta-amyloid on PET scan, as well as safety, i.e., adverse events and amyloid-related imaging abnormalities (ARIA). The extracted review-level dataset was entered into SPSS Version 26 for descriptive statistical analysis. Results: This umbrella review included 11 systematic reviews and/or meta-analyses. Patients treated with lecanemab or donanemab showed statistically significant changes on cognitive scales such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB) (mean effect estimate -0.485, SD = 0.152, -0.70 to -0.34) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), but most were below or around clinically meaningful thresholds. Lecanemab and donanemab showed a statistically significant decrease in amyloid PET outcomes, including centiloids or the standardized uptake value ratio. Both antibodies were linked to ARIA, including amyloid-related imaging abnormalities-edema (ARIA-E OR 8.32-12.26) and amyloid-related imaging abnormalities-hemorrhage (ARIA-H OR 2-5.77), especially in ApoEε4 carriers. Conclusions: Lecanemab and donanemab are biologically active drugs for the treatment of early AD, with cognitive benefits below or around the clinically meaningful threshold. They are, however, associated with increased ARIA risk. Their administration depends upon careful patient selection, shared decision-making, and clear communication regarding expectations.},
}

@article {pmid42741217,
year = {2026},
author = {Chen, Y and Shi, J},
title = {Serum metabolomic profiling following cerebellar repetitive transcranial magnetic stimulation combined with cognitive training on Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1887127},
pmid = {42741217},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/therapy/blood ; *Cognitive Training ; *Transcranial Magnetic Stimulation/methods ; Female ; Male ; Metabolomics ; Biomarkers/blood ; Aged ; *Cerebellum ; Combined Modality Therapy ; *Metabolome ; },
abstract = {BACKGROUND: Complex metabolic disorders are a key characteristic of Alzheimer's disease (AD). Although studies have shown that combining repetitive transcranial magnetic stimulation (rTMS) with cognitive training (CT) can alleviate AD symptoms, the specific pathophysiological processes involved remain poorly understood. Our goal is to analyze metabolomic changes associated with bilateral cerebellar rTMS plus CT in AD treatment, to identify potential biomarkers of disease progression and therapeutic outcomes, and to validate these findings against a systematic review of existing literature.

METHODS: We enrolled 12 individuals with early AD and 12 healthy controls (HC). The AD group received 2 weeks of bilateral cerebellar rTMS combined with CT. We performed ultra-high-performance liquid chromatography-tandem mass spectrometry analysis on serum samples obtained from AD patients (before and after intervention) and HC. The PubMed database was used to conduct a systematic review of AD metabolomics literature, from which differential metabolites were identified and analyzed using pathway enrichment analysis.

RESULTS: A total of 510 metabolites were differentially expressed in response to treatment, with 202 consistent with improved clinical status. Fourteen pathways were enriched, including those involved in valine, leucine, and isoleucine biosynthesis, as well as glycine, serine, and threonine metabolism, which are linked to the pathology and treatment of AD. Metabolites such as lysophosphatidylcholine (22:6) and citric acid, increased after treatment and shifted toward healthy control levels, whereas γ-guanidinobutyric acid, proline, decreased after treatment. Systematic review analysis suggested Phenylalanine as a potential biomarker for AD screening at the mild cognitive impairment stage.

CONCLUSION: This study's integrative analysis offers preliminary insights into treatment-associated metabolic alterations in AD and identifies candidate metabolites for further investigation as markers of disease status and treatment response.

TRIAL REGISTRATION: ChiCTR2200061754.},
}

Humans
*Alzheimer Disease/therapy/blood
*Cognitive Training
*Transcranial Magnetic Stimulation/methods
Female
Male
Metabolomics
Biomarkers/blood
Aged
*Cerebellum
Combined Modality Therapy
*Metabolome

@article {pmid42741654,
year = {2026},
author = {Tansey, MG and Bozeat, S and Ackerman, P and Atri, A and Barnum, CJ and Brundin, P and de Carvalho, CA and Fleisher, AS and Graf, A and Head, E and Kerchner, GA and Kolb, HC and Koyama, A and Kozberg, M and Leyns, CEG and Llibre-Guerra, JJ and Mattsson-Carlgren, N and McKissock, D and Murray, ME and Rosenthal, LS and Rubel, C and Schindler, SE and Schneider, JA and Schwarz, AJ and Scott, KM and Seredenina, T and Tosun, D and Wallings, RL and Wang, H and Wilcock, DM and Carrillo, M and Mahinrad, S and Weber, CJ},
title = {Alzheimer's disease heterogeneity and co-pathologies: Defining novel targets, biomarkers, modalities, and research methodologies.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70287},
pmid = {42741654},
issn = {2352-8737},
abstract = {Alzheimer's disease (AD) is a biologically heterogeneous condition with vascular, proteinopathic, metabolic, and immune processes jointly shaping its clinical expression, trajectory of progression, and response to therapeutic intervention. Common AD co-pathologies such as cerebral amyloid angiopathy, Lewy body pathology, α-synuclein, and transactive response DNA-binding protein of 43 kDa (TDP-43)/limbic-predominant age-related TDP-43 encephalopathy are also increasingly connected with cognitive decline and therapeutic response. Significant advances in biomarkers, including seed amplification assays, proteomic signatures, and emerging positron emission tomography tracers bolster the field's understanding of a biological staging model and discovery of previously unrecognized co-pathologies. The Fall 2025 Alzheimer's Association Research Roundtable (AARR) brought together academic, clinical, and industry leaders to discuss and explore the current advances in the heterogeneity and co-pathologies of AD, and their implications for diagnosis, clinical trial design, and precision treatment strategies. This paper presents key takeaways from the Fall 2025 AARR meeting.},
}

@article {pmid42741980,
year = {2026},
author = {Vanderlip, CR and Stark, CEL},
title = {Digital cognitive phenotyping enhances risk stratification in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71834},
pmid = {42741980},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; Female ; Aged ; Phenotype ; Male ; tau Proteins/blood ; Disease Progression ; Positron-Emission Tomography ; Amyloid beta-Peptides ; Risk Assessment/methods ; *Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Prodromal Symptoms ; Aged, 80 and over ; Biomarkers/blood ; Digital Health ; },
abstract = {INTRODUCTION: Amyloid positivity does not reliably predict near-term cognitive decline in preclinical Alzheimer's disease (AD). We tested whether digital cognitive phenotyping improves prognostic precision.

METHODS: Baseline performance on a brief self-administered digital battery was analyzed in 1146 amyloid beta (Aβ)+ and 538 Aβ- cognitively unimpaired older adults from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies. Unsupervised k-means clustering identified cognitive phenotypes. Survival models examined time to Preclinical Alzheimer Cognitive Composite decline and Clinical Dementia Rating (CDR) progression. Associations with tau positron emission tomography and plasma phosphorylated tau (p-tau)217 were evaluated.

RESULTS: Four cognitive phenotypes emerged. One phenotype (18% of Aβ+ participants) showed the steepest cognitive decline, highest progression on the CDR, greater baseline medial temporal tau, and fastest neocortical tau accumulation over 4.6 years (hazard ratio [HR] for decline ≈ 2.9). Combining this phenotype with elevated plasma p-tau217 identified a subgroup at markedly amplified risk (HR ≈ 4.5).

DISCUSSION: Digital cognitive phenotyping, especially when integrated with plasma biomarkers, identifies actionable risk heterogeneity and enables scalable precision prognostication in preclinical AD.},
}

Humans
*Alzheimer Disease/diagnosis
Female
Aged
Phenotype
Male
tau Proteins/blood
Disease Progression
Positron-Emission Tomography
Amyloid beta-Peptides
Risk Assessment/methods
*Cognitive Dysfunction/diagnosis
Neuropsychological Tests
Prodromal Symptoms
Aged, 80 and over
Biomarkers/blood
Digital Health

@article {pmid42742530,
year = {2026},
author = {Takahashi, R and Kashibayashi, T and Fujita, J and Yoshida, K and Hashiramoto, A and Kowa, H and Mizuta, E},
title = {Lower baseline cerebrospinal fluid amyloid-β 42 is associated with amyloid-related imaging abnormalities during real-world lecanemab treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488874},
doi = {10.1177/13872877261488874},
pmid = {42742530},
issn = {1875-8908},
abstract = {Amyloid-related imaging abnormalities (ARIA) are a safety concern during lecanemab treatment for early Alzheimer's disease. We examined baseline cerebrospinal fluid amyloid-β 42 (Aβ42) in 97 lecanemab-treated patients; 11 developed ARIA. Aβ42 was lower in ARIA cases than in non-ARIA cases (483.2 ± 108.6 versus 667.4 ± 185.4 pg/mL; p < 0.001). ROC analysis yielded an AUC of 0.806 (95% CI, 0.670-0.919). Aβ40 was also lower, whereas the Aβ42/Aβ40 ratio was not significantly different and tau biomarkers were not higher. Lower Aβ42 was associated with subsequent ARIA, but the internally derived cutoff requires external validation.},
}

@article {pmid42742914,
year = {2026},
author = {Perneczky, R and Jessen, F and Grimmer, T and Levin, J and Hufnagel, A and Flöel, A and Peters, O and Froelich, L and Hofmann, A and , },
title = {From Proof of Principle to Therapeutic Discipline: Strategies to Improve the Benefit/Risk Profile of Amyloid-Targeting Treatments for Alzheimer's Disease.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {42742914},
issn = {1179-1934},
abstract = {The first generation of clinically approved amyloid-targeting treatments has changed the terms of debate in Alzheimer's disease. It is no longer persuasive to argue that amyloid removal is biologically irrelevant or clinically inert in early symptomatic Alzheimer's disease. Lecanemab and donanemab have both demonstrated statistically robust and clinically meaningful, albeit still modest, slowing of disease progression, thereby establishing disease modification as a realistic therapeutic objective rather than a speculative aspiration. At the same time, these agents have exposed the defining limitation of the current therapeutic concept: although clearly beneficial for some patients, the margin for benefit versus risk remains narrow, and its realization in routine care is operationally demanding and heavily dependent on careful patient selection and surveillance rather than on drug effect alone. The central task for the field is therefore no longer to prove that amyloid-targeting treatments can work, but to make them work more effectively, more safely, more targeted, and less burdensome. In current practice, most plausible gains in net clinical value will come from earlier and more precise patient selection, structured risk stratification using the APOE genotype and baseline magnetic resonance imaging status, strict management of vascular risk factors, intensified monitoring during the early hazard period, more personalized treatment exposure, and amyloid antibodies engineered for lower vascular toxicity, for example, using brain shuttle technology. Further, alternative routes of administration have the potential to reduce burden on patients, caregivers, and providers likewise. Real-world registries will be essential to define long-term safety, effectiveness, and treatment patterns outside clinical trial populations. Therefore, future improvement of amyloid-targeting treatments is likely to come from widening the therapeutic margin by drug engineering as well as precision implementation in real-world settings.},
}

@article {pmid42724471,
year = {2026},
author = {Li, X and Xu, L and Song, Q and Chu, Q},
title = {Exosomes: emerging biomarkers and therapeutic potential in postoperative delirium and postoperative cognitive dysfunction.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1854680},
pmid = {42724471},
issn = {2296-634X},
abstract = {BACKGROUND: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are common and clinically significant perioperative neurocognitive disorders that disproportionately affect elderly surgical patients. Despite their substantial impact on postoperative recovery and long-term outcomes, the lack of validated biomarkers and effective targeted therapies remains a major challenge in perioperative medicine.

Owing to their intrinsic ability to cross the blood-brain barrier and stably encapsulate central nervous system-derived biomolecules, exosomes have emerged as promising candidates for non-invasive biomarker discovery in POD and POCD. Disease-associated alterations in exosomal cargo, encompassing proteins such as P-tau and Aβ1-42, nucleic acids including miR-584-5p and circRNA_089763, and lipid-associated constituents, provide valuable molecular signatures for early diagnosis, disease stratification, prognostic assessment, and dynamic monitoring of perioperative neurocognitive disorders. It should be noted, however,that the majority of current evidence is extrapolated from Alzheimer's disease and other neurodegenerative conditions rather than directly validated in POD and POCD cohorts, and dedicated prospective studies remain warranted.

Exosomes exert therapeutic effects through two complementary mechanisms: serving as vehicles for targeted drug delivery and acting as endogenous neuroprotective mediators. Their excellent biocompatibility,low immunogenicity, and inherent capacity to traverse the blood-brain barrier render them attractive platforms for attenuating neuroinflammation, promoting synaptic repair, enhancing neurogenesis, and restoring blood-brain barrier integrity.

Despite their considerable promise, several challenges continue to impede clinical translation, including limitations in large-scale production, the lack of standardized isolation and characterization protocols, biological heterogeneity, and regulatory barriers. Future research should focus on establishing POD/POCD-specific exosomal biomarker panels, developing GMP-compliant manufacturing systems, engineering precision-targeted exosomal therapeutics, and conducting rigorous multicenter clinical studies to validate their safety and efficacy.

CONCLUSION: Exosomes hold substantial promise for transforming the diagnosis and treatment of POD and POCD. With continued advances in engineering technologies, mechanistic understanding, and clinical validation, exosome-based diagnostic and therapeutic strategies are expected to become an integral component of precision perioperative medicine.},
}

@article {pmid42725220,
year = {2026},
author = {Khaliq, AS and Khan, K},
title = {Before the bolus: why anti-amyloid therapy must become part of every stroke code.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {9},
pages = {5550-5553},
pmid = {42725220},
issn = {2049-0801},
abstract = {Anti-amyloid monoclonal antibodies provide disease-modifying treatment options for selected patients with early symptomatic Alzheimer disease, but introduce new challenges for acute stroke care. Amyloid-related imaging abnormalities (ARIA) are often asymptomatic; however, symptomatic ARIA may cause aphasia, focal weakness, visual disturbance, confusion, headache, or seizures, and can resemble acute ischemic stroke. Initial noncontrast computed tomography may be nondiagnostic in both conditions, and failure to identify anti-amyloid exposure can complicate time-sensitive reperfusion decisions. Current regulatory guidance advises caution when considering thrombolytic therapy because serious and fatal intracerebral hemorrhage has been reported, although the absolute risk and a safe interval following anti-amyloid administration remain uncertain. Conversely, attributing every acute neurological deficit to ARIA could delay effective reperfusion for a true ischemic stroke. This editorial examines the clinical and imaging features relevant to this diagnostic overlap and proposes a systems-based response involving reliable medication identification, rapid vascular imaging, targeted magnetic resonance imaging, specialist collaboration, and separate consideration of intravenous thrombolysis and mechanical thrombectomy. Anti-amyloid exposure should be recognized as time-critical information during stroke evaluation. The objective is not automatic exclusion from reperfusion, but an individualized approach that minimizes avoidable hemorrhagic harm while preserving appropriate treatment for confirmed cerebral ischemia.},
}

@article {pmid42725517,
year = {2026},
author = {Kaur, J and Kainth, R and Mittal, R and Kaur, A and Kushwah, AS},
title = {Circadian Rhythm Disruption in Alzheimer's Disease: Mechanistic Insights, Diagnostic Implications, and Emerging Chronotherapeutic Strategies: A Narrative Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273425623260210180623},
pmid = {42725517},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex etiology that involves environmental, genetic, and metabolic components. Among these, circadian rhythm disruption has been seen critical but underexplored component in the pathogenesis of Alzheimer's disease. The suprachiasmatic nucleus (SCN), the central pacemaker of circadian regulation, coordinates all the physiological processes, such as sleep-wake cycles, metabolism, and neuroendocrine signalling. Tau-pathology, neuroinflammation, amyloid-β build-up, and cognitive decline in Alzheimer's disease are all becoming gradually linked to dysregulation of the system. A detailed review of literature was performed to study the role of circadian disruption in Alzheimer's disease. Alzheimer's disease-related circadian rhythm dysregulation is expressed through decreased melatonin secretion, sleep disturbances, and modified SCN signalling. Neuronal dysfunction could be caused by mutations in important clock genes (BMAL1, PER, CRY, and CLOCK). Sleep deprivation increases the buildup of amyloid-β and impairs glymphatic clearance. Also, tau pathology interrupts the circadian clock, further speeding up cognitive decline. Chronotherapies involving melatonin supplementation, light therapy, environment, and sleep hygiene provide promising effects in restoring circadian regulation and enhancing cognitive performance. According to the research from both experimental and clinical studies, there is a link between circadian rhythm abnormalities and Alzheimer's disease. Non-invasive biomarkers for the early identification of circadian nonalignment may aid in preventative measures. Researchers are currently looking into new treatment options that could slow down the progression of Alzheimer's disease. The integration of circadianbased therapies into individualised therapy paradigms for Alzheimer's disease patients should be the main focus of future research.},
}

@article {pmid42725519,
year = {2026},
author = {Dzierzbicka, K and Gensicka-Kowalewska, M},
title = {Synthesis, Structure-Activity Studies, and Therapeutic Potential of Met-enkephalin Derivatives.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266485871260827072414},
pmid = {42725519},
issn = {1873-4294},
abstract = {One potential drug with analgesic, anticancer, and immune-enhancing properties is the endogenous pentapeptide M-ENK (opioid growth factor, OGF). A significant problem limiting its therapeutic application is its low bioavailability and short half-life in human plasma. Therefore, new analogues, as well as suitable delivery vehicles and administration routes for these potential drugs, are being sought. This article reviews the synthesis methods for OGF and its analogues, as well as the structure-activity relationships. Among other things, it describes: Compounds obtained by shortening or modifying the amino acid sequence in the peptide chain, methylated derivatives, compounds with hydrazine and phenylhydrazine, and with quercetin and resveratrol, which exhibit antioxidant properties, as well as derivatives containing bifunctional adamantane analogs, glycosylated derivatives with increased bioavailability, derivatives containing trifluoromethylamino acid residues in the G2 or G3 position, alkylamide derivatives, cyclic analogs containing thiazoles, cyclic peptidomimetic analogs, and the OGF-Gem conjugate. The M-ENK nanocarrier with RGD molecules is also presented for the controlled delivery of OGF to cancer cells. We highlight OGF and its derivatives in anticancer, analgesic, and immunomodulatory studies, and the potential for use in the treatment of other diseases, such as neurodegenerative (Alzheimer's, Parkinson's), diabetes, and viral diseases. The therapeutic potential of OGF is very large; therefore, it can be expected that the synthesis of new analogues and conjugates with used chemotherapeutic agents will be continued.},
}

@article {pmid42725558,
year = {2026},
author = {Chang, CP and Chang, CW and Wu, CW and Siew, JJ and Blum, D and Jin, LW and Chen, YY and Chern, Y},
title = {ENT1 inhibition links oligodendrocyte lipid metabolism to connectivity in tauopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71789},
pmid = {42725558},
issn = {1552-5279},
support = {P30 AG010129/AG/NIA NIH HHS/United States ; AS-BRPT-112-14//Academia Sinica/ ; P30-AG010129/NH/NIH HHS/United States ; AS-KPQ-111-KNT//Academia Sinica/ ; },
mesh = {Animals ; *Oligodendroglia/metabolism/drug effects ; *Lipid Metabolism/drug effects/physiology ; Humans ; *Tauopathies/metabolism/pathology ; Mice ; *Equilibrative Nucleoside Transporter 1/antagonists & inhibitors/metabolism ; *Hippocampus/metabolism/pathology ; Myelin Sheath/metabolism ; Mice, Transgenic ; Male ; Female ; Diffusion Tensor Imaging ; Disease Models, Animal ; },
abstract = {INTRODUCTION: Metabolic dysfunction, altered adenosine signaling, and white matter abnormalities are implicated in tauopathies, but their relationship to network disconnection remains unclear. Myelinating oligodendrocytes may represent a metabolically vulnerable hub linking these processes to circuit dysfunction.

METHODS: We assessed human hippocampal tissue by immunofluorescence and profiled THY-Tau22 mice using diffusion tensor imaging, metabolomics, lipidomics, and single-nucleus RNA sequencing. Symptomatic mice were treated with the equilibrative nucleoside transporter 1 (ENT1) inhibitor J4 to evaluate therapeutic modulation.

RESULTS: Hippocampal tissue from patients with tauopathy showed reduced oligodendrocyte- and myelin-associated CNPase signal. THY-Tau22 mice exhibited progressive reductions in hippocampal-prefrontal fractional anisotropy, myelin-associated alterations, purine and lipid metabolic remodeling, and oligodendrocyte-enriched lipid-associated transcriptional changes. J4 treatment selectively modulated purine and lipid metabolic pathways and improved myelin-associated markers and structural connectivity measures.

DISCUSSION: ENT1 inhibition links adenosine homeostasis to oligodendrocyte-associated metabolic pathways and supports further investigation as a potential therapeutic approach for tauopathy-associated network dysfunction.},
}

Animals
*Oligodendroglia/metabolism/drug effects
*Lipid Metabolism/drug effects/physiology
Humans
*Tauopathies/metabolism/pathology
Mice
*Equilibrative Nucleoside Transporter 1/antagonists & inhibitors/metabolism
*Hippocampus/metabolism/pathology
Myelin Sheath/metabolism
Mice, Transgenic
Male
Female
Diffusion Tensor Imaging
Disease Models, Animal

@article {pmid42727071,
year = {2026},
author = {Islam, MM and Foraker, R and Hossain, MS and Arnold, WD and Dandachi, D and Mosa, ASM},
title = {Association of Herpes Simplex Virus Type-1 With Dementia Outcomes: Longitudinal Retrospective Cohort Study Using Real-World Electronic Health Record Data.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e83028},
pmid = {42727071},
issn = {2561-326X},
support = {UL1 TR002345/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; Electronic Health Records/statistics & numerical data ; Retrospective Studies ; *Herpesvirus 1, Human/pathogenicity ; Female ; Longitudinal Studies ; *Dementia/epidemiology/virology/etiology ; Male ; Aged ; *Herpes Simplex/complications/epidemiology ; Aged, 80 and over ; Risk Factors ; },
abstract = {BACKGROUND: Global dementia cases, currently exceeding 55 million, are projected to triple by 2050. In the absence of disease-modifying therapies, identifying modifiable risk factors is critical. Preclinical studies show that herpes simplex virus type-1 (HSV-1) is neurotropic and can drive amyloid-beta accumulation and tau hyperphosphorylation. Epidemiologic findings remain inconsistent, partly because many studies lack standardized designs for real-world data.

OBJECTIVE: To quantify the association between clinically coded HSV-1 diagnosis and incident cognitive impairment or dementia among patients receiving care in a health-system electronic health record (EHR) network.

METHODS: We assembled a retrospective cohort within an Observational Medical Outcomes Partnership (OMOP)-mapped EHR data lake (2010-2024), comparing patients with a first HSV-1 diagnosis (n=6274) to those without HSV-1 codes but with parallel baseline criteria (n=379,975). Eligibility required at least 365 days of prior observation and absence of baseline cognitive, HIV, selected neurotropic viral, or recent transplant codes. The outcome combined mild cognitive impairment and Alzheimer disease and related dementias (ADRD). A high-dimensional propensity score (PS) incorporating approximately 17,000 baseline covariates was estimated with regularized logistic regression; 4 strata weights were applied in a Cox model. Sensitivity analyses examined equipoise trimming, doubly adjusted models, fixed 1-, 5-, and 10-year censoring horizons, and a dementia-only outcome subset. Negative-control outcomes (n=271) were prespecified to assess empirical calibration.

RESULTS: The HSV-1 cohort contributed 23,186 person-years (PY) and 469 events; the non-HSV-1 cohort contributed 1,519,827 PY and 24,764 events. Crude incidence was 20.23 (95% CI 18.44-22.14) per 1000 PY in the HSV-1 cohort and 16.29 (95% CI 16.09-16.50) in the non-HSV-1 cohort, an absolute difference of 3.94 events per 1000 PY. PS-stratified analysis yielded a hazard ratio (HR) of 1.14 (95% CI 1.03-1.25; P=.007). Estimates were comparable after equipoise trimming (HR 1.12, 95% CI 1.01-1.25, P=.04), doubly adjusted modeling (HR 1.13, 95% CI 1.02-1.24, P=.01), and fixed 5-year (P=.008) and 10-year follow-up (P=.004) (both HR 1.15). The 1-year censored model showed HR 1.00 (95% CI 0.84-1.20; P=.96). The dementia-only endpoint mirrored the primary analysis (HR 1.14, 95% CI 1.03-1.25; P=.008). No postindex events occurred for any negative-control outcome, so empirical calibration could not be performed and all estimates are uncalibrated.

CONCLUSIONS: Within an OMOP-standardized EHR cohort, an HSV-1 diagnosis was associated with a small elevation in the hazard of subsequent cognitive impairment or dementia compared with individuals with no recorded HSV-1 diagnosis. Given the ubiquity of HSV-1, even a modest elevation in individual hazard could translate to a meaningful population-level increment if the association is causal. Confirmation in external data sets with laboratory viral typing, antiviral treatment records, and mortality linkage is warranted.},
}

Humans
Electronic Health Records/statistics & numerical data
Retrospective Studies
*Herpesvirus 1, Human/pathogenicity
Female
Longitudinal Studies
*Dementia/epidemiology/virology/etiology
Male
Aged
*Herpes Simplex/complications/epidemiology
Aged, 80 and over
Risk Factors

@article {pmid42727480,
year = {2026},
author = {Wang, J and Pu, H and Peng, L and Cai, S and Ding, Q and Chen, X and Liu, Y and Xiong, W and Liao, Y and Tang, G},
title = {Effects and mechanisms of Stauntonia brachyanthera Hand.-Mazz against Alzheimer's disease through network pharmacology and experimental validation.},
journal = {Biochemical and biophysical research communications},
volume = {836},
number = {},
pages = {154546},
doi = {10.1016/j.bbrc.2026.154546},
pmid = {42727480},
issn = {1090-2104},
abstract = {Stauntonia brachyanthera Hand.-Mazz. (SB), a traditional medicinal plant of the Dong ethnic group with nutraceutical applications, exhibits broad-spectrum pharmacological activity. However, the therapeutic effects and mechanisms of SB on Alzheimer's disease (AD) remain unclear. This study aims to investigate the neuroprotective potential and underlying mechanisms of SB against AD. We utilized network pharmacology and molecular docking to predict the active components, targets, and pathways of SB associated with AD treatment. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were further used to identify potential therapeutic targets and underlying mechanisms of SB in relation to AD. Then, the neuroprotective effects, neuronal differentiation-promoting activity and potential mechanism of key active components of SB on the main therapeutic targets were verified by in vitro experiments. The network pharmacological prediction results showed that the treatment of AD with SB was closely related to MAPK and PI3K/Akt pathways. Further experiments showed that the SB active component kaempferol (KMF) alleviated Aβ1-42-induced injury and promoted neuronal differentiation. Additionally, we found that KMF-mediated promotion of neuronal differentiation in N2a cells was dependent on the PI3K/Akt and MAPK pathways. In this study, we employed a combined computational-experimental approach to elucidate the neuroprotective mechanisms of SB against Alzheimer's disease. We further validated KMF as a key active component of SB that alleviates Aβ1-42-induced injury and promotes neuronal differentiation through the PI3K/Akt and MAPK pathways.},
}

@article {pmid42727959,
year = {2026},
author = {Palleis, CT and Bernhardt, A and Höglinger, G},
title = {[4-Repeat Tauopathies: Progressive Supranuclear Palsy and Corticobasal Degeneration].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {94},
number = {9},
pages = {389-399},
pmid = {42727959},
issn = {1439-3522},
mesh = {Humans ; *Supranuclear Palsy, Progressive/therapy/diagnosis/pathology/genetics ; *Corticobasal Degeneration/therapy/diagnosis/genetics/pathology ; *tau Proteins/genetics ; *Tauopathies/therapy/diagnosis/pathology/genetics ; Diagnosis, Differential ; },
abstract = {Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are primary tauopathies that are neuropathologically characterized by deposits of 4-repeat tau proteins. Both diseases lead to a progressive impairment of motor skills, balance, speech, cognition, and everyday functioning. While PSP is often associated with axially emphasized symptoms and characteristic midbrain atrophy, CBD usually presents with asymmetric frontoparietal atrophy with cortical and subcortical deficits. Due to overlapping clinical phenotypes, it is often difficult to distinguish the two diseases from other neurodegenerative diseases in everyday clinical practice. A distinction must be made between neuropathologically defined CBD and the clinical phenotype of corticobasal syndrome (CBS), which can also be caused by other pathologies, such as Alzheimer's disease. The diagnosis of PSP or CBD is made according to current clinical criteria, based on the evaluation of multiple functional domains and the severity of presenting symptoms. Disease-modifying therapies are not yet available. Treatment currently follows symptom-oriented approaches with the aim of maintaining the quality of life and independence of patients for as long as possible. This article provides an up-to-date overview of the diagnosis, clinical presentation, management strategies, and treatment options for individuals affected by PSP and CBD.},
}

Humans
*Supranuclear Palsy, Progressive/therapy/diagnosis/pathology/genetics
*Corticobasal Degeneration/therapy/diagnosis/genetics/pathology
*tau Proteins/genetics
*Tauopathies/therapy/diagnosis/pathology/genetics
Diagnosis, Differential

@article {pmid42729321,
year = {2026},
author = {Huang, D and Zhou, R and Ling, J},
title = {Astragaloside IV attenuates hypoxia-reoxygenation-induced endothelial senescence and vascular inflammation by modulating the NOTCH1/VCAM-1 axis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1855522},
pmid = {42729321},
issn = {1663-4365},
abstract = {OBJECTIVE: Alzheimer's disease (AD) progression involves cerebral microvascular endothelial cell senescence induced by brain hypoperfusion, which contributes to blood-brain barrier (BBB) dysfunction. While Notch1 signaling is known to exacerbate endothelial senescence and neuroinflammation via vascular cell adhesion molecule-1 (VCAM-1), the mechanism by which it mediates hypoxia-induced endothelial aging in AD remains unclear. Furthermore, although Astragaloside IV (AS-IV) has been shown to alleviate cerebral hypoperfusion in AD, whether it acts by directly modulating the Notch1/VCAM-1 axis is unknown. This study aimed to determine whether AS-IV mitigates endothelial senescence and AD pathology by modulating the Notch1/VCAM-1 pathway.

METHODS: Transcriptomic analysis of AD patient data and network pharmacology identified NOTCH1 as a key target. Molecular docking and 100-ns molecular dynamics simulations (using Desmond) characterized AS-IV-Notch1 interactions. Human brain microvascular endothelial cells (HBMECs) were subjected to hypoxia-reoxygenation (HR) to model AD-associated hypoperfusion. Cells were treated with AS-IV (25, 50, or 100 μM) or N-acetylcysteine (NAC) as a positive antioxidant control. Notch1 signaling was experimentally modulated using a recombinant decoy receptor to simulate signaling blockade, creating a contrast with HR-induced overactivation. Assessments included CCK-8 assays, MDA and ROS detection, qPCR, and Western blotting.

RESULTS: NOTCH1 expression was upregulated in AD patients. Molecular docking and dynamics simulations predicted a stable binding mode between AS-IV and Notch1. HR exposure significantly increased oxidative stress and upregulated senescence markers (p16, p21, and p53), proinflammatory senescence-associated secretory phenotype (SASP) factors (IL-6, IL-1β, and TNF-α), and Notch1/VCAM-1 expression. Conversely, AS-IV treatment improved cell viability, reduced oxidative stress (with efficacy comparable to NAC), and downregulated Notch1/VCAM-1, senescence, and SASP markers. Notably, perturbing Notch signaling, either through HR-induced overactivation or decoy receptor-mediated blockade, exacerbated the senescent phenotype. Importantly, AS-IV co-treatment effectively rescued cellular damage induced by both forms of Notch pathway dysregulation.

CONCLUSION: AS-IV alleviates HR-induced endothelial senescence by modulating the Notch1/VCAM-1 axis. Our data suggest that AS-IV does not merely inhibit Notch1 but acts by modulating its signaling toward a protective equilibrium, thereby attenuating endothelial senescence and inflammation associated with the restoration of Notch1/VCAM-1 signaling balance. These findings highlight the potential of AS-IV as a therapeutic candidate for AD vascular pathology.},
}

@article {pmid42729372,
year = {2026},
author = {Han, J and Fang, Y and Esiaka, D and Abraham, O},
title = {Real-world anti-amyloid therapy beyond traditional symptomatic populations: a longitudinal case series.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1900651},
pmid = {42729372},
issn = {1664-0640},
abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies are approved as disease-modifying therapies for early Alzheimer's disease (AD), but real-world evidence remains limited, particularly among individuals treated during preclinical or minimally symptomatic stages. This study characterized clinical and biomarker trajectories among anti-amyloid therapy recipients across disease stages.

METHOD: We conducted a longitudinal retrospective case series of three biomarker-positive individuals from the Alzheimer's Disease Neuroimaging Initiative who received lecanemab or donanemab. Clinical, cognitive, cerebrospinal fluid, plasma biomarker, and amyloid PET data were examined.

RESULTS: In all three cases, most of the observation period preceded anti-amyloid therapy initiation. Clinical trajectories varied by biomarker profile and treatment timing. Two participants received donanemab while cognitively normal or at an early transitional stage despite persistent amyloid- and tau-positive profiles. One participant received lecanemab after clinically significant impairment emerged. Cases 1 and 2 showed prolonged preservation of cognitive and functional performance despite sustained AD biomarker abnormalities and amyloid PET positivity. In case 2, age- and education-adjusted Wechsler Logical Memory testing detected progression to mild cognitive impairment despite preserved Mini-Mental State Examination and Clinical Dementia Rating scores. In contrast, case 3 showed persistent cognitive impairment and progression toward mild dementia. Conclusion: This case series illustrates substantial heterogeneity among real-world anti-amyloid therapy recipients. Persistent biomarker abnormalities may precede clinical decline for years, especially among highly educated individuals with substantial cognitive reserve. Conventional global screening tools may underestimate early decline and affect treatment eligibility decisions. Although not generalizable, these observations underscore the need for larger real-world studies characterizing clinical trajectories following anti-amyloid therapy.},
}

@article {pmid42729566,
year = {2026},
author = {Amrutha, S and Kadandelu, M and Paidi, MK and Raghu, SV and Prasad, TSK and Modi, PK},
title = {Glycyrrhiza glabra exhibits disease-modifying effects in Alzheimer's disease through restoration of mitochondrial function, synaptic plasticity, and kinase signaling.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1894678},
pmid = {42729566},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and neuronal dysfunction. Current therapeutic treatments are limited to symptomatic relief and often cause significant adverse effects, underscoring the need for alternative medicinal approaches with potent neuroprotective efficacy and minimal side effects. Glycyrrhiza glabra, rich in major bioactive constituents such as Glycyrrhizic acid, glabridin, liquiritin, rhamnoliquirilin, liquiritigenin, and prenyllicoflavone A, has been historically used in Ayurveda and exhibits therapeutic potential; however, its efficacy in mitigating AD-associated pathological conditions remains poorly understood.

METHODS: This study investigates the neuroprotective properties of G. glabra root extract in Aβ42-treated human neuroblastoma (IMR-32) cells and Aβ42-overexpressing Drosophila melanogaster transgenic flies. Various behavioral and molecular biology techniques were employed, including immunofluorescence, qRT-PCR, flow cytometry, and western blotting, to investigate the effects of G. glabra root extract.

RESULTS: Our results demonstrated that Aβ42 treatment induced aberrant alterations in several proteins associated with Alzheimer's pathology, mitochondrial dysfunction, cell-cycle re-entry, and synaptic activity. Co-treatment with G. glabra extract restored these protein levels and mitigated Aβ42-induced hyperactivation of key signaling pathways. Furthermore, G. glabra attenuated Aβ42-induced apoptotic signaling, modulating pro- and anti-apoptotic protein expression profiles in both in vitro and in vivo models.

CONCLUSION: Our findings indicate that G. glabra treatment restores the expression of key proteins altered in AD pathology, suggesting a potential neuroprotective mechanism mediated through the regulation of the MEK/ERK-1/2, PI3K/AKT/GSK3β, and CDK5/p35/p25 pathways. This study provides a molecular rationale for the historical use of G. glabra, demonstrating its ability to rescue altered AD-associated protein markers in both cellular and Drosophila models. While further research is necessary to fully elucidate the neuroprotective mechanisms of G. glabra, these findings pave the way for downstream validation of the extract as a promising natural therapeutic candidate for Alzheimer's disease.},
}

@article {pmid42730239,
year = {2026},
author = {Comert Onder, F and Onder, A and Ural, K and Sıkık, M and Abusharkh, KAN and Ozpolat, B and Ay, M},
title = {Design, Synthesis, In Vitro Biological Evaluation, and In Silico Analyses of Novel Pyrano[3,4‑b]indole-Containing Compounds as Promising Multitarget Candidates for Alzheimer's Disease and Cancer Therapy.},
journal = {ACS omega},
volume = {11},
number = {35},
pages = {52714-52730},
pmid = {42730239},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease associated with decreased activity of the cholinergic system in the brain. Identifying a drug that has no side effects and can prevent or delay the progression of this neurodegenerative disease is crucial. In this study, 11 novel pyrano-[3,4-b]-indole derivatives (ECA-ECM) were designed and synthesized as AChE and BChE inhibitors, and their structures were elucidated by spectroscopic analyses. Enzyme activity studies were conducted in vitro. Inhibitory potentials for both cholinesterase enzymes were determined by in silico analyses, and protein-ligand interactions were elucidated. The ECB compound (AChE IC50 = 35.31 ± 0.81 nM and BChE IC50 = 28.91 ± 0.19 nM) is a potential candidate as a dual AChE/BChE inhibitor. These findings indicate that the synthesized pyrano-[3,4-b]-indole derivatives have inhibitory potential for AD. The cytotoxic activities of the synthesized compounds were evaluated in vitro. The ECK compound showed a strong cytotoxic effect in five different human cancer cell lines in the ranging concentrations from 10.37 ± 1.43 to 29.34 ± 1.71 μM. The ECD compound exhibited strong cytotoxic activity at a concentration of 9.27 ± 0.97 μM in the colon cancer cell line. The cytotoxic activities of ECK and ECM were found to be below 25 μM in four human cancer cell lines. In silico analyses, including molecular docking, molecular dynamics simulations, and binding free energy calculations, confirmed that the synthesized compounds are potential candidates targeting AChE and BChE. Consequently, the synthesized compounds showed promising results for the treatment of AD and cancer.},
}

@article {pmid42730882,
year = {2026},
author = {Liu, XR and Zhang, M and Chen, DD and Chang, JR and Kou, XJ},
title = {Dihydromyricetin ameliorates cognitive dysfunction in SAMP8 mice via autophagy-mediated degradation of the NLRP3 inflammasome.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42730882},
issn = {1573-7365},
support = {2025GXNSFBA069048//the Guangxi Natural Science Foundation for Young Scholars/ ; 2025KY1486//the Project of Basic Scientific Research Capability Improvement of Young and Middle-Aged Teachers in Guangxi Colleges and Universities/ ; T2024019//the Excellent Young and Middle-Aged Science and Technology Innovation Team Program for Higher Education Institutions of Hubei Province/ ; 2026AFC0982//the Key Project of Natural Science Foundation of Hubei Province/ ; },
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Autophagy/drug effects ; *Flavonols/pharmacology/therapeutic use ; *Inflammasomes/metabolism/drug effects ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Microglia/drug effects/metabolism ; Hippocampus/metabolism/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuropathology, but its mechanisms remain incompletely understood. Impaired autophagy and overactivation of the NLRP3 inflammasome are thought to contribute to AD progression. Dihydromyricetin (DHM) is a natural flavonoid with known neuroprotective effects, yet it remains unclear whether DHM modulates the autophagy-lysosome pathway to suppress NLRP3 inflammasome activation and improve cognitive deficits. Here, we combined bioinformatics predictions with in vitro and in vivo experiments to investigate DHM's effects on autophagy and NLRP3 inflammasome signaling. Bioinformatic analysis of aging, AD, and cognition-related gene sets identified autophagy and immune regulation as key enriched pathways. Molecular docking predicted that DHM binds favorably to core autophagy and inflammasome proteins. In vitro, DHM (6.25-25 µg/mL) increased autophagy in BV2 microglia, as evidenced by an increased LC3-II/LC3-I ratio and ULK1 expression and reduced p62 accumulation, and markedly reduced LPS/ATP-induced upregulation of NLRP3, cleaved caspase-1, IL-1β, and IL-18. DHM also reduced LPS-induced intracellular ROS accumulation in BV2 cells and attenuated NF-κB p65 phosphorylation in SAMP8 hippocampus. In vivo, 8-week oral administration of DHM to senescence-accelerated mouse-prone 8 (SAMP8) mice, an accelerated aging model with AD-like cognitive and pathological features, enhanced hippocampal autophagy marker expression, reduced NLRP3 inflammasome-related proteins and AD-related pathological protein changes. Immunofluorescence and Western blot analyses showed that DHM increased the spatial association of NLRP3 with LC3- and LAMP1-positive structures, reduced ASC expression, and increased the lysosomal protease Cathepsin D. These molecular changes corresponded with improved spatial learning and memory in the Morris water maze. However, co-treatment with the autophagy inhibitor chloroquine (CQ) abolished the DHM's effects on autophagy markers, reversed its reduction of NLRP3-related inflammatory proteins, and negated its cognitive benefits. Taken together, these results suggest that DHM enhances autophagy-lysosome pathway activity and facilitates autophagy-associated suppression of NLRP3 inflammasome activation, thereby mitigating neuroinflammation and cognitive impairment in SAMP8 mice. This autophagy-dependent mechanism suggests that DHM, a well-tolerated natural compound, has potential as a multitarget therapeutic candidate for AD-like cognitive impairment.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Autophagy/drug effects
*Flavonols/pharmacology/therapeutic use
*Inflammasomes/metabolism/drug effects
Mice
*Cognitive Dysfunction/drug therapy/metabolism
Male
Microglia/drug effects/metabolism
Hippocampus/metabolism/drug effects
Neuroprotective Agents/pharmacology/therapeutic use

@article {pmid42732414,
year = {2026},
author = {Rohatgi, S and Younan, CM and Martinez Imbett, RE and Ford, JN and Wleklinski, M and Zhu, S and Romero, J},
title = {Demographic and Clinical Characteristics of Patients Treated With Lecanemab Stratified by Amyloid-Related Imaging Abnormality Status.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114472},
pmid = {42732414},
issn = {2168-8184},
abstract = {Background Amyloid-related imaging abnormalities (ARIAs) are among the most important safety considerations during lecanemab treatment for Alzheimer's disease (AD). Although APOE ε4 carrier status is a recognized ARIA risk factor, the relationship between ARIAs and routine demographic and clinical characteristics in real-world practice remains incompletely characterized. This study evaluated demographic, vascular comorbidity, and APOE genotype characteristics among patients treated with lecanemab, stratified by ARIA status. Methodology We conducted a retrospective cohort study of patients with AD treated with lecanemab at a single academic institution from December 4, 2023, to October 28, 2025. Of 324 identified patients, 318 were included in the primary analysis. Demographic and clinical variables were extracted from the electronic health record. ARIA status and subtype were determined from clinical MRI interpretations by board-certified neuroradiologists. Patients were stratified by presence and type of ARIA development during treatment. Results Among 318 included patients, 98 (30.8%) developed ARIA and 220 (69.2%) did not. Among ARIA-positive patients, nine (9.2%) had ARIA-E only, 50 (51.0%) had ARIA-H only, and 39 (39.8%) had mixed ARIA-E/H. Age was similar between ARIA-positive and ARIA-negative patients (74.4 vs. 73.6 years; p = 0.437). ARIAs occurred in 33.9% of female patients and 26.8% of male patients (p = 0.218), and in 52.9% of non-White patients and 29.6% of White non-Hispanic patients (p = 0.078). Hypertension, hyperlipidemia, and diabetes were not associated with ARIA. APOE ε4 carriers had a higher incidence of ARIA than non-carriers (35.3% vs. 22.8%; p = 0.029), although differences across individual APOE genotypes did not reach statistical significance (p = 0.135). Conclusions In this real-world cohort of patients treated with lecanemab, ARIAs occurred in nearly one-third of patients. APOE ε4 carrier status was the only evaluated demographic, clinical, or genetic variable significantly associated with ARIAs. Sex- and race/ethnicity-related differences were exploratory and require validation in larger, more diverse prospective cohorts. These findings support genotype-informed ARIA surveillance while emphasizing the need for broader representation in studies of anti-amyloid therapy safety.},
}

@article {pmid42733706,
year = {2026},
author = {Behrouzfar, H and Gholami, M and Hassani, S and Maghsoudi, AS and Bekheir, SA},
title = {Physical exercise as a therapeutic strategy in animal models of Alzheimer's disease: Molecular, behavioral, and histopathological evidence.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102765},
pmid = {42733706},
issn = {2405-5808},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, imposing a substantial economic burden. As the population ages and cases rise, interest in early identification, prevention, and treatment has intensified. After establishing that pathology involves neurofibrillary tangles, neuroinflammation, and neuronal loss, interventions have been tested in laboratory animals to slow disease progression. One commonly tested intervention is physical exercise, an economical approach. Laboratory animal models of AD aim to demonstrate how different types and intensities of exercise affect disease pathology. This review aims to categorize and elucidate the mechanisms and their outcomes.

MATERIALS AND METHODS: Original manuscripts concerning the impact of exercise, with or without medicinal intervention, on Alzheimer's dementia progression modeled in laboratory animals from 2020 onwards were included. The routes through which exercise exerts its impact at molecular, behavioral, and histomorphological levels were categorized.

RESULTS: The most frequent modeling approach was Aβ injection into the hippocampus of Wistar rats, followed by Streptozocin and other chemicals, and transgenic models. Exercise mainly consisted of treadmill or swimming. Interventions were categorized into short-, medium-, and long-term protocols, ranging from 3 to 24 weeks, with most at 4 weeks, 30-60 min per session, 5 days/week. Molecular tests primarily measured Reactive Oxygen Species (ROS), while the most common behavioral test was the Morris Water Maze (MWM), assessing learning and memory. Histopathological assessments focused on β-Amyloid plaque formation, dark cells, and glial activation. Most studies agreed on AD modeling methods, but exercise protocols varied in intensity, duration, and type. The combined use of molecular, behavioral, and histological tests to assess intervention effects was consistent.

CONCLUSION: Physical exercise has been linked to lower oxidative stress and neuroinflammation, enhanced cognitive function, and fewer pathological changes in animal models of AD. However, variability in disease models and exercise protocols makes it difficult to identify the best exercise approach.},
}

@article {pmid42723527,
year = {2026},
author = {Lei, L and Hu, X and Lu, R and Yang, JJ and Meng, Q},
title = {Advances in Targeting Central Cholinergic Dysfunction for Neurodegenerative Diseases: From Pharmacotherapy to Neuromodulation.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71151},
pmid = {42723527},
issn = {1755-5949},
support = {U23A20421//National Natural Science Foundation of China/ ; ZYCXTD2023012//Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/therapy/metabolism/drug therapy ; Animals ; Cholinesterase Inhibitors/therapeutic use ; Deep Brain Stimulation/methods ; *Cholinergic Neurons/drug effects ; },
abstract = {BACKGROUND: The central cholinergic system has long been a cornerstone therapeutic target for neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). For decades, acetylcholinesterase inhibitors (AChEIs) have served as the standard symptomatic treatment, providing cognitive and functional relief by enhancing synaptic acetylcholine levels. However, their limited efficacy and inability to modify disease progression underscore the fundamental constraint of purely neurochemical enhancement, especially in the context of progressive cholinergic neuron loss.

RESULTS AND CONCLUSION: This review critically examines the evolution of cholinergic therapies beyond AChEIs. We first explore the shift from broad neurotransmitter enhancement toward precision targeting of receptor subtypes and the development of multi-target pharmacological strategies. Furthermore, we highlight how neuromodulation techniques-including vagus nerve stimulation, deep brain stimulation, and non-invasive brain stimulation-directly engage and restore dysfunctional neural circuits, moving beyond mere chemical enhancement. Emerging directions such as advanced cholinergic imaging, gene therapy, and cell-based regeneration are also discussed as promising pathways toward true disease modification. Ultimately, the integration of sophisticated pharmacological agents with circuit-level neuromodulation represents the next frontier in treating cholinergic dysfunction across the spectrum of neurodegenerative disorders, advancing the therapeutic goal from chemical enhancement to circuit repair and regeneration.},
}

Humans
*Neurodegenerative Diseases/therapy/metabolism/drug therapy
Animals
Cholinesterase Inhibitors/therapeutic use
Deep Brain Stimulation/methods
*Cholinergic Neurons/drug effects

@article {pmid42723990,
year = {2026},
author = {Zhu, M and Dasgupta, A and Jotsinghani, D and Hsu, J and D'Cunha, R and Choi, A and Haystead, A and Stinnett, SS and Johnson, KG and Grewal, DS and Fekrat, S},
title = {Retinal and Choroidal Structure and Microvasculature in Dementia With Lewy Bodies and Alzheimer Disease.},
journal = {Journal of vitreoretinal diseases},
volume = {},
number = {},
pages = {24741264261479309},
pmid = {42723990},
issn = {2474-1272},
abstract = {PURPOSE: To compare retinal and choroidal structural and microvascular imaging parameters between patients with dementia with Lewy bodies and those with Alzheimer disease using optical coherence tomography (OCT) and OCT angiography (OCTA).

METHODS: In this cross-sectional study, patients with dementia with Lewy bodies and those with Alzheimer disease underwent imaging with the Cirrus HD-5000 AngioPlex system (Carl Zeiss Meditec). OCT metrics included central subfield thickness, ganglion cell-inner plexiform layer thickness, retinal nerve fiber layer thickness, and choroidal vascularity index. Macular OCTA metrics included perfusion density, vessel density, and foveal avascular zone area. Peripapillary OCTA metrics included capillary perfusion density and capillary flux index. Generalized estimating equations adjusted for years of education were used to account for intereye correlation.

RESULTS: A total of 36 eyes from 20 patients with dementia with Lewy bodies and 42 eyes from 21 patients with Alzheimer disease were included. Compared with eyes from patients with Alzheimer disease, eyes from patients with dementia with Lewy bodies demonstrated significantly lower perfusion density and vessel density within the 3 × 3 mm Early Treatment Diabetic Retinopathy Study circle and ring (P = .03-.04). Structural OCT and peripapillary OCTA metrics did not differ significantly between the groups.

CONCLUSIONS: Compared with Alzheimer disease, dementia with Lewy bodies was associated with reduced macular perfusion density and vessel density on OCTA. These findings suggest disease-specific differences in the retinal microvasculature between dementia with Lewy bodies and Alzheimer disease.},
}

@article {pmid42722128,
year = {2026},
author = {Basavaraju, KC and Harshitha, DK and Priyadarshini, P},
title = {Alcohol-induced dysregulation of tau and acetylation pathways in the pathogenesis of Alzheimer's disease.},
journal = {Neuroscience},
volume = {615},
number = {},
pages = {447-461},
doi = {10.1016/j.neuroscience.2026.09.012},
pmid = {42722128},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose global prevalence is rapidly increasing, highlighting the urgent need to identify modifiable risk factors. Chronic alcohol consumption has emerged as one such significant factor contributing to the risk and progression of AD. Importantly, alcohol metabolism impacts cellular acetylation pathways, creating an environment that promotes protein dysregulation and disrupts cellular functions. Among these alterations, tau acetylation has garnered attention as a crucial post-translational modification that accelerates tau pathology, impairs tau clearance, and facilitates the formation of neurofibrillary tangles (NFTs), the key hallmarks of AD. Growing evidence indicates that chronic alcohol consumption leads to disruptions in acetyl-CoA homeostasis, NAD[+] pathways, dysregulation of acetyltransferase, sirtuin activity, and epigenetic aberrations promoting abnormal tau acetylation and neurodegeneration. Thus, understanding the molecular mechanisms that link alcohol consumption, acetylation dysregulation, and tau pathology has significant therapeutic potential in AD treatment.},
}

@article {pmid42719255,
year = {2026},
author = {El Fadili, M and Er-Rajy, M and Mujwar, S and Aloui, M and Samadi, A and Chtita, S and Elhallaoui, M},
title = {Multiscale mechanistic modeling for the rational design of novel dual-target candidates against acetylcholinesterase and NADPH oxidase: an advanced computational study.},
journal = {Frontiers in chemistry},
volume = {14},
number = {},
pages = {1917677},
pmid = {42719255},
issn = {2296-2646},
abstract = {INTRODUCTION: Alzheimer's disease is a complex neurodegenerative illness strongly associated with oxidative stress, which requires immediate intervention for therapeutic agents with potent antioxidant properties.

METHODS: In this work, novel derivatives based on benzofuran and pyrazole scaffolds were designed and assessed for their antioxidant potential and acetylcholinesterase inhibitory activity. The identification of key molecular characteristics that are important for the ability of a compound to scavenge DPPH radicals and AChE cholinesterase and has been accomplished through SAR, then both CoMFA and CoMSIA 3D-QSAR modelling have been used to design fifteen new compounds (D1-D15) which inhibit both DPPH and AChE to a significantly greater extent than the parent compound. Density functional theory calculations at the B3LYP/6-31G (d,p) level revealed that the three most promising candidates (M12, D8, and D9) have quite high electronic and molecular stability.

RESULTS AND DISCUSSION: The results of pharmacokinetic tests, molecular docking, and 100 ns molecular dynamics experiments confirm that these examined compounds interact favorably with both human acetylcholinesterase and NADPH oxidase enzymes with excellent thermodynamic stability. These results provide further evidence for the potential of the designed compounds to behave as multi-target ligands with AChE inhibition and antioxidant properties that would be effective in the treatment of the complex Alzheimer's disease.},
}

@article {pmid42719334,
year = {2026},
author = {Huang, Q and Xie, Y and Zhang, X and Zuo, Y and Wang, L and Xu, H and Yu, M and Liu, C},
title = {Traditional Chinese medicine ginseng regulates neurotrophic factors to improve neurodegenerative diseases: A potential strategy for Alzheimer's disease treatment.},
journal = {Journal of ginseng research},
volume = {50},
number = {5},
pages = {101078},
pmid = {42719334},
issn = {1226-8453},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment and progressive cognitive decline. Its core pathological mechanisms include β-amyloid deposition, abnormal tau phosphorylation, neuroinflammation, and decreased levels of neurotrophic factors. In recent years, the deficiency of neurotrophic factors has been recognized as a key driver of impaired neuronal survival and synaptic dysfunction. Consequently, restoring or enhancing neurotrophic factor signaling has emerged as a major therapeutic target for AD. As a traditional medicinal plant, ginseng exhibits multi-targeted, multi-level neuroprotective effects. Its active components-including ginsenosides, ginseng polysaccharides, and ginseng proteins-have been demonstrated to promote neuronal survival, inhibit apoptosis, and enhance synaptic plasticity by upregulating signaling pathways such as BDNF/TrkB and NGF/TrkA. Additionally, ginseng suppresses inflammatory responses and oxidative stress, thereby indirectly correcting neurotrophic factor imbalances and demonstrating significant neuroprotective potential. This review summarizes recent advances in ginseng's regulation of neurotrophic factor levels and signaling pathways, focusing on its molecular mechanisms for improving neuronal dysfunction and delaying AD progression. It also outlines future research strategies and prospects for clinical translation. In summary, ginseng's neuroprotective effects achieved through regulating the neurotrophic factor network offer a potential natural drug intervention strategy for AD treatment.},
}

@article {pmid42720212,
year = {2026},
author = {Song, B and Wang, W and Liu, S and Jin, X and Qi, Y and Li, M and Yue, D and Liu, Y and Li, X and Yin, L and Feng, L},
title = {Novel Therapeutic Insights Into Alzheimer's Disease: Glymphatic System and Meningeal Lymphatic Vessels.},
journal = {Aging cell},
volume = {25},
number = {9},
pages = {e70699},
doi = {10.1111/acel.70699},
pmid = {42720212},
issn = {1474-9726},
support = {ZR2023QH159//Natural Science Foundation of Shandong Province/ ; ZR2020MH357//Natural Science Foundation of Shandong Province/ ; 82274538//National Natural Science Foundation of China/ ; 2023NS469//Taian City Science and Technology Innovation Development Project/ ; Z20243705//Shandong Province Traditional Chinese Medicine Science and Technology Project/ ; YPM202532//Clinical Research Special Project of Shanghai Yangpu District Health System/ ; 202313011384//Shandong Province Medical Health Science and Technology Development Plan Project/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; *Glymphatic System/metabolism/pathology ; *Lymphatic Vessels/metabolism/pathology ; Animals ; *Meninges/pathology/metabolism ; },
abstract = {With the acceleration of global aging, the relationship between Alzheimer's disease (AD) and the glymphatic system (GS) has become a research hotspot in the field of neuroscience in recent years. Traditionally, the central nervous system was thought to lack a lymphatic system; however, research over the past decade has overturned this view. Studies have revealed the existence of GS and meningeal lymphatic vessels (mLVs) in the brain, which clear metabolic waste (such as amyloid-β and tau proteins) through the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF). Dysfunction of the GS can lead to abnormal deposition of pathological proteins, which may trigger or exacerbate AD. Currently, the association between the GS and AD treatment mainly focuses on drug development (such as small molecules that promote glymphatic circulation), physical therapies (such as 40 Hz photoacoustic therapy), and surgical interventions (primarily deep cervical lymphatic-vein anastomosis and cranial bone maneuver), all of which are under exploration. With the precision of diagnostic technologies and the targeting of therapeutic methods, future intervention strategies surrounding GS may become a significant breakthrough in overcoming the treatment impasse of AD, bringing new hope to tens of millions of AD patients worldwide.},
}

Humans
*Alzheimer Disease/therapy/pathology/metabolism
*Glymphatic System/metabolism/pathology
*Lymphatic Vessels/metabolism/pathology
Animals
*Meninges/pathology/metabolism

@article {pmid42720565,
year = {2026},
author = {Pereira Da Silva, AM and Haddad Santos, D},
title = {GLP-1 receptor agonism in Alzheimer's disease after EVOKE: From single hypothesis to stratified program.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485580},
doi = {10.1177/13872877261485580},
pmid = {42720565},
issn = {1875-8908},
abstract = {The phase 3 EVOKE and EVOKE + trials of oral semaglutide in early Alzheimer's disease missed their primary endpoint and every cognitive or functional secondary endpoint. A recent article by Hölscher revisits extension-phase data and reports partial separation at later timepoints, attributing the failure to limited brain penetration. We argue that attrited extension cohorts bear limited inferential weight and that the biomarker substudy, read in full, complicates a clean disease-modification reading. EVOKE does not refute the cardiometabolic hypothesis but reframes the open questions: which pathways, which patients, and which disease stages are most likely to benefit.},
}

@article {pmid42720842,
year = {2026},
author = {Demirdaş, A and Nazıroğlu, M},
title = {Brain-derived neurotrophic factor via TRPM2 inhibition reduces amyloid-beta-mediated increases of apoptosis and mitochondrial oxidative neurotoxicity in neuronal cells.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42720842},
issn = {1573-7365},
support = {TDK-2021-8386//Süleyman Demirel Üniversitesi/ ; },
mesh = {*Apoptosis/drug effects/physiology ; *TRPM Cation Channels/antagonists & inhibitors/metabolism ; Humans ; *Amyloid beta-Peptides/toxicity/pharmacology ; *Oxidative Stress/drug effects/physiology ; *Neurons/drug effects/metabolism ; *Brain-Derived Neurotrophic Factor/pharmacology ; Cell Line, Tumor ; *Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Calcium/metabolism ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {Brain-derived neurotrophic factor (BDNF) has particular importance in the modulation of Alzheimer's disease (AD)-related pathologies such as apoptosis and mitochondrial reactive oxygen species (mROS). The cation channel, transient receptor potential melastatin 2 (TRPM2), stimulation is important for the generation of AD-related pathologies. Antioxidant treatments through the inhibition of TRPM2 play an essential role in the inhibition of Ca[2+] entry, mROS, and apoptosis changes in the SH-SY5Y neuronal cells. However, the effects of antioxidant and antiapoptotic roles of BDNF have not yet been studied in SH-SY5Y treated with amyloid-beta (Aβ). The aim of the present study was to investigate the protective action of BDNF via TRPM2 inhibition on the apoptotic and oxidant values in Aβ-induced SH-SY5Y cells. Five groups of SH-SY5Y cells were established: control, BDNF, Aβ, Aβ + BDNF, and Aβ + TRPM2 channel blockers. The Aβ-induced increases in intracellular Ca[2+] and TRPM2 currents were decreased by BDNF and PARP-1 inhibition. The levels of mROS, intracellular ROS, dysfunction of mitochondrial membrane, SH-SY5Y death, apoptosis, and caspases (caspases-3, -8, and - 9) were increased in the cells treated with Aβ, although glutathione (GSH) and glutathione peroxidase (GSH-Px) were decreased by the treatment. However, the levels of these oxidative and apoptotic markers through the increases in GSH and GSH-Px were reduced in the cells by the incubations of BDNF and TRPM2 channel blockers. Finally, it was shown that BDNF protects neuronal cells against Aβ-induced excessive Ca[2+] entry, oxidative stress, and apoptotic parameters via inhibiting TRPM2. Treatment with BDNF appears to have the capacity to reduce apoptosis and oxidative stress caused by Aβ through inhibiting TRPM2.},
}

*Apoptosis/drug effects/physiology
*TRPM Cation Channels/antagonists & inhibitors/metabolism
Humans
*Amyloid beta-Peptides/toxicity/pharmacology
*Oxidative Stress/drug effects/physiology
*Neurons/drug effects/metabolism
*Brain-Derived Neurotrophic Factor/pharmacology
Cell Line, Tumor
*Mitochondria/drug effects/metabolism
Reactive Oxygen Species/metabolism
Calcium/metabolism
Membrane Potential, Mitochondrial/drug effects

@article {pmid42720909,
year = {2026},
author = {Lista, S and Filippi, L and Emanuele, E and López-Ortiz, S and Cisale, GY and Minoretti, P and Garaci, F and Santos-Lozano, A},
title = {Amyloid-β PET Radioligands in Alzheimer's Disease: From Plaque Detection to Biomarker-Guided Patient Stratification and Therapeutic Monitoring.},
journal = {Molecular diagnosis & therapy},
volume = {},
number = {},
pages = {},
pmid = {42720909},
issn = {1179-2000},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {Amyloid-β (Aβ) positron emission tomography allows direct in vivo visualization of insoluble fibrillar Aβ deposition and has been used to detect Alzheimer's disease pathology across the clinical continuum, from preclinical stages to overt dementia. Aβ tracers progressed from the prototypical [[11]C]Pittsburgh Compound-B ([[11]C]PiB), which is limited by [[11]C] half-life, to [[18]F]-labeled agents, including [[18]F]Florbetapir, [[18]F]Florbetaben, and [[18]F]Flutemetamol, which allowed centralized production and wide clinical use, with [[18]F]NAV4694 currently in development. In this narrative review, we sought to examine the principal Aβ positron emission tomography radioligands and their methodological framework, including visual reads, the standardized uptake value ratio, and the Centiloid scale, which harmonized quantitative output across tracers, scanners, and protocols and may enable cross-site comparison in multicenter studies and disease-modifying trials. The regulatory approval of lecanemab and donanemab has recently expanded the clinical use of Aβ positron emission tomography. Beyond diagnostic confirmation, the modality can currently confirm eligibility for anti-Aβ therapy, enrich trial populations, monitor target engagement through serial Centiloid measurements, and inform treatment discontinuation at predefined clearance thresholds. However, significant limitations remain, including the imperfect correlation between a high Aβ plaque burden and clinical cognitive decline that constrains its standalone diagnostic utility, tracer-specific variability, restricted accessibility, and the inability of fibril-targeted tracers to image the soluble oligomeric species most directly engaged by anti-Aβ antibodies. Probes for non-fibrillar species and computational tools for assisted interpretation are likely to shape the field in the near future.},
}

@article {pmid42721942,
year = {2026},
author = {Zhang, S and Huang, L and Wang, M and Li, Y and Guo, Q and Wang, Z and Lv, H and Jiang, J},
title = {DIPOG: A dynamic pooling graph neural network with spatial-temporal-frequency awareness for diagnosis of Alzheimer's disease.},
journal = {Medical image analysis},
volume = {115},
number = {},
pages = {104280},
doi = {10.1016/j.media.2026.104280},
pmid = {42721942},
issn = {1361-8423},
abstract = {Resting-state functional magnetic resonance imaging (rsfMRI) discloses the spatiotemporal states of the brain and, through brain network modeling, enables the analysis of time-varying patterns associated with Alzheimer's disease (AD). To extract the spatial-temporal-frequency and dynamic features of brain networks and achieve generalizable AD diagnosis, this paper proposes a dynamic pooling graph neural network with spatial-temporal-frequency awareness. Specifically, a novel autoencoder is proposed to capture the accurate temporal features of rsfMRI through time interval representation learning. To improve the model's ability to fit abnormal spatial-temporal-frequency features associated with AD, a masked self-supervised learning strategy has been designed, and the reconstruction tasks are defined according to the masked brain regions and time periods. Considering the time-varying patterns in rsfMRI, a dynamic pooling method is employed, which utilizes dynamic time warping to merge the features of time steps exhibiting the same pattern, thereby avoiding the loss of time-varying features. A total of 2,857 samples from eight centers were included, and AD classification experiments were conducted. We compared 12 state-of-the-art models, and the results showed that the accuracy of our model was 6.4% higher than that of the best-performing comparison models. Furthermore, we used an explainability method to identify salient brain regions, and demonstrated that these regions were correlated with neuropsychological scale. In addition, AD progression could be reflected by the spatial-temporal-frequency features and time-varying patterns. This study presents a spatiotemporal learning framework that facilitates the individualized and precise diagnosis and treatment of AD.},
}

@article {pmid42722093,
year = {2026},
author = {Dai, C and Yang, Y and Lin, X and Xiang, K and Zhuo, L and Fang, Z and Liu, J and Sun, J},
title = {Betulin supplementation reduces oxidative stress in Alzheimer's disease via the activation of KEAP1/NRF2 pathway.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110504},
doi = {10.1016/j.jnutbio.2026.110504},
pmid = {42722093},
issn = {1873-4847},
abstract = {Betulin (BE) is extracted from pentacyclic triterpenoids of many natural plants and has antioxidation activities. However, the neuroprotective effects and underlying mechanism of Betulin in Alzheimer's disease (AD) have remained limited. Integrate SuperPred, SEA, and Targeted Net databases, as well as KEGG pathway enrichment analysis, to predict and analyze BE-related target genes. Male APP/PS1 mice were treated intragastrically with Betulin for 4 weeks, followed by evaluation of cognitive function and pathological changes, and the levels of ROS, HO‑1, SOD2 and GPX4 were detected. Subsequently, molecular docking and molecular dynamics simulations were utilized to investigate the potential interaction between Betulin and KEAP1 protein, and KEAP1 mutant transfection was used to assess the involvement of KEAP1/NRF2 signaling in the antioxidant response to BE. Finally, KEAP1 and NRF2 protein levels were examined in the animal model. Our results showed that KEGG pathway enrichment analysis revealed that Betulin-related target genes were enriched in pathways associated with AD. Moreover, Betulin significantly alleviated cognitive impairment, neuronal damage, Aβ deposits and Tau phosphorylation in the APP/PS1 mice. Moreover, Betulin significantly increased GSH level, while significantly decreased MDA level. Meanwhile, Betulin significantly decreased ROS level, while significantly increased the levels of HO-1, SOD2, and GPX4 in vitro. Notably, molecular docking and molecular dynamics simulations suggested a potential interaction between Betulin and KEAP1, while KEAP1 mutant transfection attenuated the Betulin-induced increase in NRF2 and antioxidant proteins in vitro. Moreover, Betulin treatment was accompanied by decreased KEAP1 and increased NRF2 protein levels in APP/PS1 mice. These findings indicate that Betulin alleviates oxidative stress and modulates KEAP1/NRF2 signaling in AD models.},
}

@article {pmid42712219,
year = {2026},
author = {Wang, H and Li, L and He, X and Shen, S and Chao, L and You, P and Ji, K and Liu, Y and Hong, Z},
title = {UHPLC-Q/TOF-MS Characterization of Danshen-Chuanxiong and Mechanistic Insights Into Its Protective Effects Against Aβ1-42-Induced Brain Endothelial Injury Through Metabolomics.},
journal = {Journal of separation science},
volume = {49},
number = {9},
pages = {e70527},
doi = {10.1002/jssc.70527},
pmid = {42712219},
issn = {1615-9314},
support = {82173777//National Natural Science Foundation of China/ ; 82504742//National Natural Science Foundation of China/ ; 82473885//National Natural Science Foundation of China/ ; },
mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Humans ; *Metabolomics ; Chromatography, High Pressure Liquid ; *Endothelial Cells/drug effects/metabolism ; *Drugs, Chinese Herbal/pharmacology/chemistry/metabolism/analysis ; *Peptide Fragments/antagonists & inhibitors ; Salvia miltiorrhiza/chemistry ; *Brain/drug effects/metabolism ; Cell Survival/drug effects ; Mass Spectrometry ; },
abstract = {Danshen-Chuanxiong is a traditional herb pair used for cardiovascular and cerebrovascular disorders, but its chemical basis and potential effects in Alzheimer's disease (AD)-related endothelial injury remain incompletely defined. Here, an integrated analytical workflow combining reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC) with quadrupole time-of-flight mass spectrometry (Q-TOF-MS), cellular assays, metabolomics, and network pharmacology was applied in an amyloid-β1-42 (Aβ1-42) oligomer-induced human brain microvascular endothelial cell (hBMEC) injury model. The complementary RPLC/HILIC and positive/negative electrospray-ionization strategy expanded coverage across a broad polarity range. UHPLC-Q/TOF-MS detected 90 compounds, mainly phenolic acids, phthalides, tanshinones, diterpenoids, and other aromatic or terpenoid constituents. The reductions in cell viability and zonula occludens-1 expression following Aβ1-42 exposure confirmed the successful establishment of the cellular injury model, whereas pretreatment with Danshen, Chuanxiong, or their combination increased cell viability and alleviated Aβ1-42-induced cellular injury. Untargeted metabolomics annotated 38 differential metabolites, of which 30 showed a recovery-associated shift toward the control state after Danshen-Chuanxiong treatment; the associated pathways included amino-acid, purine, glutathione, and glycerophospholipid metabolism. Integrative analysis prioritized seven candidate targets of Danshen-Chuanxiong, namely ACHE, VEGFA, NOS2, NOS3, AKR1B1, MDM2, and XDH. These findings provide a separation-MS-based chemical characterization and mechanistic framework for further validation of Danshen-Chuanxiong in AD-related endothelial injury models.},
}

*Amyloid beta-Peptides/antagonists & inhibitors/metabolism
Humans
*Metabolomics
Chromatography, High Pressure Liquid
*Endothelial Cells/drug effects/metabolism
*Drugs, Chinese Herbal/pharmacology/chemistry/metabolism/analysis
*Peptide Fragments/antagonists & inhibitors
Salvia miltiorrhiza/chemistry
*Brain/drug effects/metabolism
Cell Survival/drug effects
Mass Spectrometry

@article {pmid42714032,
year = {2026},
author = {Li, Y and Ye, T and Lu, H and Wang, S and Yu, T and Li, H and Cheng, X},
title = {Effects of Qi-fu-yin on Improving Cognitive Impairment and Reducing Cellular Senescence in the Brains of 5xFAD Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {235},
pages = {},
doi = {10.3791/72118},
pmid = {42714032},
issn = {1940-087X},
mesh = {Animals ; Mice ; *Brain/drug effects/metabolism/pathology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Cellular Senescence/drug effects ; *Drugs, Chinese Herbal/pharmacology ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; Male ; },
abstract = {Although the mechanism of Qi-fu-yin (QFY), a traditional Chinese medicine prescription, remains incompletely understood, it has shown therapeutic potential in Alzheimer's disease (AD). This study aimed to investigate the association between QFY treatment and cognitive impairment in 5xFAD mice. We used grip strength, gait, colony nesting, shuttle box, Morris water maze test, and ELISA to evaluate the levels of Amyloid-β protein 1-42 (Aβ1-42), Aβ1-40, Growth-associated protein 43 (GAP-43), Synaptophysin (SYN), and Postsynaptic density protein 95 (PSD-95) in the brains of 5xFAD mice. Luminex cytokine analysis was used to quantify Senescence-associated secretory phenotype (SASP) levels in the cortex. The amount of Senescence-associated β-galactosidase (SA-β-Gal), Aβ deposition, and dendritic spines in the animals' brains was measured by SA-β-Gal staining, immunohistochemistry, and Golgi-Cox staining, respectively. QFY treatment dramatically reduced cortical Aβ plaque burden and decreased p21 expression in 5xFAD mice, according to immunofluorescence tests. In 5xFAD mice, QFY therapy markedly enhanced learning and memory performance, alleviated aging, and increased the amounts of GAP-43, PSD-95, and SYN proteins in the mice's cortex. Following QFY treatment, there was a significant decrease in Aβ plaque and SA-β-Gal activity in the brain, as well as Aβ1-42 and Aβ1-42/Aβ1-40 levels in the hippocampus. The levels of IL-1α, IL-1β, IL-6, IL-17A, and IFN-γ were considerably reduced in the cortex of the 5xFAD mice. PCA and Pearson correlation analyses demonstrated a strong negative association between SASP cytokines and synaptic protein levels. These findings suggest an association between QFY treatment and improvements in age‑related cognitive decline and cellular senescence phenotypes in 5xFAD mice, alongside mitigated synaptic structural damage. These findings support further investigation of QFY as a potential therapeutic candidate for Alzheimer's disease.},
}

Animals
Mice
*Brain/drug effects/metabolism/pathology
*Alzheimer Disease/drug therapy/metabolism/pathology
*Cellular Senescence/drug effects
*Drugs, Chinese Herbal/pharmacology
Mice, Transgenic
Amyloid beta-Peptides/metabolism
*Cognitive Dysfunction/drug therapy/metabolism/pathology
Male

@article {pmid42714614,
year = {2026},
author = {Schnieder, M},
title = {[Antibody therapy in Alzheimer's disease].},
journal = {Zeitschrift fur Gerontologie und Geriatrie},
volume = {},
number = {},
pages = {},
pmid = {42714614},
issn = {1435-1269},
abstract = {Alzheimer's disease, the leading cause of dementia, is defined by extracellular amyloid‑β (Aβ) plaques, intracellular tau aggregates and neurodegeneration. Lecanemab and donanemab, are the first disease-modifying antibodies available for early Alzheimer's disease. Both reduce Aβ plaques and slow cognitive decline. Lecanemab targets soluble protofibrils and donanemab targets fibrillar Aβ. The primary side effect is amyloid-related imaging abnormalities (ARIA), which can occur as edema (ARIA-E) or hemorrhages (ARIA-H). The risk is higher in APOE4 homozygotes, anticoagulation or cerebrovascular diseases. Therefore, during treatment a regular monitoring with magnetic resonance imaging (MRI) is mandatory.},
}

@article {pmid42714783,
year = {2026},
author = {Verma, E and Mishra, S and Chellammal, HSJ and Khandige, PS and Gasmi, A},
title = {Gut microbiota as a modulator of HDAC: insights into Alzheimer's disease treatment.},
journal = {Pharmacological reports : PR},
volume = {},
number = {},
pages = {},
pmid = {42714783},
issn = {2299-5684},
abstract = {The human gut microbiota (GMB) has a significant impact on physiological function, including gastrointestinal health, immune regulation, and redox homeostasis. It consists of diverse microorganisms that support digestion, nutrient absorption, and intestinal barrier function. Emerging evidence suggests that gut microbiota-derived metabolites may influence the gut-brain axis and regulate epigenetic mechanisms through modulation of histone deacetylases (HDAC). HDAC are key enzymes involved in gene expression, neuronal survival, neuroinflammation, and the pathogenesis of Alzheimer's disease (AD). Gut microbiota-derived metabolites have been reported to modulate HDAC activity and may contribute to neuroprotective and anti-inflammatory effects. Through these mechanisms, the GMB may influence cognitive function and the progression of AD. However, the precise molecular mechanisms involved in these interactions are not yet fully understood and continue to be extensively investigated. Therefore, this review focuses on the correlation between HDAC and the restoration of a healthy GMB as a therapeutic approach for the treatment and prevention of AD. It emphasizes the role of gut-derived metabolites, peptides, and dietary bioactive compounds in regulating HDAC-mediated epigenetic pathways. These interactions may influence gene expression, neurotransmitter biosynthesis, neuroinflammation, and neuroprotective signalling associated with cognitive function. Furthermore, the review delineates the bidirectional interplay among neurotransmitter signalling, GMB composition, and HDAC-mediated epigenetic regulation, along with their potential roles in the pathophysiology of neurodegenerative disorders.},
}

@article {pmid42716045,
year = {2026},
author = {Teunissen, CE and Vermunt, L and Barthélemy, NR and Benzinger, TLS and Graff-Radford, J and Verberk, IMW and Zetterberg, H and Schindler, SE and Jack, CR},
title = {Fluid biomarkers in the evolving care landscape of Alzheimer's disease and related disorders.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {926-938},
doi = {10.1016/S1474-4422(26)00246-2},
pmid = {42716045},
issn = {1474-4465},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood ; tau Proteins/cerebrospinal fluid ; Animals ; },
abstract = {Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, α-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/diagnosis/blood
tau Proteins/cerebrospinal fluid
Animals

@article {pmid42716046,
year = {2026},
author = {Benzinger, TLS and Cogswell, PM and Arani, A and Chaney, AM and Hutson, K and Glasser, MF and Graff-Radford, J and McConathy, J and Raji, CA and Teunissen, C and Vemuri, P and Zaharchuk, G and Jack, CR},
title = {Neuroimaging in the era of biologically defined Alzheimer's disease and disease-modifying therapy.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {939-951},
doi = {10.1016/S1474-4422(26)00285-1},
pmid = {42716046},
issn = {1474-4465},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy/drug therapy ; *Neuroimaging/methods ; *Brain/diagnostic imaging/pathology ; Positron-Emission Tomography/methods ; Magnetic Resonance Imaging/methods ; Biomarkers ; },
abstract = {Disease-modifying therapies and biomarker-based diagnostic frameworks will fundamentally altered the clinical diagnosis and management of Alzheimer's disease. Diagnosis is increasingly anchored in the biological evidence of pathology rather than clinical presentation alone, with implications for treatment eligibility, prognosis, and monitoring. In clinical practice, patients with memory complaints can present with complex mixed pathologies that develop across the lifespan. Brain imaging, particularly MRI and PET, plays a crucial role in visualising these cumulative abnormalities. With Alzheimer's disease-specific therapies now available in many regions of the world, amyloid PET plays a central role in establishing Alzheimer's disease diagnosis, determining eligibility for amyloid-targeting therapies, and quantifying treatment-related amyloid clearance. In settings where available, tau PET informs biological stage, prognosis, and clinical heterogeneity. MRI remains indispensable for differential diagnosis, the assessment of comorbid and vascular pathology, and monitoring for complications, particularly amyloid-related imaging abnormalities. Technological advances-including quantitative imaging, artificial intelligence, accelerated acquisition, and workflow optimisation-are improving reliability, efficiency, and access to these tools. Neuroimaging is now a cornerstone of Alzheimer's disease care and a crucial discriminator tool for characterising brain injury across the lifespan. With emerging fluid biomarkers, neuroimaging supports accurate diagnosis, prognosis, and treatment monitoring.},
}

Humans
*Alzheimer Disease/diagnostic imaging/therapy/drug therapy
*Neuroimaging/methods
*Brain/diagnostic imaging/pathology
Positron-Emission Tomography/methods
Magnetic Resonance Imaging/methods
Biomarkers

@article {pmid42716047,
year = {2026},
author = {Graff-Radford, J and Karliner, L and Barnes, DE and Frisoni, GB and Sperling, R and Villain, N and Benzinger, TLS and Teunissen, C and Jack, CR},
title = {Clinical pathways for cognitively unimpaired individuals with Alzheimer's disease neuropathological change.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {952-964},
doi = {10.1016/S1474-4422(26)00248-6},
pmid = {42716047},
issn = {1474-4465},
mesh = {Humans ; *Alzheimer Disease/pathology/therapy/diagnosis/drug therapy ; Biomarkers ; *Brain/pathology ; },
abstract = {The recent approval of disease-modifying therapies for symptomatic Alzheimer's disease is a major advance for a condition with few therapeutic options. Anti-amyloid monoclonal antibodies have shown clinically meaningful benefits in slowing cognitive decline. Clinical trials in symptomatic Alzheimer's disease suggest that anti-amyloid therapies might provide the greatest benefit in subgroups who have low baseline levels of Alzheimer's disease pathology; ongoing prevention trials are evaluating these therapies in cognitively unimpaired individuals who have biomarker evidence of Alzheimer's disease neuropathological change (ADNC). However, the possibility of biomarker testing and treatment in cognitively unimpaired people raises key questions about ethics and the consequences that follow from a positive test or an uncertain result (ie, the so-called downstream effects on patients and health systems). Furthermore, test accuracy might be questioned when ADNC has a low prevalence in the population being tested and in the case of intermediate-range biomarker concentrations that might not reliably indicate true ADNC or be false positives. If anti-amyloid therapies prove beneficial for cognitively unimpaired people with ADNC and become part of routine practice, several key knowledge gaps must be addressed to support safe, scalable, real-world implementation of Alzheimer's disease treatment.},
}

Humans
*Alzheimer Disease/pathology/therapy/diagnosis/drug therapy
Biomarkers
*Brain/pathology

@article {pmid42716318,
year = {2026},
author = {Bu, X and Yuan, Y and Song, W and Wang, W},
title = {Music intervention as a therapeutic approach to cognitive impairments in APP/PS1 mice.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112113},
doi = {10.1016/j.brainresbull.2026.112113},
pmid = {42716318},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is typified by progressive deterioration in memory and executive capacities. Although music-based interventions represent a promising non-pharmacological strategy for AD, the underlying mechanisms remain insufficiently understood. APP/PS1 transgenic mice were subjected to 30 consecutive days of musical stimulation, with wild-type C57BL/6 J and untreated APP/PS1 mice serving as controls. Neurobehavioral assessments revealed that music intervention substantially improved memory performance in transgenic AD mice. Mechanistically, music attenuated oxidative stress in both serum and hippocampus of APP/PS1 mice, as evidenced by decreased nitric oxide (NO) and malondialdehyde (MDA) levels along with enhanced antioxidant activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC). Peripheral and hippocampal inflammatory responses were also effectively inhibited following musical treatment. Music restored synaptic plasticity-related protein expression, increased postsynaptic density thickness, narrowed synaptic cleft, and elevated dendritic spine density. Additionally, music exposure alleviated Aβ deposition and neuronal loss in APP/PS1 mice. These findings indicate that music-based auditory enrichment exerts neuroprotective effects against AD through synergistically modulating oxidative stress, neuroinflammation, synaptic plasticity, and neuronal survival, providing mechanistic insights into its intervention potential for AD.},
}

@article {pmid42718894,
year = {2026},
author = {Lin, W and Grewal, SS and Byrne, RW},
title = {Two serial MoCA assessments may support biomarker-sparing triage between Parkinson's disease/Lewy body dementia and frontotemporal dementia: a progressive inclusion analysis of 1,129 participants.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1848105},
pmid = {42718894},
issn = {1663-4365},
abstract = {Reliable differentiation of Parkinson's disease/Lewy body dementia (PD/LBD) from frontotemporal dementia (FTD) affects treatment strategy and clinical trial eligibility, yet confirmatory biomarker testing remains costly and unevenly available. Whether routine cognitive trajectories can support testing prioritization has not been systematically quantified. We performed a progressive inclusion analysis of 1,129 National Alzheimer's Coordinating Center participants with PD/LBD (n = 385) or FTD (n = 744) to determine the minimum number of serial Montreal Cognitive Assessment (MoCA) administrations required for diagnostic separation. Random forest classifiers used seven MoCA subdomain slopes from the first k chronological assessments (k = 2 through k = 8), with five-fold stratified cross-validation and 500-iteration bootstrap confidence intervals. In the primary full-cohort analysis, two assessments yielded AUC = 0.785 (95% CI 0.757-0.814; sensitivity = 0.922; specificity = 0.525). The interval-restricted 6-12 month subset yielded AUC = 0.837 (95% CI 0.787-0.885), near the lower edge of published biomarker-panel ranges in an indirect comparison, although its lower confidence bound remained below 0.85. Discrimination persisted after age matching (AUC = 0.794, 95% CI 0.761-0.826; residual age gap = -0.3 years) and age restriction to 55-75 years (AUC = 0.777, 95% CI 0.741-0.814). Age alone yielded lower discrimination (AUC = 0.721, 95% CI 0.691-0.751) than MoCA slopes, while slopes plus age yielded AUC = 0.867 (95% CI 0.845-0.888). Four-assessment performance was AUC = 0.831 (95% CI 0.791-0.873), consistent with an apparent sample-size-limited plateau as eligible N contracted from 391 at k = 4 to 98 at k = 6. These findings support serial MoCA trajectory analysis as an exploratory tool for prioritizing confirmatory diagnostic testing, with age sensitivity, subtype sensitivity, and operating-point performance quantified.},
}

@article {pmid42719214,
year = {2026},
author = {Mittal, D and Solanki, P and Jain, GK and Jhawat, V and Kesharwani, P and Dutt, R and Arora, S and Singh, RP},
title = {Herbal nanoparticles in the treatment of neurodegeneration: from molecular mechanisms to therapeutic translation.},
journal = {3 Biotech},
volume = {16},
number = {10},
pages = {420},
pmid = {42719214},
issn = {2190-572X},
abstract = {UNLABELLED: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss involving multiple pathological mechanisms, including protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although conventional therapies provide symptomatic relief, they fail to halt disease progression and are limited by poor blood-brain barrier (BBB) penetration, off-target effects, and systemic toxicity. Likewise, several herbal bioactives, such as curcumin, resveratrol, quercetin, and epigallocatechin gallate, exhibit promising neuroprotective properties but suffer from poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate brain delivery. Nanotechnology-based delivery systems have emerged as a promising approach to overcome these pharmacokinetic limitations by enhancing stability, controlled release, BBB transport, and brain accumulation of herbal therapeutics. This review critically summarizes recent advances in herbal nanoformulations, emphasizing disease-specific molecular targets, BBB-targeting strategies, comparative nanocarrier systems, pharmacokinetic optimization, intracellular trafficking, and translational challenges. Unlike previous reviews, it integrates recent evidence on nanotoxicology, manufacturing scalability, quality control, regulatory considerations, and emerging technologies, including biomimetic nanoparticles and extracellular vesicles. Despite encouraging preclinical outcomes, clinical evidence remains limited, and no herbal nanoformulation has yet demonstrated definitive efficacy or received regulatory approval for neurodegenerative diseases. Future clinical translation will require standardized formulations, rigorous safety evaluation, and well-designed clinical trials. Unlike previous reviews that primarily summarize individual nanocarrier systems or herbal therapeutics, the present review provides a comprehensive and critical synthesis of the current evidence by integrating disease-specific molecular mechanisms, herbal bioactives, nanocarrier design strategies, blood-brain barrier transport mechanisms, intracellular trafficking, pharmacokinetic considerations, translational barriers, regulatory challenges, clinical evidence, and emerging technologies. Furthermore, the review identifies major knowledge gaps and future research priorities to facilitate the successful clinical translation of herbal nanoformulations for neurodegenerative disorders.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05048-8.},
}

@article {pmid42708270,
year = {2026},
author = {Rajput, R and Sharma, A and Mittal, V and Sharma, D},
title = {Circadian Rhythm Disruption in Alzheimer's Disease: Molecular Mechanisms, Clinical Implications, and Therapeutic Approaches.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026473002260820065219},
pmid = {42708270},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a progressive neurological disorder characterized by unusual behavior, memory deterioration, and a decline in cognitive abilities. A growing body of research indicates that circadian rhythm disturbances play a crucial role in the pathophysiology of AD, impacting both molecular processes and clinical outcomes. This review critically evaluates the molecular interplay between circadian rhythm disruption and AD pathology, explores its impact on clinical manifestations and disease progression, and assesses emerging diagnostic and therapeutic strategies to restore circadian regulation and improve patient outcomes.

METHODS: A thorough analysis of recent research on molecular clock genes (CLOCK, BMAL1, PER, and CRY) and their roles in regulating hormone rhythms, metabolism, and sleep-wake cycles was conducted. Research on technology-based methods, therapeutic treatments, and circadian biomarkers was assessed to determine their applicability in AD.

RESULTS: Circadian gene dysregulation was found to exacerbate tau hyperphosphorylation, amyloid- β accumulation, oxidative stress, and neuroinflammation. Clinically, circadian disruption manifests itself as mood disorders, sleep-wake abnormalities, and accelerated cognitive deterioration.

DISCUSSION: Light therapy, melatonin supplements, chrono-pharmacology, and behavioural techniques are among the interventions that have shown promise in restoring rhythm stability. Wearables, smart lighting, neuromodulation, and multi-omics modelling are examples of technological advancements that increase the range of diagnostic and treatment possibilities.

CONCLUSION: Patient heterogeneity, translational gaps, and a lack of mechanistic knowledge continue to pose difficulties despite progress. To enhance AD outcomes, future research should focus on integrated, customized therapies that target the circadian rhythm.},
}

@article {pmid42708376,
year = {2026},
author = {Hosoki, S and Sachdev, PS and Ihara, M},
title = {Arterial spin labeling-derived cerebral blood flow as a translational biomarker and candidate surrogate endpoint for cognitive impairment.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCO.0000000000001112},
pmid = {42708376},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: Arterial spin labeling (ASL) MRI noninvasively quantifies cerebral blood flow (CBF), but its role as a mechanistic biomarker and surrogate endpoint in trials of cognitive impairment remains undefined. This review evaluates evidence linking regional CBF to cognition across Alzheimer's disease, mild cognitive impairment (MCI), and cerebral small vessel disease (SVD), with particular emphasis on CADASIL as a mechanistically informative model.

RECENT FINDINGS: Multipostlabeling-delay ASL, spatial coefficient of variation metrics, and harmonized processing pipelines have improved reproducibility. Cross-sectional and longitudinal studies consistently link reduced CBF to cognitive impairment, with baseline CBF predicting cognitive decline, MCI-to-Alzheimer's disease conversion, white matter hyperintensity progression, and vascular events. In CADASIL, CBF is independently associated with cognitive performance and predicts subcortical hyperintensity progression over 2 years. Interventional data from SPRINT MIND, PRESERVE, and pilot lecanemab studies indicate that ASL-CBF is responsive to therapy.

SUMMARY: Within the FDA-NIH BEST framework, ASL-CBF appears to meet several criteria consistent with a reasonably likely surrogate endpoint, capturing upstream, potentially reversible hemodynamic dysfunction beyond established structural markers. CADASIL provides an optimal context for qualifications. Larger clinical trials linking treatment-induced CBF changes to clinical benefit, further protocol harmonization, and regulatory engagement are needed to translate ASL-CBF into a validated trial endpoint.},
}

@article {pmid42709250,
year = {2026},
author = {Yang, W and Lu, Y},
title = {Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42709250},
issn = {1590-3478},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; *alpha-Synuclein/metabolism ; Animals ; *DNA-Binding Proteins/metabolism ; *Alzheimer Disease/metabolism ; *Protein Aggregation, Pathological/metabolism/therapy ; },
abstract = {BACKGROUND: Neurodegenerative diseases have traditionally been classified by their predominant protein pathology. However, accumulating evidence reveals extensive molecular cross-talk between distinct pathological proteins, particularly in Alzheimer's disease (AD).

OBJECTIVE: This review examines cross-disease protein interactions and their implications for diagnosis and treatment.

METHODS: We systematically reviewed peer-reviewed literature published between 2020 and 2025, complemented by seminal earlier studies, examining molecular mechanisms of protein cross-seeding, clinical evidence of co-pathology, and emerging therapeutic strategies.

RESULTS: Cross-seeding between amyloid-β (Aβ), tau, α-synuclein, and TDP-43 has been demonstrated in vitro and in vivo. Harmonized autopsy studies reveal that 91% of individuals over 80 years harbor multiple neuropathologies. Co-pathology accelerates cognitive decline and complicates biomarker interpretation. Anti-amyloid immunotherapies lecanemab and donanemab demonstrate 27-35% slowing of cognitive decline, while anti-tau antibodies targeting N-terminal epitopes have uniformly failed, prompting investigation of combination approaches.

CONCLUSIONS: Recognition of cross-disease protein interactions necessitates a paradigm shift toward multi-target therapeutic strategies and precision medicine approaches accounting for individual co-pathology burden.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
*alpha-Synuclein/metabolism
Animals
*DNA-Binding Proteins/metabolism
*Alzheimer Disease/metabolism
*Protein Aggregation, Pathological/metabolism/therapy

@article {pmid42709336,
year = {2026},
author = {Colosimo, C},
title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {42709336},
issn = {1179-1918},
abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.},
}

@article {pmid42709795,
year = {2026},
author = {Du, X and Liu, N and Zhang, T and Yang, C and Luo, H},
title = {Size-tailored nanoparticle-antibody conjugates overcome hepatic sequestration in Alzheimer's disease treatment.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {37},
pages = {e2603034123},
doi = {10.1073/pnas.2603034123},
pmid = {42709795},
issn = {1091-6490},
support = {0214187096//Huazhong University of Science and Technology (HUST)/ ; XJ2400008870//Hainan University (HU)/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/therapy/metabolism/immunology ; *Nanoparticles/chemistry ; Amyloid beta-Peptides/metabolism/immunology ; *Liver/metabolism/drug effects ; Silicon Dioxide/chemistry ; Mice ; *Antibodies, Monoclonal/chemistry ; Particle Size ; Mice, Transgenic ; Polyethylene Glycols/chemistry ; Brain/metabolism ; Humans ; *Immunoconjugates/chemistry ; },
abstract = {Antibody-based immunotherapy targeting amyloid-β (Aβ) is a promising approach for Alzheimer's disease (AD). However, its efficacy is limited by rapid hepatic sequestration, complement activation, and liver dysfunction. In this study, we synthesized low-immunogenic 450-nm functionalized mesoporous silica nanoparticles (PEG-MSN-1F12) by conjugating the anti-Aβ42 monoclonal antibody 1F12 to polyethylene glycol-modified mesoporous silica nanoparticles to address these challenges. In APP/PS1 mice, intravenous PEG-MSN-1F12 administration markedly enhanced peripheral Aβ clearance, promoted intestinal excretion, reshaped gut microbiota, and alleviated intestinal inflammation, thus reducing AD-associated hepatic burden. Peripheral Aβ removal further led to decreased brain Aβ deposition, attenuated microglial activation, and improved cognition. These findings highlight that the use of particle size-engineered antibody-nanoparticle conjugates is a safe and effective strategy to overcome hepatic sequestration, augment Aβ clearance, and improve AD outcomes.},
}

Animals
*Alzheimer Disease/drug therapy/therapy/metabolism/immunology
*Nanoparticles/chemistry
Amyloid beta-Peptides/metabolism/immunology
*Liver/metabolism/drug effects
Silicon Dioxide/chemistry
Mice
*Antibodies, Monoclonal/chemistry
Particle Size
Mice, Transgenic
Polyethylene Glycols/chemistry
Brain/metabolism
Humans
*Immunoconjugates/chemistry

@article {pmid42709901,
year = {2026},
author = {},
title = {In brief: Subcutaneous lecanemab (Leqembi Iqlik) for initial treatment of Alzheimer's disease.},
journal = {The Medical letter on drugs and therapeutics},
volume = {68},
number = {1763},
pages = {151},
doi = {10.58347/tml.2026.1763c},
pmid = {42709901},
issn = {1523-2859},
}

@article {pmid42710551,
year = {2026},
author = {Kosa, AC and Lopez-Gutierrez, L and Ando, K and Doeraene, E and Aydin, E and Lasri, H and Wathelet-Depauw, A and Pieters, K and Van Morckhoven, D and Dubois, C and Hupkens, E and Jespers, P and Dewachter, L and Stamatopoulos, B and Brion, JP and Leroy, K},
title = {Effect of tau silencing on tau pathology propagation, a treatment efficient at the earliest stages of the disease?.},
journal = {Neurobiology of disease},
volume = {229},
number = {},
pages = {107598},
doi = {10.1016/j.nbd.2026.107598},
pmid = {42710551},
issn = {1095-953X},
abstract = {Cognitive decline in Alzheimer's disease (AD) correlates more strongly with tau pathology than with amyloid plaques, switching the therapeutic focus towards targeting tau pathology. Tau silencing therapies present an increasing interest as potential therapeutical approaches to treat AD due to their efficiency in reducing pathological tau burden. However, the effects of tau silencing on tau pathology formation and spreading, as well as on cognitive deficits, have not been investigated in AD or AD preclinical models expressing WT tau. In this study, we investigated the effects of Tau siRNA on tau pathology propagation in a mouse model of AD expressing 6 human WT tau isoforms, in which tau pathology formation and spreading has been initiated by intracerebral injection of pathological tau from a human AD brain. Specifically, we examined whether tau silencing affects tau pathology progression when started either simultaneously with the induction of tau pathology or subsequent to the onset of tau lesions, thereby mimicking the clinical scenario in which AD patients are typically diagnosed. Three months after tau pathology was induced, spatial learning and tau pathology were assessed. Cognitive performance was rescued, and tau pathology development was reduced when tau silencing started simultaneously with the induction of tau lesions. Nevertheless, Tau siRNA was ineffective on both cognitive performance and tau pathology propagation when administered after some development of tau pathology. Our results indicate that tau silencing therapy should be administered in early stages of the disease to achieve therapeutic efficacy on the development of tau pathology in AD.},
}

@article {pmid42710608,
year = {2026},
author = {Liu, S and Ren, L and Liu, L and Chen, LL and Zhang, Y and Wang, P and Xie, GJ},
title = {Du-Shu-Wan alleviates Tau protein phosphorylation in Alzheimer's disease by regulating MAPK/JNK signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122380},
doi = {10.1016/j.jep.2026.122380},
pmid = {42710608},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is one of the leading causes of cognitive impairment and dementia among the elderly and has become an urgent public health challenge due to population ageing. Du-Shu-Wan (DSW) is an ancient Chinese herbal medicine that aims to enhance memory and soothe the spirit, and has long been applied for forgetfulness and cognitive decline. At present, there is still no systematic research on the pharmacological basis of DSW and its specific molecular mechanisms for alleviating AD.

AIM OF THE STUDY: The researchers aimed to investigate the mechanisms by which DSW attenuates AD-related pathological changes in animal models and in vitro cultured cells.

MATERIALS AND METHODS: The chemical composition of DSW was characterized using UPLC-Q-TOF-MS. Subsequently, HE staining, Nissl staining, and silver staining were employed to evaluate the effects of DSW on neuronal damage in an AD rat model induced by intracerebral injection of Aβ1-42 into the lateral ventricle. Potential mechanisms of action were investigated through network pharmacology, molecular docking, and transcriptomics. Finally, the results of the in vivo experiments were validated in an HT22 cell model.

RESULTS: This study reports the identification of 101 compounds from DSW for the first time. After a four-week course of DSW treatment, AD model rats exhibited significantly improved cognitive function, along with decreased neuronal injury and reduced neurofibrillary tangle pathology. A comprehensive analysis suggests that DSW enhanced cognitive function, an effect associated with inhibition of the MAPK/JNK pathway and reduction in the level of phosphorylated Tau at Ser422 sites. Additionally, in vitro experiments further showed that the protective effect of DSW-containing serum against Aβ1-42-induced neurotoxicity was associated with reduced JNK activation, and this reversal was obviously compromised by a JNK activator.

CONCLUSIONS: According to this study, DSW may enhance cognitive function in AD rats, an effect that is associated with reduced JNK pathway activity and reduced tau protein hyperphosphorylation at Ser422.},
}

@article {pmid42710609,
year = {2026},
author = {Zheng, J and Tan, Q and Liu, G and Xie, R and Wang, Q and Liang, Y},
title = {Bushen-Yizhi formula promotes neurogenesis and ameliorates cognitive impairment by activating ST8Sia Ⅱ/Ⅳ-PSA-NCAM pathway in ibotenic acid induced mice.},
journal = {Journal of ethnopharmacology},
volume = {374},
number = {Pt 1},
pages = {122356},
doi = {10.1016/j.jep.2026.122356},
pmid = {42710609},
issn = {1872-7573},
abstract = {Bushen-Yizhi formula (BSYZ), a traditional Chinese herbal prescription, has been widely used to treat kidney deficiency syndrome and alleviate cognitive impairment associated with Alzheimer's disease (AD). Loss of polysialylation of the neural cell adhesion molecule (PSA-NCAM) is closely associated with cognitive dysfunction. However, whether BSYZ regulates PSA-NCAM polysialylation and the underlying mechanisms remain unclear.

AIM OF THE STUDY: This study aimed to investigate whether BSYZ promotes hippocampal neurogenesis and ameliorates cognitive impairment through activation of the ST8Sia II/IV-PSA-NCAM pathway.

METHODS: An AD-like mouse model was established by bilateral ibotenic acid (IBO) injections into the basal nuclei of C57BL/6 mice. Animals were randomly assigned to five groups: control, model, low- BSYZ (1.46 g/kg), high-dose BSYZ (5.84 g/kg), and donepezil (3 mg/kg). Cognitive function was evaluated using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Hippocampal PSA-NCAM expression was assessed by immunofluorescence staining and further investigated using proteomic analysis combined with network pharmacology. PSA-NCAM-associated polysialic acid levels were quantified by hydrochloric acid hydrolysis followed by 4,5-methylenedioxy-1,2-phenylenediamine dihydrochloride (DMB) derivatization coupled with mass spectrometry. The mRNA and protein expression levels of α-2,8-sialyltransferase II and IV (ST8Sia II/IV) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. Hippocampal neurogenesis was evaluated by immunofluorescence double-labeling. The bioactive compounds targeting ST8Sia II/IV were identified using HPLC-Q-TOF MS/MS, followed by molecular docking and molecular dynamics simulations to predict their binding affinities.

RESULTS: The IBO-induced mouse model exhibited significant cognitive deficits, confirming successful model establishment. Behavioral assessments demonstrated that both low- and high-dose BSYZ significantly improved learning and memory performance. Proteomic analysis and immunofluorescence staining revealed that BSYZ markedly increased hippocampal PSA-NCAM expression (**P < 0.01, n = 5). Quantitative analysis further showed that PSA-NCAM-associated polysialic acid levels increased by 78% (*P < 0.05, n = 5) and 102% (**P < 0.01, n = 5) following low- and high-dose BSYZ treatment. BSYZ significantly increased the number of PSA-NCAM[+]/DCX[+] cells in the hippocampal dentate gyrus (*P < 0.05), accompanied by significant increases in Nestin[+]/BrdU[+] (*P < 0.05), DCX[+]/BrdU[+] (**P < 0.01), and NeuN[+]/BrdU[+] (**P < 0.01) double-positive cells, indicating enhanced neurogenesis and neuronal maturation. Furthermore, BSYZ significantly upregulated both the mRNA and protein expression of ST8Sia II (**P < 0.01) and ST8Sia IV (**P < 0.01) in the hippocampus. HPLC-Q-TOF MS/MS, molecular docking, and molecular dynamics simulations identified isoimperatorin as a major active constituent of BSYZ with strong binding affinity toward both ST8Sia II/IV, exhibiting docking energies of -8.7 and -7.6 kcal/mol, respectively (n = 3, RSD < 2%).

CONCLUSIONS: Our study demonstrates BSYZ promotes hippocampal neurogenesis to ameliorate cognitive impairment by activating ST8Sia II/IV-PSA-NCAM pathway. These findings provide mechanistic evidence supporting the therapeutic potential of BSYZ for AD treatment.},
}

@article {pmid42711466,
year = {2026},
author = {Mimica, N and Dumitrescu, L and Gregorič Kramberger, M and Hort, J and Kovács, T and Popadić, K and Popescu, BO and Rakuša, M and Rejdak, K and Turčáni, P},
title = {Expert opinion on Alzheimer's disease diagnostics and management in Central Eastern European countries representing 88 million population.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42711466},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology ; Europe, Eastern/epidemiology ; *Disease Management ; },
abstract = {The expert panel from Croatia, Czech Republic, Hungary, Poland, Romania, Slovakia and Slovenia discussed the current situation of various topics related to the diagnostics, general management and treatment of Alzheimer's disease (AD) in these Central Eastern European (CEE) countries, representing around 88 million population. The aim was to estimate AD prevalence, confirm the presence of AD patients/caregivers' associations and AD registries, and establish the availability and reimbursement of costs for AD diagnostic biomarkers and treatment. The panel acknowledged similarities and differences among CEE countries and issued recommendations for cross specialty collaboration between experts in neurology, psychiatry and general practitioners for the early AD diagnosis. They also agreed that CEE countries should provide comprehensive education and training and encourage collaboration between health experts. The panel suggested that CEE countries should involve various stakeholders, policymakers, implement routine screening, combine advanced diagnostic tools and use telemedicine and remote monitoring technologies, invest in research to develop AI-based analyses, new AD diagnostic and monitoring methods, digital tools and wearables. The focus is to address the stigma, reimburse costs of diagnostic tests and therapy, and reduce the modifiable risk factors for AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/epidemiology
Europe, Eastern/epidemiology
*Disease Management

@article {pmid42711740,
year = {2026},
author = {Papait, A and Natale, F and Silini, AR and Nifo Sarrapochiello, I and Orecchini, E and Sollazzo, R and Rinaudo, M and Farigu, S and Garofalo, N and Mantini, G and Giuffrè, GM and Romele, P and Ragozzino, E and Dellaria, A and Giacò, L and Marra, C and Ripoli, C and Grassi, C and Parolini, O and Fusco, S},
title = {Human amniotic mesenchymal stromal cell-derived extracellular vesicles reprogram microglia and prevent neurodegeneration in experimental models of Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42711740},
issn = {2047-9158},
mesh = {*Alzheimer Disease/pathology/metabolism ; *Extracellular Vesicles/transplantation/metabolism ; Animals ; Humans ; *Microglia/metabolism/pathology ; Female ; Mice ; *Mesenchymal Stem Cells/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Amnion/cytology ; Hippocampus/metabolism ; Administration, Intranasal ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and disproportionately affects women, with neuroinflammation emerging as a key driver of disease onset and progression. Beyond amyloid-β (Aβ) and hyperphosphorylated tau protein accumulation, chronic activation of microglia and astrocytes amplifies synaptic dysfunction and neuronal loss. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising translational strategy due to their capacity to modulate inflammation and promote neuroprotection. Here, we investigated whether intranasal administration of extracellular vesicles derived from human amniotic membrane MSCs (hAMSC-EVs) could counteract cognitive decline, neuroinflammation, and synaptic alterations in experimental and human cellular models of AD.

METHODS: hAMSC-EVs were isolated and characterized for size, markers, and biodistribution. Female 3 × Tg-AD mice received chronic intranasal hAMSC-EV administration from 3 to 9 months of age. Cognitive performance was assessed using novel object recognition, object place recognition, and Y-maze tests. Hippocampal Aβ levels, tau phosphorylation, glial density, microglial morphology, cytokine profiles, and synaptic protein expression were analyzed by immunoblotting, ELISA, immunofluorescence, and morphometric analyses. Bioinformatic analyses were performed to investigate the miRNA cargoes of hAMSC-EVs. Translational relevance of the hAMSC-EV effects was assessed in glutamatergic neurons differentiated from induced pluripotent stem cells derived from sporadic AD patients.

RESULTS: The hAMSC-EVs delivered intranasally reached the hippocampus and were internalized by neurons and microglia. hAMSC-EV treatment significantly improved cognitive performance of female 3 × Tg-AD mice and reduced hippocampal Aβ levels without affecting tau phosphorylation. The hAMSC-EVs attenuated neuroinflammation by reducing microglial and astrocytic density, inducing microglial structural remodeling, and downregulating TMEM119 and TREM2 expression. We also detected a shift toward an anti-inflammatory cytokine profile and increased expression of neuroplasticity-related proteins, including BDNF, GluA1, and ARC in the hippocampus of 3 × Tg-AD mice. Bioinformatic analyses identified EV miRNA cargoes enriched in immunomodulatory and neuroprotective pathways. In human AD neurons, hAMSC-EVs prevented neurite atrophy and rescued synaptic protein expression without affecting the cell viability.

CONCLUSIONS: hAMSC-EVs exert robust anti-inflammatory and neuroprotective effects in both murine and human AD models, improving cognition, modulating glial activation, and restoring synaptic integrity. These findings highlight the translational potential of intranasal hAMSC-EVs as an adjuvant therapeutic strategy targeting neuroinflammation and neurodegeneration in AD.},
}

*Alzheimer Disease/pathology/metabolism
*Extracellular Vesicles/transplantation/metabolism
Animals
Humans
*Microglia/metabolism/pathology
Female
Mice
*Mesenchymal Stem Cells/metabolism
Disease Models, Animal
Mice, Transgenic
*Amnion/cytology
Hippocampus/metabolism
Administration, Intranasal

@article {pmid42711950,
year = {2026},
author = {Hwang, J and Pietras, A and Naasan, G and Elahi, FM and Gandy, S},
title = {Rapid plaque clearance with anti-amyloid therapy for Alzheimer's disease: in consideration of donanemab treatment duration from real-world cases.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/13554794.2026.2730462},
pmid = {42711950},
issn = {1465-3656},
abstract = {To assess the possibility that individualized duration of donanemab treatment might enable early pausing of therapy, and to explore the possible utility of plasma P-tau[217] as a biomarker for treatment response monitoring in real-time, two unrelated patients with early-stage Alzheimer's disease were treated with donanemab at the Icahn School of Medicine at Mount Sinai. Clinical progress was monitored via medical chart review, including serial brain MRI, amyloid PET scans, and blood-based biomarker assays (Quanterix Simoa® and Fujirebio Lumipulse®). Both patients achieved complete amyloid clearance as judged by amyloid PET prior to their 6th and 9th infusions, which were significantly earlier than the 12-month mark typically recommended for follow-up amyloid assessment. In agreement with the amyloid PET, concurrently measured plasma P-tau[217] levels fell within a low range. Treatment was discontinued for both patients. These patients highlight the possibility of individualized treatment durations for anti-amyloid therapy with donanemab, guided by biomarker response. Early cessation following rapid plaque clearance could reduce healthcare costs and minimize exposure to the risk of amyloid-related imaging abnormalities and the generation of neutralizing antibodies. Plasma P-tau[217] warrants further investigation as a reliable, cost-effective surrogate for PET scans to monitor real-time treatment response and guide the timing of discontinuation.},
}

@article {pmid42700810,
year = {2026},
author = {Han, Z and Liu, W and Fu, W and Wang, K and Tan, Z and Zhang, D and Yang, F and Dong, W and Sang, Z},
title = {Imidazo[1,2-a]pyridine-based HDAC6 inhibitor a17 for the treatment of Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {1034},
number = {},
pages = {179320},
doi = {10.1016/j.ejphar.2026.179320},
pmid = {42700810},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a prevalent, chronic, and progressive neurodegenerative disorder that predominantly affects the elderly population, and no effective pharmacological treatments are currently available. Histone deacetylase 6 (HDAC6) is overexpressed in the hippocampus of AD patients, and its inhibition has been shown to clear amyloid-β (Aβ) deposits, promote tau protein degradation, ameliorate mitochondrial transport deficits, and restore α-tubulin acetylation. Thus, selective HDAC6 inhibition represents a promising therapeutic strategy for AD, yet the underlying mechanisms by which HDAC6 inhibitors ameliorate cognitive impairment in AD remain elusive. In our previous study, a series of novel imidazo [1,2-a]pyridine-based HDAC6 inhibitors were developed, among which compound a17 exhibited potent HDAC6 inhibitory activity with an IC50 value of 7.51 nM, warranting further investigation into its anti-AD effects. Herein, we demonstrated that a17 exerted robust neuroprotective effects against L-Glutamate (L-Glu-)/Aβ25-35-induced HT22 cell injury. Additionally, a17 displayed favorable blood-brain barrier (BBB) permeability in vitro and drug-likeness properties. In vivo studies revealed that a17 significantly attenuated AD-like phenotypes in an Aluminium chloride (AlCl3)-induced zebrafish AD model, a mechanism potentially associated with the differential regulation of ODC1, Serpine1, and PAG-1. Furthermore, a17 markedly improved scopolamine-induced memory deficits in mice. Collectively, these findings indicate that an HDAC6 inhibitor, a17, was found to attenuate AD-associated pathological and behavioral markers by regulating the expression of ODC1, Serpine1, or PAG-1. Accordingly, a17 merit consideration for a pharmacological treatment of choice for AD.},
}

@article {pmid42701177,
year = {2026},
author = {Riedlinger, D and Karamercan, MA and Dündar, ZD and Janssens, K and Adam, VN and Bjørnsen, LP and Fabbri, A and Laribi, S and Möckel, M and Polyzogopoulou, E and Somodi, S and Koc, M and Colak, T and Slagman, A and , },
title = {Non-traumatic chief complaints in older patients in European emergency departments and associated outcomes during the Covid-19 pandemic - a secondary analysis of the cross sectional EGERS study.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {42701177},
issn = {1471-2318},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Europe/epidemiology ; *Emergency Service, Hospital/statistics & numerical data ; Male ; Aged, 80 and over ; *COVID-19/epidemiology ; Aged ; Prospective Studies ; Hospital Mortality ; Emergency Room Visits ; Hospitalization/statistics & numerical data ; Pandemics ; },
abstract = {BACKGROUND: The scope of medical conditions addressed in Emergency Departments (ED) increases with growing numbers of older patients among the ED patient population. More information on their chief complaints and related treatment outcomes is essential to ensure high-quality ED care. The objective of this study was to describe the pattern of chief complaints of older ED patients and evaluate the associations between these complaints and outcomes such as mortality and hospital admission.

METHODS: This secondary analysis is based on the observational 'Epidemiology of Geriatric patients in Europe' (EGERS) study. This prospective, routine data cross-sectional study was conducted in 36 EDs across 9 European countries. Data collection from routine clinical records of all patients aged 65 and older over a 7-day period from October 19 to November 30, 2020 during the Covid-19 pandemic. Patients with one documented non-traumatic chief complaint were analyzed. Descriptive statistics, logistic regression, and general linear mixed models were used to assess factors associated with hospital admission and in-hospital mortality. Odds ratios (OR) and 95% confidence intervals (CI) were reported.

RESULTS: The study population consisted of 2,794 patients with one specified chief complaint. The mean age was 77.4 (± 8.2) years. The most frequent chief complaints were shortness of breath, abdominal pain, chest pain, weakness and fatigue, and extremity pain and numbness, representing 59% of the cohort. Highest age (≥ 85), geriatric risks (i.e. presence of dementia/Alzheimer's disease (AD), home help service or previous falls), polypharmacy, and shortness of breath increased the odds of being admitted to hospital (OR 1.4 [1.2-1.9]; OR 1.6 [1.3-1.9]; OR 1.3 [1.1-1.6]; OR 3.0 [2.4-3.8]), while female sex was negatively associated with admission (OR 0.7 [0.6-0.8]). Shortness of breath was positively associated with in-hospital mortality (OR 2.2 [1.4-4.3]).

CONCLUSION: Older patients frequently require hospital admission. As chief complaints do not reflect underlying condition or severity, structured evaluation, staff training and geriatric specific care pathways may improve care and reduce adverse clinical outcomes.},
}

Humans
Cross-Sectional Studies
Female
Europe/epidemiology
*Emergency Service, Hospital/statistics & numerical data
Male
Aged, 80 and over
*COVID-19/epidemiology
Aged
Prospective Studies
Hospital Mortality
Emergency Room Visits
Hospitalization/statistics & numerical data
Pandemics

@article {pmid42701205,
year = {2026},
author = {Gabb, VG and Harding, S and Lemke, T and Alderman, S and Woodward, N and Clayton, J and McNair, A and Barrett-Muir, W and Richardson, A and Dooley, J and Rudd, S and Coulthard, E and Turner, N},
title = {Outcomes reported in interventional studies for mild cognitive impairment: a scoping umbrella review to inform core outcome set development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71800},
pmid = {42701205},
issn = {1552-5279},
support = {NIHR204135//National Institute for Health Research (NIHR)/ ; },
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Outcome Assessment, Health Care ; Treatment Outcome ; },
abstract = {There is currently no consensus on the most important treatment outcomes in patients with mild cognitive impairment (MCI). As part of developing a core outcome set for MCI, we conducted a pragmatic scoping umbrella review to summarize outcomes reported in previous studies. Six electronic databases were searched from inception to August 2023. Systematic and scoping reviews in English with ≥70% of studies describing at least one quantitative outcome of interventions involving adults with MCI were eligible. Verbatim outcomes were extracted from eligible papers within selected reviews. From 170 papers covering 153 studies from 42 reviews, 143 unique outcomes were identified. Global cognition was the only outcome reported by more than 50% of studies. Two-thirds of outcomes were reported by no more than three studies. Heterogeneous outcome reporting limits evidence synthesis and treatment evaluation. A core outcome set for MCI is warranted to standardize outcome reporting and offer stronger evidence for decision-making.},
}

Humans
*Cognitive Dysfunction/therapy
*Outcome Assessment, Health Care
Treatment Outcome

@article {pmid42702949,
year = {2026},
author = {Moro, V and Vianello, G and Gambina, G and Gobbetto, V and Gasparini, M and Beccherle, M},
title = {The clinical implications of anosognosia in Alzheimer's disease.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/14737175.2026.2726416},
pmid = {42702949},
issn = {1744-8360},
abstract = {INTRODUCTION: Assessing awareness of patients with Alzheimer's disease (AD) is essential for diagnosis and treatment. Anosognosia, defined as impaired awareness of cognitive and functional deficits, is associated with poorer prognosis, reduced decision-making capacity, increased risk of accidents, and earlier institutionalization.

AREAS COVERED: This narrative review examines 53 studies. After outlining the main theoretical models of awareness in dementia, the multidimensional nature of anosognosia and its impact on patients' autonomy and decision-making abilities are discussed. This review also describes the main instruments available for assessing awareness deficits and highlights their relevance in clinical practice. Particular attention is given to the implications of anosognosia for treatment adherence, patient care, and decision making.

EXPERT OPINION: Taking care of unaware AD patients represents a challenge, and anosognosia is often underestimated in clinical practice. Evidence suggests that awareness deficits may emerge even in the earliest stages of AD, affecting patients' autonomy and capacity to make informed decisions. A two-step assessment process is recommended, consisting of an initial screening followed by a comprehensive evaluation carried out by specialized neuropsychologists. Targeted caregiver training is also essential to address the challenges associated with impaired awareness.},
}

@article {pmid42704398,
year = {2026},
author = {Zhu, Z and Jiang, X and Huang, R and Guo, X and Wang, Y and Liu, T and Wang, J and Huang, J and Huang, W and Zhang, D and Li, Q and Chen, S and Yang, Z and Liu, Q and Wei, Z},
title = {Deferiprone Modulates Ferroptosis to Protect Macrophages and Liver during Neospora caninum Infection.},
journal = {Acta parasitologica},
volume = {71},
number = {5},
pages = {},
pmid = {42704398},
issn = {1896-1851},
support = {32002309//the National Natural Science Foundation of China/ ; 2022A1515010960//Guangdong Basic and Applied Basic Research Foundation/ ; NJTG20240253//Guangdong Provincial Department of Agriculture and Rural Affairs - Guangdong Agricultural Technical Service "Light Cavalry" Project 2024/ ; SWU-KQ24021//Central University Basic Scientific Research Program of Southwest University/ ; },
mesh = {Animals ; *Ferroptosis/drug effects ; *Neospora/drug effects/physiology ; *Deferiprone/pharmacology/administration & dosage ; *Coccidiosis/drug therapy/parasitology ; *Liver/parasitology/drug effects ; Mice ; *Macrophages/drug effects/parasitology ; Mice, Inbred C57BL ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Female ; },
abstract = {BACKGROUND: Neospora caninum (N. caninum), an obligate intracellular apicomplexan parasite, infects nucleated cells across diverse mammalian hosts, resulting in severe clinical outcomes, including reproductive failure (abortion, stillbirth) and neurological impairment. Ferroptosis, an iron-dependent, non-apoptotic cell death pathway characterized by excessive lipid peroxidation, is closely associated with disrupted iron metabolism and oxidative stress. Deferiprone (DFP), a clinically approved iron chelator, is widely used in the treatment of iron overload disorders such as β-thalassemia, Alzheimer's disease, and superficial hemosiderosis. While ferroptosis has been implicated in various disease states, its role in N. caninum infection remains unknown.

METHODS: This study established in vitro and in vivo infection models to investigate the role of ferroptosis in N. caninum pathogenesis and the protective mechanism of DFP. In vitro, RAW 264.7 were infected with N. caninum and treated with DFP, followed by comprehensive assessment of reactive oxygen species (ROS), glutathione (GSH) levels, intracellular iron content, GPX4 expression, and parasite proliferation via qPCR. In vivo, C57BL/6 mice were intraperitoneally inoculated with 1 × 10[^7] tachyzoites and orally administered DFP for seven days. Body weight, food intake, hepatic pathology, oxidative stress markers (GSH and MDA), iron levels, and ferroptosis-related gene expression (GPX4, FTH1, and TRF) were monitored.

RESULTS: Our in vitro findings demonstrated that N. caninum infection significantly elevated ROS production and intracellular iron accumulation while depleting GSH and suppressing GPX4 transcription-hallmarks of ferroptosis. Remarkably, DFP treatment reversed these effects, restoring redox balance and protecting host tissue, not host control of infection. In vivo, DFP alleviated N. caninum-induced hepatic ferroptosis, as evidenced by normalized iron homeostasis, upregulated GPX4 and ferritin expression, and reduced histopathological damage. However, DFP exacerbated weight loss, suggesting a potential trade-off between ferroptosis inhibition and metabolic adaptation.

CONCLUSIONS: In summary, these results establish ferroptosis as a critical pathogenic mechanism in N. caninum infection and highlight DFP's dual role in mitigating oxidative injury while possibly impairing host metabolic responses. Our findings provide novel insights into iron-targeted therapeutic strategies for combating intracellular parasitic infections, paving the way for future investigations into optimizing host-directed antiparasitic interventions.},
}

Animals
*Ferroptosis/drug effects
*Neospora/drug effects/physiology
*Deferiprone/pharmacology/administration & dosage
*Coccidiosis/drug therapy/parasitology
*Liver/parasitology/drug effects
Mice
*Macrophages/drug effects/parasitology
Mice, Inbred C57BL
Iron/metabolism
Reactive Oxygen Species/metabolism
Oxidative Stress/drug effects
Female

@article {pmid42705162,
year = {2026},
author = {Guarneri, L and Beh, C and de Campo, L and Whitten, AE and Moir, M and Hung, A and Clulow, AJ and Conn, CE and van 't Hag, L},
title = {Nanoscale localisation of memantine governs structural modulation and loading in bicontinuous cubic phase systems.},
journal = {Journal of colloid and interface science},
volume = {726},
number = {},
pages = {141405},
doi = {10.1016/j.jcis.2026.141405},
pmid = {42705162},
issn = {1095-7103},
abstract = {Memantine is a primary pharmacological treatment for moderate-to-severe Alzheimer's disease but its efficacy and brain delivery remain limited. Lipid bicontinuous cubic phases and their nanoparticle dispersions (cubosomes) offer platforms for enhancing central nervous system drug delivery, yet the rigid adamantane scaffold of memantine can destabilise lipid organisation. This study resolves how an amphiphilic, adamantane-containing drug interacts with non-lamellar lipid bilayers using monoolein-based bulk cubic mesophases and cubosomes formulated with biomimetic lipid compositions and multiple stabilisers. SAXS revealed that lipid composition primarily governed mesophase structure, while memantine induced only modest structural changes in bulk cubic phases. Following memantine incorporation, cubosomes retained cubic symmetry and colloidal stability across stabilisers, although they were more susceptible than bulk phases to additive-induced disorder, with cryo-TEM showing transitions toward less ordered, lower curvature sponge-like structures. Bulk mesophases exhibited 3-5-fold higher apparent drug retention than nanoparticle dispersions. Under excess hydration, however, even bulk phases released memantine rapidly, losing ∼65% of the drug within 24 h. SANS and molecular dynamics simulations revealed a mobile state of memantine with predominantly interfacial localisation rather than stable burial within the hydrophobic tails, providing a mechanistic explanation for its mesophase-dependent structural effects and its limited retention. These findings show that the adamantane scaffold alone is insufficient to ensure efficient incorporation into cubic phases. Localisation, accommodation, and retention are governed by the balance between hydrophobic anchoring and the hydration demands of attached functionalities, establishing a mechanistic framework for predicting the behaviour of amphiphilic adamantane-containing therapeutics in non-lamellar lipid nanocarriers.},
}

@article {pmid42705844,
year = {2026},
author = {Zhou, Q and Yang, MX and Zhang, QQ and Li, YQ and Wang, ZQ},
title = {Efficacy and Durability of Repetitive Transcranial Magnetic Stimulation on Cognitive Function in Patients With Mild-to-Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70199},
pmid = {42705844},
issn = {1479-8301},
support = {2022ZD0208506//STI 2030-Major Projects/ ; 82201628//National Natural Sciencen Foundation of China/ ; U24A20274//National Natural Sciencen Foundation of China/ ; S23042//SiChuan Province Medical Research Project Program/ ; 513//2024 Annual Specialized Research Project on Traditional Chinese Medicine of SiChuan Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Transcranial Magnetic Stimulation/methods ; *Cognition/physiology ; Treatment Outcome ; Cognitive Enhancement ; Randomized Controlled Trials as Topic ; Aged ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has shown potential for improving cognitive function in Alzheimer's disease (AD), though findings remain inconsistent. This meta-analysis evaluated the efficacy and durability of rTMS in patients with mild to moderate AD and explored potential moderating factors. Randomised controlled trials (RCTs) comparing active rTMS with sham stimulation were identified through systematic searches of major databases. Effect sizes were calculated using Hedges' g, with random-effects models applied. Risk of bias was assessed using the Cochrane RoB 2 tool. Five RCTs (N = 143) were included in the primary analysis. rTMS showed a small-to-moderate improvement in MMSE scores (g = 0.41, 95% CI [0.06, 0.75], p = 0.021, I[2] = 6.5%). Excluding two studies with methodological concerns yielded a similar effect (g = 0.46), though with wider confidence intervals. Sensitivity analysis including studies with change scores confirmed the robustness of results (g = 0.48). Given the limited number of studies (k < 10), formal publication bias tests and trim-and-fill adjustment were not applied, in line with current methodological guidance. Notably, all five studies employed excitatory stimulation protocols (high-frequency rTMS or iTBS), with four of five targeting the left dorsolateral prefrontal cortex (DLPFC), suggesting that excitatory stimulation of key cognitive network hubs represents the most consistent evidence base to date. Meta-regression identified treatment duration as a significant moderator (β = -0.193, p = 0.034), suggesting shorter, more intensive protocols may be more effective. Follow-up analyses indicated a nonsignificant trend towards sustained benefits (g = 0.25), while time-trend analysis demonstrated a stable overall effect (g = 0.38). In conclusion, rTMS provides modest cognitive benefits in mild to moderate AD, with excitatory protocols targeting the left DLPFC showing the most consistent efficacy and treatment duration influencing outcomes. However, evidence remains limited, highlighting the need for larger, standardised, multi-centre trials with long-term follow-up.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Transcranial Magnetic Stimulation/methods
*Cognition/physiology
Treatment Outcome
Cognitive Enhancement
Randomized Controlled Trials as Topic
Aged

@article {pmid42706500,
year = {2026},
author = {Ding, J and Miao, J and Zhang, L and Liu, Q and Zhang, Y and Li, J and Li, Y},
title = {Cognitive safety of statin use in the elderly: Evidence from a nationally representative sample.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70159},
pmid = {42706500},
issn = {1365-2796},
support = {SCYG2025-1//Sichuan Hospital Management and Development Research Center/ ; YF25-Y15//Sichuan Medical and Health Rule of Law Research Center-Chinese Society of Health Law Joint Project/ ; scsyxh202502//Hospital Pharmaceutical Research Funding Project of 'Yue·Stealth' of Sichuan Province Pharmaceutical Association/ ; 26MSZX599//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; 26MSZX601//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; CSXL-26209//Foundation of the Sichuan Research Center of Applied Psychology/ ; MZSJ202602//Mianyang Key Laboratory of Anesthesia and Neuroregulation/ ; 17PJ332//Sichuan Province Health Commission Project/ ; },
abstract = {OBJECTIVE: To systematically evaluate the association between current statin use and global cognitive impairment in US older adults and examine potential variations across treatment intensity, duration, and specific cognitive domains to guide clinical cardiometabolic management.

METHODS: This survey-weighted cross-sectional study included 3137 National Health and Nutrition Examination Survey 2011-2014 participants aged ≥60 years. Cognitive performance across Consortium to Establish a Registry for Alzheimer's Disease, animal fluency, and digit symbol substitution test (DSST) was composite-summarized to define impairment (Z-score ← 1.5 standard deviation). Survey-weighted multivariable models adjusted for sociodemographic, lifestyle, cardiometabolic, psychotropic medication, polypharmacy, and substance-use proxies, supplemented by inverse probability of treatment weighting (IPTW) and multiple imputation.

RESULTS: In the primary fully adjusted model, current statin use was not associated with global cognitive impairment (odds ratio [OR] = 0.90, 95% confidence interval: 0.48-1.67, p = 0.736). Results remained consistent across psychotropic-adjusted (OR = 0.91), IPTW (OR = 1.03), and multiply imputed models (OR = 0.86). Domain-specific analyses showed statin use was associated with lower odds of DSST impairment (OR = 0.51, p = 0.009), with no clear trend across statin intensity or duration categories.

CONCLUSION: Current statin use was not significantly associated with global cognitive impairment in older adults. Although cross-sectional observational neutrality precludes inferring long-term safety, indicated statin therapy should not be routinely withheld over cognitive concerns, with prescribing remaining firmly guided by established atherosclerotic cardiovascular disease risk guidelines.},
}

@article {pmid42706972,
year = {2026},
author = {Yu, X and Yi, Y and Liu, X and Zhao, C and Li, C and Shang, Y and He, K and Zhai, Y},
title = {Scutellaria Barbata Flavonoids Mitigate Alzheimer's Disease-related Aβ25-35 Toxicity in N2a Cells through CREB Phosphorylation.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673438931260822121059},
pmid = {42706972},
issn = {1875-533X},
abstract = {BACKGROUND: Mouse neuroblastoma cells (N2a) are spontaneously derived from mice and possess the characteristics of neural stem cells. The proliferation, differentiation, and protrusion growth of N2a cells in vitro are consistent with those in vivo. Flavonoids isolated from the aerial parts of Scutellaria barbata (SBFs) can improve learning and memory deficits and protect against neuronal injury in many in vivo AD-- like models. N2a cells exposed to Aβ25-35 for Alzheimer's disease-related toxicity were subsequently used to observe the ameliorative effects of SBFs, and the effective mechanism through which SBFs promote the phosphorylation of CREB was further studied by using BI-D1870, an indirect inhibitor, and Rolipram, an activator of CREB phosphorylation.

METHODS: Immunofluorescence (IF) was used to detect the protein expression of the neuron-specific proteins NeuN, NeuroD1, and DCX. N2a cells were exposed to 100 μM Aβ25-35 and treated with SBFs at doses of 17.5, 35 and 75 mg·L-1 or 363 μM Rolipram. Cell morphology was observed under an inverted microscope, the cell survival rate was detected by the Cell Counting Kit-8 (CCK-8) method, and the release of lactate dehydrogenase (LDH) into the cell culture medium was determined by the pyruvate reduction method. The mRNA expression levels of ERK, RSK, CREB, and EGR-1 in cells were detected by real-time quantitative polymerase chain reaction (qPCR). IF and/or western blotting (WB) were used to measure the protein expression levels of BDNF, NGF, TrkB, Ras, ERK/p-ERK, Rsk/p90RSK, CREB/p-CREB-Ser133, and EGR-1 in N2a cells.

RESULTS: NeuN, NeuroD1, and DCX expression in N2a cells was positive, as indicated by green fluorescence. Both Aβ25-35 and BI-D1870 resulted in abnormal morphological changes in N2a cells, reduced the cell survival rate (P<0.01), increased the release of LDH (P<0.01) into the culture medium, and decreased the mRNA expression levels of ERK, RSK, and CREB and the protein expression levels of p-ERK, TrkB, p90RSK, pCreb-SER133, BDNF, NGF and EGR-1 (P<0.01) in cells. However, SBFs, to varying degrees, reversed the aforementioned abnormal changes in N2a cells caused by Aβ25-35 or BI-D1870, and the effects of SBFs were consistent with those of Rolipram.

CONCLUSION: SBFs protected against N2a cell damage induced by toxic Aβ25-35, and the effective mechanism by which SBFs promote the phosphorylation of CREB at the Ser133 site was confirmed through the application of the indirect CREB phosphorylation inhibitor BI-D1870 and the activator Rolipram. These findings suggest that SBFs may be helpful in the treatment of AD by intervening in CREB phosphorylation.},
}

@article {pmid42706977,
year = {2026},
author = {Saxena, B and Sisodiya, N and Khabiya, R and Pandit, A and Rajput, MS and Gupta, R},
title = {AI-Driven Precision Medicine in Alzheimer's Disease: Drug Repurposing, Digital Therapeutics and Clinical Decision Support.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128478269260818075055},
pmid = {42706977},
issn = {1873-4286},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disease that causes significant clinical, social, and economic burden worldwide. Despite improvements in understanding its multifaceted pathogenesis, current treatments are mostly symptomatic and ineffective across varied patient populations. To overcome these constraints, AI-driven precision medicine allows tailored risk assessment, treatment selection, and disease monitoring. This review covers AI's role in AD precision medicine, focusing on drug repurposing, digital therapies and clinical decision support systems. Machine and deep learning models are used to predict medication response, integrate heterogeneous data sources such as genomics, transcriptomics, neuroimaging and electronic health records, and uncover pharmacogenomic treatment success factors. The paper covers AIenabled precision pharmacology, including tailored dosing algorithms, adaptive therapeutic monitoring, and adverse drug reaction prediction. Bioinformatics-based target identification, network pharmacology, graphbased AI models, virtual screening, and real-world and clinical data validation are emphasized in AI-driven medication repurposing. AI-powered digital treatments like personalized cognitive training platforms, wearable- derived digital biomarkers, virtual and mixed reality interventions, adherence monitoring, and digital twins for therapy optimization have been discussed. AI-based clinical decision support systems are also thoroughly assessed for clinical value, accuracy, and explainability in disease subtyping, trajectory prediction, and risk stratification in preclinical and prodromal AD. Despite these promises, data heterogeneity, algorithmic bias, legal barriers, and privacy concerns exist. Federated learning enables safe multi-center collaboration and hybrid AI-human approaches, and it represents the future. AI's ability to alter AD care opens the door to precision medicine paradigms that use repurposed medications, digital tools and intelligent decision-making to improve patient outcomes.},
}

@article {pmid42707167,
year = {2026},
author = {Zhao, K and Dai, S and Zhang, Y and Liu, G and Gu, P and Lin, C and Thompson, PM and Leow, A and Huang, H and He, L and Zhan, L and Tang, H},
title = {Interpretable multimodal learning for integrating neuroimaging and genetic data in Alzheimer's disease.},
journal = {Frontiers in radiology},
volume = {6},
number = {},
pages = {1912277},
pmid = {42707167},
issn = {2673-8740},
abstract = {INTRODUCTION: Early detection of Alzheimer's disease (AD) requires models that combine brain structure changes with genetic risk, but existing methods struggle to align these different data types.

METHODS: We present R-GenIMA, an interpretable multimodal large language model that pairs a region-of-interest vision transformer with genetic prompting to jointly analyze structural MRI and single nucleotide polymorphisms (SNPs). Each brain region becomes a visual token and SNP profiles are encoded as structured text, letting the model link regional atrophy to genetic factors through cross-modal attention. Tested on the ADNI cohort, R-GenIMA performs well in classifying four groups: normal cognition, subjective memory concerns, mild cognitive impairment, and AD.

RESULTS: Beyond accuracy, it produces biologically meaningful explanations, identifying stage-specific brain regions and genes. The model consistently highlighted known AD risk genes (APOE, BIN1, CLU, RBFOX1) and revealed stage-specific patterns: striatal involvement in subjective decline, frontotemporal changes in early impairment, and broad network disruption in AD.

DISCUSSION: These results show that interpretable multimodal AI can integrate imaging and genetics to reveal disease mechanisms, providing a foundation for clinical tools that enable earlier risk assessment and inform precision treatment in Alzheimer's disease.},
}

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

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

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

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

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

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

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

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

FUNDING: National Institutes of Health.},
}

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

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

@article {pmid42697346,
year = {2026},
author = {Cai, J and Luo, J and Cai, Y and Xu, Y and Ran, R and Xiao, M and Ye, Q and Zheng, W and Li, S},
title = {Artemether alleviates Aβ1-42-induced neuronal cell damage via PGC-1α-mediated mitochondrial homeostasis in Alzheimer's disease.},
journal = {Cellular signalling},
volume = {149},
number = {},
pages = {112879},
doi = {10.1016/j.cellsig.2026.112879},
pmid = {42697346},
issn = {1873-3913},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia. Mitochondrial dysfunction is a key pathogenic event that drives neuronal damage and disease progression. Thus, protecting against mitochondrial damage in neuronal cells has become a critical therapeutic target for AD prevention and treatment. Our previous research has shown that artemether can protect PC12 cells from oxidative stress damage induced by Aβ and oxygen-glucose deprivation, but its underlying regulatory mechanisms remain elusive. Therefore, it is essential to elucidate the role and mechanism of artemether in Aβ-induced mitochondrial damage.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid42699553,
year = {2026},
author = {Laginha, I and Schmitz, M and da Silva Correia, Â and Saleem, T and da Silva Correia, S and Zafar, S and Younas, N and Canaslan, S and Göbel, S and Root, E and Breitbarth, M and Fischer, AL and Dittmar, K and Žakova, D and Hermann, P and Zerr, I},
title = {Prion protein (PrP) profiles in blood and CSF: insights into pre-symptomatic and symptomatic prion disease.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag321},
pmid = {42699553},
issn = {2632-1297},
abstract = {The conversion of native prion protein (PrP) into its misfolded isoform, scrapie (PrP[Sc]) and its intracellular accumulation represent central events in the pathogenesis of prion diseases. Reduction of native PrP in the central nervous system (CNS) has emerged as a promising strategy for treatment and prevention of prion diseases in humans. To facilitate translation into clinical practice, it is essential to identify at-risk individuals through biomarker development and to elucidate PrP behaviour across prion disease subtypes and biological fluids. Measurements of PrP in accessible biofluids, such as plasma and cerebrospinal fluid (CSF), may provide a pharmacodynamic readout and enable monitoring for PrP-targeted therapies. This study systematically quantifies PrP in plasma and CSF of individuals with sporadic and genetic prion diseases, healthy controls (HC), patients with non-neurodegenerative neurological conditions (ND) and Alzheimer's disease (AD). We analysed 136 plasma and 84 CSF samples, including HC, AD, sporadic Creutzfeldt-Jakob disease (sCJD), as well as symptomatic patients and asymptomatic carriers of the mutations D178N, E200K and P102L. Quantification of PrP was performed using a BetaPrion Human ELISA. Statistical analyses assessed differences between diagnostic groups, associations with demographic factors and PRNP codon 129 polymorphism, and diagnostic accuracy via ROC curves. Plasma PrP was significantly reduced in patients with sCJD (P = 0.043), in symptomatic patients with the E200K (P = 0.0078) and in both symptomatic and asymptomatic D178N carriers (P = 0.0002) compared to HC. Furthermore, symptomatic and asymptomatic D178N carriers had significantly lower plasma PrP levels than patients with AD (P = 0.0025 and P = 0.0041, respectively). In CSF, PrP concentrations were notably lower in D178N symptomatic patients (P = 0.0026) versus non-neurodegenerative (ND) controls. Plasma PrP levels showed no association with age, sex or disease onset and were lower in genetic prion disease patients with the methionine/valine (MV) genotype at PRNP codon 129. The diagnostic accuracy for PrP quantification in plasma as a biomarker discriminated D178N asymptomatic carriers [area under the curve (AUC) = 0.96] and D178N symptomatic patients (AUC = 0.90) from HC with excellent accuracy. In CSF, PrP quantification discriminated D178N symptomatic patients from ND with good accuracy (AUC = 0.64). Taken together, this study defines a characteristic profile of persistently low plasma and CSF PrP in D178N symptomatic and asymptomatic mutation carriers. Low plasma levels in sCJD and E200K, in contrast to P102L, are puzzling. Mutation-specific patterns of PrP need to be considered for monitoring purposes in clinical trials.},
}

@article {pmid42700283,
year = {2026},
author = {Atiq, A and Choe, K and Kang, MH and Park, HY and Atiq, U and Ahmad, W and Ali, W and Park, TJ and Kim, MO},
title = {Neuroprotective Effect of Isorhapontigenin (ISO) Against LPS-Induced Neurodegenerative Condition via TLR4/RAGE-Mediated p-NF-kB Activation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42700283},
issn = {1559-1182},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Stilbenes/pharmacology/therapeutic use ; Signal Transduction/drug effects ; *Receptor for Advanced Glycation End Products/metabolism ; Oxidative Stress/drug effects ; Male ; Mice ; *Neurodegenerative Diseases/metabolism/drug therapy/chemically induced/pathology ; Microglia/metabolism/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by persistent neuroinflammation, oxidative imbalance, cognitive decline, Aβ buildup, tau phosphorylation, and synaptic dysfunction. Despite progress in understanding AD's development, effective treatments are still limited. Isorhapontigenin (ISO), a methoxylated stilbenoid similar to resveratrol, shows neuroprotective, anti-inflammatory, and antioxidative effects. In this study, we explored ISO's therapeutic potential in a mouse model of AD-like pathology induced by LPS, focusing on TLR4/RAGE-triggered NF-κB signaling pathway and related neuroinflammatory responses, oxidative stress, GSK3β signaling, tau pathology, Aβ accumulation, glial activation, and synaptic health. Western blot and immunofluorescence techniques were used to measure the levels of TLR4/RAGE signaling components, glial markers (GFAP and Iba-1), p-NF-κB signaling pathway activation, proinflammatory cytokines (TNF-α, COX-2, and IL-1β), oxidative stress indicators (Nrf2 and HO-1), neurodegeneration markers (p-GSK3β, p-tau, and Aβ), and synaptic proteins (PSD-95, SNAP-23, and SYP). Nissl staining helped assess neuronal density and structure. BV2 microglial cells were treated similarly in vitro, followed by viability tests and Apotox-Glo™ triplex assays, along with protein expression analysis. The levels of TLR4, RAGE, GFAP, and Iba-1 increased in the LPS-treated group, along with proinflammatory mediators, ROS, LPO, and neurodegenerative markers. Yet, ISO treatment significantly reduced their expression. Moreover, LPS lowered Nrf2 and HO-1 levels, reduced p-GSK3β, and decreased synaptic proteins, indicating oxidative damage and synaptic failure. ISO reversed these changes by restoring p-GSK3β, activating Nrf2/HO-1, and boosting synaptic protein levels, followed by behavioral improvement as evidenced by reduced escape latency and increased spontaneous alternations in the Morris water maze (MWM) and Y-maze tests. Additionally, ISO preserved neuronal and synaptic integrity and provided consistent neuroprotection in BV2 cells. Overall, these results demonstrate that ISO reduces LPS-induced AD-like pathology by activating TLR4/RAGE-driven p-NF-κB, decreasing neuroinflammation, enhancing Nrf2/HO-1 activity, inhibiting GSK3β, lowering Aβ and p-Tau accumulation, preserving synaptic health, and prominent improvement in spatial memory, emphasizing its potential as an AD treatment.},
}

Animals
*Toll-Like Receptor 4/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Lipopolysaccharides
*NF-kappa B/metabolism
*Stilbenes/pharmacology/therapeutic use
Signal Transduction/drug effects
*Receptor for Advanced Glycation End Products/metabolism
Oxidative Stress/drug effects
Male
Mice
*Neurodegenerative Diseases/metabolism/drug therapy/chemically induced/pathology
Microglia/metabolism/drug effects
Glycogen Synthase Kinase 3 beta/metabolism
Mice, Inbred C57BL

@article {pmid42700644,
year = {2026},
author = {Cote, I and Valfort, AC and Sanders, RK and Burris, SL and Hayes, ME and Arya, R and Maram, L and Elgendy, B and Yue, F and Burris, TP},
title = {BE2012 a novel, REV-ERB antagonist that promotes regenerative myogenesis in vivo with substantially improved pharmacokinetics relative to SR8278.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {9},
pages = {105011},
doi = {10.1016/j.jpet.2026.105011},
pmid = {42700644},
issn = {1521-0103},
abstract = {Pharmacological inhibition of REV-ERBs has emerged as a potential therapeutic strategy for several diseases with unmet medical needs. Indeed, chronic treatment with SR8278, a synthetic REV-ERB antagonist, has mitigated pathology in various preclinical models of human musculoskeletal and neurological diseases, including Duchenne muscular dystrophy, epilepsy, Alzheimer disease, Parkinson disease, and frontotemporal dementia. However, SR8278, the first and most widely used REV-ERB antagonist, has poor pharmacokinetic properties, which limits its utility. The REV-ERBs (α and β) are widely expressed nuclear receptors that function as ligand-dependent transcriptional repressors, and the therapeutic potential for inhibition of these receptors remains unclear because of the lack of adequate pharmacological tools. Here, we report BE2012, a significantly improved REV-ERB antagonist with >22-fold longer half-life than SR8278. In a cell-based reporter assay, BE2012 exhibited greater potency toward REV-ERBα (EC50 = 0.38 μM) and REV-ERBβ (EC50 = 0.57 μM) compared with SR8278. Notably, in primary myoblast differentiation assays, BE2012 outperformed SR8278 in increasing the proportion of MyoG[+] cells as well as differentiation and fusion indices. In a cardiotoxin-induced muscle injury model, both BE2012 and SR8278 led to increased myofiber cross-sectional area (22%-34% higher than controls). Lastly, transcriptomic profiling revealed remarkable overlap of differentially expressed genes between the 2 compounds, with oxidative phosphorylation and mitochondrial protein complex emerging as the most significantly enriched pathways for both ligands, which have been shown to accelerate regenerative myogenesis. These results establish BE2012 as a refined REV-ERB antagonist for in vivo applications and a valuable tool for deeper exploration of the therapeutic potential of inhibiting REV-ERB activity. SIGNIFICANCE STATEMENT: This study establishes BE2012 as a novel REV-ERBα/β antagonist with a 22-fold longer half-life and improved potency compared with SR8278, the only available REV-ERB antagonist whose poor bioavailability has limited its utility for in vivo use. In an acute muscle injury model in mice, BE2012 promoted regenerative myogenesis and induced a broad transcriptomic reprogramming that was highly concordant with that of SR8278, suggesting it could serve as a new gold-standard REV-ERB antagonist tool compound in the field.},
}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid42689394,
year = {2026},
author = {Liu, Y and Wu, J},
title = {Low-dose N-methyl-D-aspartate protects against amyloid-β-induced neurotoxicity by suppressing the MLK3-MKK7-JNK3 pathway and activating the PI3K-PDK1-Akt pathway.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002310},
pmid = {42689394},
issn = {1473-558X},
abstract = {OBJECTIVE: Oligomeric amyloid-β (Aβ) peptide-induced neuronal apoptosis is a key process in Alzheimer's disease pathogenesis. Low-dose N-methyl-D-aspartate (NMDA) has been shown to promote cell survival both in vitro and in vivo, but its effect on Aβ neurotoxicity remains largely unknown. This study aimed to investigate whether low-dose NMDA protects against Aβ-induced neurotoxicity and to elucidate the underlying molecular mechanisms.

METHODS: Primary rat cortical neurons were exposed to 10 μM Aβ25-35 to establish a neurotoxicity model. Neuronal apoptosis was assessed by 4',6-diamidino-2-phenylindole staining. The effects of low-dose NMDA (10 μM) on the PI3K-Akt and MLK3-MKK7-JNK3 signaling pathways were examined by immunoprecipitation and Western blotting. The PI3K inhibitor LY294002 was used to verify the role of PI3K signaling in NMDA-mediated regulation of the JNK3 pathway.

RESULTS: Low-dose NMDA (10 μM) significantly reduced 10 μM Aβ25-35-induced neuronal apoptosis. Mechanistically, NMDA reversed the Aβ-induced decrease in p-PDK1 and p-Akt levels and concurrently suppressed the activation of the MLK3-MKK7-JNK3 cascade. Moreover, treatment with LY294002 attenuated the inhibitory effect of NMDA on the MLK3-MKK7-JNK3 pathway.

CONCLUSION: Low-dose NMDA exerts neuroprotective effects against Aβ-induced neurotoxicity. These effects are mediated by the dual modulation of the pro-survival PI3K-PDK1-Akt pathway and the pro-apoptotic MLK3-MKK7-JNK3 pathway.},
}

@article {pmid42689975,
year = {2026},
author = {Pupyshev, AB and Ovsyukova, MV and Akopyan, AA and Tenditnik, MV and Korolenko, TA and Dubrovina, NI and Tikhonova, MA},
title = {Role of AMPK Signaling in the Neuroprotective Effects of Trehalose in Mice With a Pharmacological Model of Alzheimer's Disease.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {8},
pages = {53657},
doi = {10.31083/FBL53657},
pmid = {42689975},
issn = {2768-6698},
support = {theme no. 126020316369-9 (2026-2028)//Ministry of Science and Higher Education of the Russian Federation for the Scientific Research Institute of Neurosciences and Medicine/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; *Trehalose/pharmacology ; Mice ; *AMP-Activated Protein Kinases/metabolism ; Disease Models, Animal ; Signal Transduction/drug effects ; Male ; Mice, Inbred C57BL ; Autophagy/drug effects ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism/pathology ; Hippocampus/drug effects/metabolism ; Cognition/drug effects ; Pyrazoles ; Pyrimidines ; },
abstract = {BACKGROUND: Trehalose (TRE) has demonstrated neuroprotective potential in models of Alzheimer's disease (AD)-like pathology and has been shown to activate AMP-activated protein kinase (AMPK) and induce autophagy in hepatocytes. The molecular mechanisms underlying the neuroprotective effects of TRE in the brain, including the involvement of AMPK signaling and autophagy, remain unclear.

METHODS: AD was modeled in C57BL/6 mice by intracerebroventricular administration of the amyloid-β (Aβ) fragment Aβ(25-35). The effects of TRE treatment (a 3% water solution in drinking water for 20 days) on AD-like pathology in the brain (frontal cortex, amygdala, and hippocampus) were assessed by immunohistochemical analysis, while cognitive function was evaluated using the passive avoidance test. AMPK activation was assessed by measuring AMPK (p-AMPK) levels in the brain and by evaluating the effects of its inhibitor dorsomorphin (DM; 10 mg/kg, i.p., 20 days, every other day for 20 days).

RESULTS: Aβ-treated mice exhibited markedly increased Aβ levels and neuroinflammatory responses in the brain, whereas levels of the autophagy marker LC3-II and p-AMPK were moderately reduced. TRE markedly reduced Aβ accumulation and neuroinflammation and restored cognitive performance to levels comparable to those of the Control group; it also increased LC3-II immunoreactivity and p-AMPK levels in the hippocampus and amygdala. DM did not abolish the neuroprotective effects of TRE but moderately inhibited AMPK in the hippocampus.

CONCLUSIONS: Marked changes in brain Aβ levels and cognitive performance were not associated with either p-AMPK or autophagy marker levels, suggesting that additional mechanisms contribute to the neuroprotective effects of TRE in AD. Markers of autophagy initiation and AMPK activity responded similarly to AD modeling and TRE treatment and were positively correlated in the hippocampus, suggesting a role for AMPK in the regulation of TRE-induced hippocampal autophagy.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
*Neuroprotective Agents/pharmacology
*Trehalose/pharmacology
Mice
*AMP-Activated Protein Kinases/metabolism
Disease Models, Animal
Signal Transduction/drug effects
Male
Mice, Inbred C57BL
Autophagy/drug effects
Amyloid beta-Peptides/metabolism
Brain/drug effects/metabolism/pathology
Hippocampus/drug effects/metabolism
Cognition/drug effects
Pyrazoles
Pyrimidines

@article {pmid42690003,
year = {2026},
author = {Sonkodi, B},
title = {Alzheimer's Disease, Piezo2 Channelopathy, Piezo1 Channelopathy, and the Body-Wide Piezo2 System.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {8},
pages = {52555},
doi = {10.31083/FBL52555},
pmid = {42690003},
issn = {2768-6698},
support = {23-2026/ HUSS_PUBL_FUND//Hungarian University of Sports Science/ ; },
mesh = {*Alzheimer Disease/metabolism/genetics/physiopathology ; *Ion Channels/metabolism/genetics ; Humans ; Animals ; *Channelopathies/metabolism/genetics ; Mice ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; },
abstract = {Alzheimer's disease initiates pathophysiology in the 10 to 20 years prior to detectable clinical symptoms. A recent genetic analysis implicated the critical role of Piezo2 in Alzheimer's disease pathophysiology. A recent genetic study, involving PIEZO1 manipulation, showed that phosphatidylinositol 4,5-bisphosphate (PIP2) rectified brain capillary endothelial Piezo1 channelopathy in a mouse model of Alzheimer's disease. However, the present opinion paper posits that the initiating microdamage is in the prefrontal cortex, further upstream of pathophysiology, namely an irreversible Piezo2 channelopathy of glutamatergic terminals that is proposed to finely regulate oxytocin release resulting from stressful ultradian events, leading to impaired ultradian rhythm. The involvement of Piezo2 in the defensive arousal response reveals an underlying body-wide Piezo2 system of which the proposed prefrontal Piezo2 channelopathy is possibly a critical locus. PIP2 is emerging as a potential treatment method for Piezo channelopathy in Alzheimer's disease. However, the challenge of its more precise administration to target affected regions of the brain still remains.},
}

*Alzheimer Disease/metabolism/genetics/physiopathology
*Ion Channels/metabolism/genetics
Humans
Animals
*Channelopathies/metabolism/genetics
Mice
Phosphatidylinositol 4,5-Diphosphate/metabolism