@article {pmid42255958,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Meeker, KL and Braskie, MN and Toga, AW and Gauthier, S and Vitali, P and Schindler, SE and O'Bryant, SE and Rosa-Neto, P},
title = {Eligibility for anti-amyloid treatment in a multiethnic community-based study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70314},
pmid = {42255958},
issn = {2352-8729},
abstract = {INTRODUCTION: The approval of anti-amyloid monoclonal antibodies (mAbs), including lecanemab and donanemab, represents a significant advance in disease-modifying therapies (DMTs) for early Alzheimer's disease (AD). While appropriate use recommendations (AURs) have been established to guide clinical decision-making, the proportion of individuals with cognitive impairment in real-world, multiethnic populations meeting eligibility criteria remains unknown, as do potential differences in treatment-related risks across ethnic groups.

METHODS: We included 513 cognitively impaired individuals from the Health and Aging Brain Study-Health Disparities study, a multiethnic community-based cohort. Eligibility for lecanemab and donanemab was determined using published AUR criteria. Counts of amyloid-related imaging abnormalities were estimated based on apolipoprotein E (APOE) ε4 genotype and ethnicity using published incidence rates.

RESULTS: Only 15% of participants met eligibility criteria for lecanemab or donanemab. Black individuals had a numerically higher estimated ARIA burden, though differences were not statistically significant.

DISCUSSION: Few individuals in this community-based, multiethnic cohort met eligibility for anti-amyloid therapy, highlighting limited real-world applicability of current AURs.

HIGHLIGHTS: Only 15% of community-based individuals with MCI or dementia met eligibility criteria for lecanemab and donanemab.Black participants had numerically higher estimated ARIA cases, though not statistically significant.Current AUR criteria have limited real-world applicability across multiethnic populations.Broader inclusion criteria and real-world safety data are needed to ensure equitable, safe implementation.},
}

@article {pmid42255964,
year = {2026},
author = {Rosenbloom, M and Adams, C and Allen, B and Berry, B and Camargo, C and Cooper, G and Giles, S and Leahy, C and Sabbagh, M and Sadowski, M and Schreiber, C and Schulz, PE and Soria, J and Weisman, D and Frech, F and Jones, DR},
title = {Real-world use of lecanemab: patient pathway findings from a US multicenter study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70376},
pmid = {42255964},
issn = {2352-8729},
abstract = {INTRODUCTION: To ensure Alzheimer's disease-modifying treatments can be initiated in diverse populations, efficient pathways to obtain timely diagnoses are required.

METHODS: This interim sub-analysis of a multicenter US study included cross-sectional surveys and interviews with neurologists at 12 diverse sites to assess real-world lecanemab use.

RESULTS: At survey completion, ∼1342 patients had received lecanemab. Most referrals originated from primary care. Amyloid pathology was confirmed primarily by positron emission tomography (58%) or cerebrospinal fluid (35%), with blood-based biomarkers (BBMs) increasingly used to reduce diagnostic delays. All sites performed apolipoprotein E4 (APOE ε4) testing to inform risk/benefit decisions. Infusions usually started within 6 months of diagnosis. Delayed/incomplete referrals were identified as the most significant barrier in the current patient pathway.

DISCUSSION: These findings demonstrate the feasibility of lecanemab integration in diverse clinical settings and highlight the importance of primary care physician engagement, optimization of referral pathways, and expanding BBM use in improving timely diagnosis, equitable access, and early treatment initiation.},
}

@article {pmid42250049,
year = {2026},
author = {Khan, Y and Rekha, A and Ballal, S and Maharana, L and Maqbool, M and Goyal, K and Mishra, R and Uniyal, P and Alam, P and Aljarba, TM and Gupta, G and Hussain, MS},
title = {Omics-driven strategies for identifying biomarkers in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42250049},
issn = {1573-7365},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options, mainly due to late diagnosis and partial understanding of its molecular aspects. Traditional biomarker discovery approaches have significantly contributed to AD diagnostics but suffer from limitations. The advent of omics technologies (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) has revolutionized the search for novel biomarkers by enabling comprehensive molecular profiling. Genomic studies have identified risk-associated variants such as APOE4, while epigenomic alterations, including DNA methylation alterations, offer insight into gene regulation in AD. Transcriptomic analyses, particularly single-cell and spatial transcriptomics, have uncovered molecular pathways linked to neuroinflammation and synaptic dysfunction. Proteomic advancements, including mass spectrometry and extracellular vesicle profiling, have identified potential blood- and CSF-based biomarkers for early-stage detection. Metabolomic and lipidomic studies indicate that cerebral glucose hypometabolism, insulin resistance, mitochondrial damage, redox imbalance, and disrupted lipid homeostasis are centra contributors to AD pathogenesis rather than secondary considerations of the disease. These metabolic dysfunctions may precede overt neurodegeneration and influence amyloid processing, tau phosphorylation, neuroinflammatory activation, and synaptic loss, thereby generating clinically informative biomarker signatures in blood and cerebrospinal fluid. Within this metabolism-centered paradigm, integrative multi-omics approaches are particularly valuable because they not only enhance biomarker specificity, but also connect molecular signatures with bioenergetic and immune-mediated mechanisms of disease. Accordingly, integrative multi-omics approaches improve biomarker specificity and predictive power, thereby supporting the development of precision medicine and targeted therapeutic interventions. Nevertheless, important challenges remain, including data integration, reproducibility, and clinical translation.},
}

@article {pmid42250112,
year = {2026},
author = {Carrasco, M and Guzman, L and Barroso, E and Olloquequi, J and Cano, A and Ureña, J and Verdaguer, E and Prohens, R and Fortuna, A and Auladell, C and Ettcheto, M and Camins, A},
title = {Licochalcone a enhances cognitive resilience in APP/PS1 Mice by modulating glucose metabolism, Aβ burden, and neuroinflammation.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42250112},
issn = {2509-2723},
support = {PID2021-123462OB-I00//Ministerio de Ciencia e Innovación/ ; PID2023-146632OB-I00//Ministerio de Ciencia e Innovación/ ; PID2021-122473OA-I00//Ministerio de Ciencia e Innovación/ ; 2021 SGR 00288//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; Grant CB06/05/2004//CIBERNED/ ; CEX2021-001159-M//Institut de neurociencies/ ; EBLE-9051//Serra Hunter Contract/ ; UB-LE-9115//Serra Hunter Contract/ ; UB-LE-9035//Serra Hunter contract/ ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder. Current therapeutic approaches targeting a single pathway have shown limited efficacy, highlighting the need for multi-target interventions. Licochalcone A (LCA), a chalcone of licorice root, has demonstrated anti-inflammatory and antidiabetic properties. However, its potential neuroprotective mechanisms in AD remain unclear. The present study aims to elucidate the beneficial effect of LCA against cognitive decline in an AD mouse model. For this purpose, five-month-old APPswe/PS1dE9 (APP/PS1) mice received intraperitoneal LCA (15 mg·kg[-1]·day[-1]) treatment for 4 weeks. Afterwards, cognitive function was assessed using Morris water maze (MWM) and Novel object recognition test (NORT). Metabolism was evaluated through glucose and insulin tolerance tests. Biochemical markers of synapses, neurogenesis, metabolism, Amyloid-β (Aβ) burden and neuroinflammation were analyzed using immunohistochemistry, Thioflavin-S staining, Golgi staining, Western blot, ELISA and RT-PCR. The results demonstrated that LCA significantly improved long-term memory in APP/PS1 mice, through MWM and NORT, accompanied by an increased dendritic spine density, upregulated PSD95 and spinophilin levels, and enhanced Ki67-positive cells in the hippocampus. Moreover, LCA treatment ameliorated glucose tolerance and initial insulin response while increasing Insr expression and GLUT1 protein levels. Furthermore, LCA-treated APP/PS1 mice showed reduced plaque burden and Aβ42 levels. Alongside, LCA demonstrated its anti-inflammatory effect by reducing glial reactivity, and Trem2 expression. In conclusion, the present study demonstrates the multiple therapeutic effects of LCA in APP/PS1 mice by simultaneously modulating glucose metabolism, reducing Aβ accumulation and attenuating neuroinflammation, ultimately enhancing cognitive resilience. These findings establish LCA as a promising multi-target compound for AD treatment.},
}

@article {pmid42250142,
year = {2026},
author = {Jalaiei, A and Kiani Darabi, AH and Sakkaki, E and Rezazadeh, M and Ghafouri-Fard, S},
title = {Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42250142},
issn = {1573-4978},
abstract = {Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays essential roles in nervous system development, neuronal maintenance, and neurogenesis. Aberrant BDNF concentrations, observed both peripherally and within the central nervous system (CNS), have been consistently implicated in the pathogenesis of a spectrum of neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Multiple sclerosis. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), regulate gene expression and are critical factors in cellular processes relevant to neurodegenerative disease pathobiology. Consequently, ncRNAs are posited as promising biomarkers and potential therapeutic modalities for CNS-related pathologies. However, robust empirical evidence substantiating ncRNA-mediated, post-transcriptional regulation of BDNF expression in the context of neurodegeneration remains relatively scarce. The objective of this systematic review is to provide a critical synthesis of the current literature on the diagnostic and prognostic utility of ncRNAs that modulate BDNF expression, specifically within the scope of neurodegenerative disorders. Furthermore, we will explore innovative therapeutic strategies centered on targeting BDNF-associated miRNAs for the treatment of these disorders.},
}

@article {pmid42250492,
year = {2026},
author = {Ahn, S and Salas, J and Cho, J and Scherrer, JF},
title = {Combined effect of anxiety disorder and insomnia on the risk of incident ADRD diagnosis.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100621},
doi = {10.1016/j.tjpad.2026.100621},
pmid = {42250492},
issn = {2426-0266},
abstract = {BACKGROUND: Anxiety disorders and insomnia are common modifiable conditions in older adults, but their independent and combined effects on the risk of incident Alzheimer's disease and related dementias (ADRD) remain unclear.

OBJECTIVES: To estimate the independent and combined associations of anxiety disorders and insomnia with the risk of incident ADRD.

DESIGN: Retrospective cohort study using an intention-to-treat approach with a 10-year follow-up period (2014-2023).

SETTING: De-identified electronic health record (EHR) data from 70 participating healthcare organizations within the TriNetX Research Network.

PARTICIPANTS: Adults aged ≥50 years without prior dementia who had regular ambulatory care during a three-year baseline period (n = 1,868,790).

MEASUREMENTS: Anxiety and insomnia were identified using ICD-based algorithms and categorized into four exposure groups: neither condition, anxiety only, insomnia only, and both. Incident ADRD was defined by two or more diagnostic codes within 12 months. Entropy balancing controlled for confounding, and weighted Cox proportional hazards models estimated hazard ratios (HRs).

RESULTS: At baseline, 4.1% had anxiety only, 3.8% had insomnia only, and 1.1% had both. Over follow-up, 2.3% developed ADRD. In weighted models, insomnia alone (HR: 1.12; 95% CI: 1.06-1.19), anxiety alone (HR: 1.49; 95% CI: 1.39-1.60), and co-occurring anxiety and insomnia (HR: 1.31; 95% CI: 1.06-1.62) were each associated with higher ADRD risk compared with neither condition. No significant effect modification by age, sex, or race was observed.

CONCLUSIONS: Anxiety and insomnia independently increase ADRD risk, though insomnia's contribution is very modest compared to the primary association demonstrated by anxiety. Co-occurrence does not confer additional risk beyond anxiety alone. Clinically, routine screening and treatment of anxiety and sleep disturbances represent actionable, broadly applicable strategies for ADRD prevention and healthy cognitive aging.},
}

@article {pmid42251444,
year = {2026},
author = {Contreras-Marciales, A and Mezquite-Garcia, D and Verdina, LA and Elnahrawy, A and Wolf, T and Guergues, J and Parikh, P and Hunter, ER and Hernandez Acosta, D and Stevens, SM and Hill, SE and Blair, LJ},
title = {FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02107-3},
pmid = {42251444},
issn = {1758-9193},
support = {R01 NS073899/NS/NINDS NIH HHS/United States ; R01 NS073899/AG/NIA NIH HHS/United States ; I01 BX004626/BX/BLRD VA/United States ; AARG-22-974562/ALZ/Alzheimer's Association/United States ; },
abstract = {The accumulation of pathogenic tau protein is linked to cognitive decline and neuronal loss in Alzheimer's disease (AD), with tau oligomers identified as particularly neurotoxic. The 51 kDa FK506-binding protein (FKBP51) stabilizes these toxic tau oligomers and has been identified as a risk factor for several neurodegenerative diseases. FKBP51 levels increase with age and are especially high in AD brains, suggesting its involvement in disease progression. The development of the selective FKBP51 inhibitor, SAFit2, which can cross the blood-brain barrier, has shown promise in reducing stress hormones, improving stress responses, and mitigating protein-related pathologies in other neurodegenerative models. However, the effects of SAFit2 on tauopathies, such as those seen in AD, have not yet been investigated. Here, the effects of the FKBP51-selective inhibitor, SAFit2, were evaluated in PS19 tau transgenic mice. Mice received a 28-day regimen of SAFit2, followed by comprehensive behavioral, neuropathological, and proteomic analyses. SAFit2 demonstrated effective brain penetrance, with sex-dependent pharmacokinetics. Treatment slowed cognitive decline and depressive-like behavior, with pronounced benefits in male PS19 mice, including improved spatial memory and reduced tau oligomer burden. In females, SAFit2 promoted clearance of AT8-positive tau multimers with some benefit to recognition memory. Proteomic profiling revealed distinct molecular signatures underlying these sex-specific responses: males exhibited upregulation of RNA processing and ribosomal proteins, while females showed restoration of calcium signaling and synaptic drivers. Notably, behavioral recovery occurred independently of widespread neuroinflammation reversal. These findings provide the first in vivo evidence that FKBP51 inhibition by SAFit2 induces sex-specific remodeling of the brain proteome. This study also provides further evidence for the therapeutic benefits of targeting FKBP51 for tauopathies.},
}

@article {pmid42251712,
year = {2026},
author = {Reyzov, M and Valcheva-Kuzmanova, S},
title = {Neuropsychopharmacological effects of Aronia melanocarpa: A narrative review.},
journal = {Psychiatria Danubina},
volume = {38},
number = {1},
pages = {12-22},
doi = {10.24869/psyd.2026.12},
pmid = {42251712},
issn = {0353-5053},
abstract = {BACKGROUND: This narrative review examines the neuropsychopharmacological effects of Aronia melanocarpa (black chokeberry), focusing on its potential in the prevention and treatment of neuropsychiatric disorders such as anxiety, depression, and cognitive decline.

SUBJECTS AND METHODS: A comprehensive literature search across Web of Science, Scopus, and Google Scholar identified 29 original studies, based on in vitro, animal, and human research.

RESULTS: Findings demonstrated that Aronia melanocarpa, rich in polyphenols like anthocyanins and proanthocyanidins, exerts cognitive-enhancing, anxiolytic-like, and antidepressant-like effects. These outcomes are mediated by mechanisms involving antioxidant activity, modulation of neurotransmitter systems, inhibition of monoamine oxidases, reduction of neuroinflammation, modulation of gut microbiota, and upregulation of brain-derived neurotrophic factor (BDNF). Animal models of Alzheimer's disease and stress-induced disorders, along with human clinical trials, corroborated these effects.

CONCLUSIONS: The review underscores the therapeutic promise of Aronia melanocarpa nutraceuticals in neuropsychiatric health and highlights the need for further clinical validation.},
}

@article {pmid42252274,
year = {2026},
author = {Yu, Z and Wang, Y and Li, Y and Shen, F and Wang, Y},
title = {[Research progress on vascular endothelial growth factor C in meningeal lymphatic vessel-mediated clearance of amyloid β-protein].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-8},
doi = {10.3724/zdxbyxb-2025-0549},
pmid = {42252274},
issn = {1008-9292},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the abnormal deposition of amyloid β-protein (Aβ) as a core pathological feature. Meningeal lymphatic vessels are crucial for Aβ clearance, and their dysfunction accelerates AD progression. Vascular endothelial growth factor C (VEGF-C), through activation of vascular endothelial growth factor receptor 3 and downstream pathways, synergistically promotes lymphangiogenesis, enhances lymphatic permeability, and regulates lymphatic fluid flow, thereby improving Aβ clearance efficiency. Genetic factors and aging-related declines in VEGF-C further impair meningeal lymphatic function, creating a vicious cycle. Although VEGF-C intervention has shown cognitive benefits in AD models, clinical translation faces challenges including non-specific activation of signaling pathways and interindividual variability. Future research should focus on precise regulation of VEGF-C and development of individualized AD therapeutic strategies targeting meningeal lymphatic vessels. This review summarizes the molecular mechanisms, influencing factors, and intervention strategies of VEGF-C in regulating meningeal lymphatic vessel function to promote Aβ clearance, aiming to provide insights for AD prevention and treatment.},
}

@article {pmid42252335,
year = {2026},
author = {Behl, T and Jayabalan, K and Ballal, S and Sahoo, S and Jayasingh Chellammal, HS and Gulati, M and Anand, K and Jha, SK and Gasmi, A},
title = {A Age Related Vascular Senescence: Mystery of Blood-brain Barrier Dysfunction in Neurodegeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42252335},
issn = {1559-1182},
mesh = {Humans ; *Blood-Brain Barrier/pathology/physiopathology/metabolism ; *Aging/pathology ; Animals ; *Neurodegenerative Diseases/pathology/physiopathology ; },
abstract = {The pathophysiology of neurodegenerative illnesses is increasingly understood to be influenced by vascular aging, with blood-brain barrier (BBB) disruption emerging as a crucial mechanistic connection. Comprising endothelial cells, pericytes, astrocytes, and microglia, the BBB is a complex neurovascular unit (NVU) that strictly regulates molecular trafficking and shields neural tissue from circulating toxins and immune cells, therefore maintaining central nervous system homeostasis. The integrity of the BBB is compromised as people age due to structural and functional changes in the cerebrovasculature, such as endothelial senescence, pericyte loss, mitochondrial dysfunction, and persistent low-grade inflammation. These alterations speed up neuronal damage and encourage the development of classical proteinopathies like tau aggregation and amyloid-β by making it easier for neurotoxic proteins, immunological mediators, and metabolic waste to enter the brain parenchyma. BBB disruption is both an early occurrence and a factor in the development of neurodegenerative diseases including Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. It exacerbates neuroinflammation, hinders clearance processes, and contributes to cognitive decline. Recent developments in single-cell omics, fluid biomarkers, and molecular imaging have made it possible to identify and characterize BBB failure in preclinical and clinical contexts, creating new opportunities for early diagnosis and treatment. Restoring BBB function and addressing vascular aging are two viable approaches to alter the course of neurodegenerative illnesses and enhance their prognoses. The processes, effects, and translational potential of vascular aging and BBB degradation in neurodegeneration are summarized in this review, which also identifies new treatment targets and research objectives for the future.},
}

Humans
*Blood-Brain Barrier/pathology/physiopathology/metabolism
*Aging/pathology
Animals
*Neurodegenerative Diseases/pathology/physiopathology

@article {pmid42252551,
year = {2026},
author = {Chiatto, LM and Buccarello, L and Carota, G and Calabrò, RS and Rifici, C and Esposito, E and Ardizzone, A and Caruso, G},
title = {The Use of Statins in Parkinson's and Alzheimer's Disease: A 2021-2025 State-of-the-Art Review of Clinical and Preclinical Evidence.},
journal = {Pharmacology research & perspectives},
volume = {14},
number = {3},
pages = {e70280},
doi = {10.1002/prp2.70280},
pmid = {42252551},
issn = {2052-1707},
abstract = {Statins, widely prescribed for cardiovascular prevention, have emerged as potential disease-modifying agents in neurodegenerative disorders due to their pleiotropic effects on cholesterol metabolism, neuroinflammation, oxidative stress, and protein aggregation. Over the past decade, growing interest has focused on the potential repurposing of statins for Parkinson's disease (PD) and Alzheimer's disease (AD); however, clinical evidence remains heterogeneous and, in some cases, contradictory. This state-of-the-art review synthesizes clinical and preclinical studies published between 2021 and 2025 to critically evaluate the therapeutic potential and limitations of statins in PD and AD. Recent observational studies and large-scale cohort analyses suggest that long-term statin use may be associated with a reduced risk of incident PD and AD, as well as slower cognitive decline in selected patients' subgroups. However, these associations appear to depend on factors such as statin lipophilicity, treatment duration, and genetic background. Preclinical models provide mechanistic support, showing that statins can attenuate neuroinflammation, modulate microglial activation, reduce α-synuclein aggregation in PD models, and interfere with amyloid-β production and tau phosphorylation in AD models. Nevertheless, randomized controlled trials remain limited in number and often underpowered, and some reports indicate neutral or even adverse neurological outcomes, underscoring the complexity of cholesterol-dependent and cholesterol-independent mechanisms in the central nervous system (CNS). Collectively, the evidence from 2021 to 2025 highlights both the therapeutic promise and the unresolved challenges of statin repurposing in neurodegenerative diseases. Future research should prioritize well-designed clinical trials and biomarker-driven patient stratification to determine whether statins can be effectively leveraged as adjunctive disease-modifying therapies in PD and AD.},
}

@article {pmid42252587,
year = {2026},
author = {Jin, H},
title = {PET Molecular Probes for Neuroinflammation in Neurodegenerative Diseases: Progress and Prospects.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00338},
pmid = {42252587},
issn = {1948-7193},
abstract = {Neuroinflammation is a central pathological process underlying neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis. Positron emission tomography (PET) molecular probes now enable the noninvasive, quantitative visualization of neuroinflammatory processes in the living brain. This review surveys recent advances in PET probes targeting microglial activation markers─including the 18 kDa translocator protein (TSPO), the purinergic P2X7 receptor (P2X7R), colony-stimulating factor 1 receptor (CSF1R), and sphingosine-1-phosphate receptor 1 (S1PR1)─as well as astrocyte reactivity markers such as monoamine oxidase B (MAO-B) and imidazoline-2 binding sites (I2BS). I discuss the evolution from first-generation TSPO ligands to polymorphism-insensitive third-generation tracers, highlight emerging targets beyond TSPO, and evaluate the translational value of these probes for early diagnosis, disease staging, treatment monitoring, and drug development. Current challenges-including limited cellular specificity, genetic polymorphism effects, quantification difficulties, and clinical accessibility barriers─are analyzed alongside promising solutions. Integrating neuroinflammation PET into multimodal biomarker frameworks will be essential for advancing precision medicine in neurodegenerative diseases.},
}

@article {pmid42253201,
year = {2026},
author = {Tarkowska, A and Furmaga-Jabłońska, W and Pluta, R},
title = {Long-Term Consequences of Perinatal Asphyxia in the Development of Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050432278251204130006},
pmid = {42253201},
issn = {1875-5828},
abstract = {Despite remarkable progress in medicine, perinatal asphyxia (PA) remains a significant clinical problem, and concerns regarding its long-term complications are increasingly being raised. Emerging evidence indicates that similar pathological pathways are activated following PA and during neurodegeneration in Alzheimer's disease (AD). These similarities involve various mechanisms, including alterations in AD-related proteins and their gene expression. Disturbances in neurotransmitter function can lead to excitotoxicity and cell death via necrosis and delayed apoptosis. Additionally, as observed in AD, dysregulation of autophagic processes has been reported. Pathological changes initiated by hypoxia in the newborn may trigger chronic neuroinflammation that persists long-term. Similarly, neuroinflammation plays a critical role in the pathogenesis of AD. Other common mechanisms include oxidative stress and mitochondrial dysfunction. Estrogens appear to have a protective effect in both PA and AD; however, ovaries exposed to PA may exhibit a reduced ovarian reserve, potentially diminishing neuroprotection later in life. Epigenetic modifications have also been proposed as a link between PA and AD. This review focuses on the changes that occur in the neonatal brain following PA, with particular emphasis on long-term consequences. We highlight common pathogenetic and causal pathways that may connect PA to the development of AD. Furthermore, we summarize key studies from the past 25 years addressing these topics and briefly discuss current research directions in the treatment of experimental and clinical PA.},
}

@article {pmid42253387,
year = {2025},
author = {Persaud, V and Wertheimer, AI},
title = {Assessing the Equitable Use of Formulary Drug Tier Systems: Consequences for Geriatric Patient Population Access and Accessible Medication.},
journal = {Innovations in pharmacy},
volume = {16},
number = {2},
pages = {},
pmid = {42253387},
issn = {2155-0417},
abstract = {Background: This study examines the implications of formulary drug tier systems on the accessibility and affordability of medications for the elderly/geriatric population within the New York metropolitan area. By systematically reviewing the Medicare insurance formularies and evaluating the most prescribed medicines with reported beneficial outcomes for ailments frequently experienced by the geriatric population, this research identifies disparities in drug tier placements and the cost of dispensing that may affect patient outcomes. The focus is on five prevalent conditions: Alzheimer's dementia, Chronic Obstructive Pulmonary Disease, Rheumatoid Arthritis, Ischemic Heart Disease, and Diabetes Mellitus Type 2 (T2DM). The findings aim to highlight the need for more equitable healthcare policies that consider the financial and medical needs of the elderly population. Methods: This study reviewed the formulary tier systems used by Medicare, the primary insurance provider for the elderly in New York City. The research focused on medications prescribed for Alzheimer's disease, COPD, rheumatoid arthritis, ischemic heart disease, and diabetes. Data on tier placements were extracted from Medicare Part D formularies, with a detailed examination of the criteria for tier assignment. The study identified the three most prescribed medications for each condition, using data from relevant health organizations and literature. An economic analysis was conducted to compare the costs associated with these medications, assessing the financial burden on patients. Results: The study revealed a prevalence of chronic conditions among New York City's elderly population. Medications commonly prescribed for these conditions were reviewed, with a focus on their placement within the Medicare Formulary Tier system and associated costs. The analysis highlighted substantial variations in cost and tier placement, affecting patient affordability and adherence. For example, Alzheimer's medications like galantamine and rivastigmine were found in higher tiers, leading to increased out-of-pocket expenses, while COPD treatments such as Symbicort and Trelegy Ellipta, although in preferred tiers, still imposed significant financial burdens. Rheumatoid arthritis drugs showed a wide cost range, with Humira in Tier 5 presenting the highest financial challenge. Similarly, ischemic heart disease and type 2 diabetes medications varied in affordability, with drugs like Eliquis and Steglatro positioned in higher tiers, significantly impacting patient costs and potential treatment adherence. Conclusion: Elderly patients in the United States, especially those dealing with chronic conditions are facing a substantial financial strain due to the increasing prices of prescription medications. Even with recent initiatives like the Inflation Reduction Act aimed at lowering expenses, the financial burden persists, causing issues with treatment adherence and negative health results. The results highlight the pressing requirement for more effective policy actions that support price transparency, promote the utilization of cost-effective generics, and deter the unwarranted classification of generic drugs in higher formulary tiers. It is crucial to handle these problems to guarantee fair access to medications for all elderly individuals, specifically those who qualify for both Medicare and Medicaid.},
}

@article {pmid42253437,
year = {2026},
author = {Harel, M and Leibovici, A and Itzhaki, N and Ravona-Springer, R and Moshier, E and Doniger, GM and Gottlieb, A and Bahat, Y and Bendlin, BB and Zeilig, G and Plotnik, M and Beeri, MS and Livny, A},
title = {Virtual reality-based cognitive-motor training in middle-aged adults at high Alzheimer's disease risk improves frontal cortex cerebral blood flow: A randomized controlled trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70265},
pmid = {42253437},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) pathological processes begin decades before symptom onset. Early intervention in high-risk populations may be crucial for prevention. We investigated the effect of an intervention utilizing virtual reality (VR) cognitive-motor training on cerebral blood flow (CBF) and cognitive functioning in middle-aged adults at high AD risk due to parental history.

METHODS: In this randomized controlled trial, participants (n = 79) were randomly assigned to: VR cognitive-motor training while walking on a treadmill (VR+T, n = 24, treatment); VR cognitive training without treadmill (VR-T, n = 21, active control); treadmill walking while watching documentaries (TV+T, n = 20, active control); or no intervention (n = 14, passive control). Training consisted of 45-min sessions, twice weekly, for 12 weeks. CBF was measured at resting state using arterial spin labeling (ASL) at baseline, 3-month, and 6-month follow-up. Cognition was assessed using a comprehensive neuropsychological battery. We applied the intent-to-treat approach.

RESULTS: All groups improved in executive functions and memory over time (all p-values < 0.05), with no consistent between-group differences at follow-up. CBF of the VR+T group significantly increased at 3 months in the superior (p = 0.013, middle (p = 0.014), and inferior (p = 0.003) frontal gyri compared to the passive control group, which showed a decline in CBF over the same period. No significant differences in frontal CBF change were observed between VR+T and the TV+T active control group. This increase was sustained for 6 months in the superior (p = 0.035) and middle (p = 0.028) frontal gyri. In contrast, in the middle temporal gyrus, the VR+T group had lower CBF at 3 months, compared to the VR-T (p = 0.033) and to the passive control groups (p = 0.004).

DISCUSSION: Cognitive-motor VR training increased CBF in frontal regions susceptible to early AD-related changes in middle-aged adults at high AD risk. This intervention shows promise as a preventive approach and may be suitable for implementation as a home-based program for individuals at high risk.},
}

@article {pmid42255952,
year = {2026},
author = {Sonson, M and Yadollahikales, G and Flores, A and Lasner, I and Lee, S and Tan, Z and Quach, C and Kremen, S},
title = {From clinical trial to clinical experience: Lecanemab therapy in a real-world case series.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70365},
pmid = {42255952},
issn = {2352-8729},
abstract = {The approval of anti-amyloid therapies has expanded therapeutic options for patients with Alzheimer's disease (AD), but the pivotal trials that proved their efficacy restrict their applicability to a selected patient population. We describe a case series of seven patients with biomarker-confirmed AD pathology evaluated in an academic memory clinic and treated with lecanemab whose characteristics would have disqualified them from trial participation. Patient histories and outcomes are presented, accompanied by description of the clinical team's reasoning and application of published Appropriate Use Recommendations for each case. Overall, lecanemab was largely well tolerated, with no unexpected safety concerns and amyloid-related imaging abnormality rates comparable to trial data. Clinically, most patients remained stable over the treatment period, though some continued to decline. This series highlights the challenges and considerations in applying disease-modifying therapies beyond trial populations, emphasizing the need for real-world data to guide treatment in diverse AD presentations.},
}

@article {pmid42255953,
year = {2026},
author = {Wallace, A and Zhou, O and Hoang, MN and Porter, G and Padilla, C and Marshall, C},
title = {Lecanemab and amyloid-related imaging abnormalities: Real-world data from a single center experience.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70377},
pmid = {42255953},
issn = {2352-8729},
abstract = {INTRODUCTION: Lecanemab has demonstrated both safety and efficacy in clinical trials; however, routine clinical data are sparse. We contribute to the growing body of real-world safety data, with a special focus on amyloid-related imaging abnormalities (ARIA).

METHODS: We conducted a retrospective chart review of 146 patients treated with lecanemab according to appropriate-use recommendations at a specialty memory center clinic.

RESULTS: Real-world safety and efficacy data closely resemble published data in the Clarity-AD trial. Thirty-three patients (23%) discontinued treatment; all remaining patients completed at least 12 months of treatment. We observed a positive trend toward increasing ARIA edema/effusion (ARIA-E) with increasing mean arterial pressure and a mean amyloid clearance of -90.6 at 18 months.

DISCUSSION: When used according to appropriate-use recommendations, lecanemab is as safe as reported in the Clarity-AD trial. Further investigation into real-world data is necessary for a more complete evaluation of lecanemab's safety and efficacy.},
}

@article {pmid42248800,
year = {2026},
author = {Miguel, ACC and Martins-Teixeira, L and Aliberti, MJR and Brucki, SMD and Caramelli, P and Laks, J and Nitrini, R and Rebello Pinho, PJDM and Suemoto, CK and Barbosa, MG and Ferri, CP},
title = {Bridging the gap: estimates of undetected dementia in Brazil.},
journal = {Age and ageing},
volume = {55},
number = {6},
pages = {},
doi = {10.1093/ageing/afag163},
pmid = {42248800},
issn = {1468-2834},
mesh = {Humans ; Brazil/epidemiology ; Male ; Female ; *Dementia/epidemiology/diagnosis ; Prevalence ; *COVID-19/epidemiology ; Aged, 80 and over ; Aged ; Middle Aged ; Alzheimer Disease/epidemiology/diagnosis ; Cholinesterase Inhibitors/therapeutic use ; SARS-CoV-2 ; },
abstract = {OBJECTIVE: To estimate the proportion of dementia underdiagnosis in Brazil and assess variations by age, sex and macro-economic regions.

METHODS: Diagnosed dementia cases were estimated using Brazilian Unified Health System (SUS) data on prescriptions for acetylcholinesterase inhibitors (AChEIs), as a proxy for recognised Alzheimer's disease (AD) cases. Estimates were adjusted for the proportion of AD among all dementias, treatment coverage and disease stages. Expected dementia prevalence was derived from national estimates. Underdiagnosis was calculated by comparing diagnosed to expected cases, stratified by sex, age group and region. Uncertainty interval (UI) bounds were calculated applying ±1 SD of the mean Delphi consensus prevalence for each stratum. Estimates were conducted for 2024 and repeated for 2019 and 2022 for pre- and post-COVID-19 pandemic comparison.

RESULTS: The overall proportion of dementia underdiagnosis among individuals aged ≥60 in 2024 was 84.3% (UI: 81.5-86.4). Proportions were higher among men (86.3%, UI: 83.5-88.2) than women (83.0%, UI: 79.9-85.2). Underdiagnosis peaked at 93.2% (UI: 92.3-93.7) in the 60-64-year age group, declined to 78.9% (UI: 78.1-79.6) among 85-89 years, then rose to 86.2% (UI: 85.7-86.7) among those ≥90 years. Proportions were highest in the poorest regions (North, Northeast and Central-West: 93.0%, UI: 91.4-94.1) and lowest in the richest (South and Southeast: 78.3%, UI: 74.3-81.2). Pre-pandemic (2019) underdiagnosis was slightly lower (81.6%, UI: 78.3-84.0) than in 2022 (84.9%, UI: 82.2-86.9) and 2024.

CONCLUSION: Dementia underdiagnosis in Brazil is high and unequally distributed, worsening after the COVID-19 pandemic. Expanding diagnostic access is critical to address disparities and improve care.},
}

Humans
Brazil/epidemiology
Male
Female
*Dementia/epidemiology/diagnosis
Prevalence
*COVID-19/epidemiology
Aged, 80 and over
Aged
Middle Aged
Alzheimer Disease/epidemiology/diagnosis
Cholinesterase Inhibitors/therapeutic use
SARS-CoV-2

@article {pmid42248874,
year = {2026},
author = {Kolypetri, P and da Silva, P and Francisco, RS and Frenkel, D and Cecere, RR and Kiliaan, PCJ and Montini, F and Saxena, S and Clementi, WA and Liu, X and Sun, C and Bergmark, RW and Singhal, T and Saraceno, TJ and Zimmermann, J and Gale, SA and Selkoe, DJ and Chitnis, T and Weiner, HL},
title = {Nasal administration of Protollin enhances monocyte phagocytosis and decreases CD8[+] T cell cytotoxicity in subjects with early Alzheimer's disease: a Phase 1 clinical trial.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-026-00397-3},
pmid = {42248874},
issn = {2731-6068},
support = {NIA R21AG072486/NH/NIH HHS/United States ; },
abstract = {Protollin, a nasal adjuvant, was evaluated in a randomized double-blind phase 1 study of 16 early Alzheimer's disease (AD) patients to determine safety and to assess its immunomodulatory effects. In a double-blind dose escalation study, subjects received nasal Protollin at doses of 0.1 mg, 0.5 mg, 1.0 mg, and 1.5 mg or placebo twice over a two-week period. Treatment was well-tolerated with minimal side effects. Transcriptomic and single-cell analyses demonstrated that prior to treatment, AD blood monocytes had downregulation of phagocytosis-related genes and an increased pro-inflammatory signature. These AD monocyte abnormalities were reversed by nasal Protollin beginning at a dose of 1.0 mg. Protollin induced a robust phagocytic gene signature, including upregulation of CD36, ITGAL, LYST, and FCGR1A. A similar phagocytic signature was observed in brain-infiltrating amyloid-clearing monocytes in an APP Tg mouse model treated with nasal Protollin. Protollin treatment decreased the expression of costimulatory molecules on monocytes and decreased CD8 [+] T cell activation and cytotoxicity. Our results provide the basis for a phase 2 study of nasal Protollin in subjects with AD in which nasal Protollin at a dose of 1.0 mg will be administered weekly over 6 months to modulate peripheral immunity and clear amyloid from the brain. ClinicalTrials.gov registration no NCT07187141.},
}

@article {pmid42244738,
year = {2026},
author = {Amontree, M and O'Leary, J and Wonnenberg, P and Nelson, M and Conant, K},
title = {4-methylumbelliferone attenuates amyloid pathology and learning deficits in the APP/PS1 mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.21.726929},
pmid = {42244738},
issn = {2692-8205},
abstract = {4-Methylumbelliferone (4-MU) inhibits hyaluronic acid (HA) synthesis and is currently approved in Europe for biliary spasm. 4-MU administration reduces perineuronal nets (PNNs), and enzymatic degradation of PNNs in mouse models of Alzheimer's disease (AD) attenuates memory impairment. Although 4-MU has therapeutic efficacy in rodent models of fibrosis and cancer, it has not been examined in an Alzheimer's model. Here, we evaluated the impact of long-term 4-MU treatment in the APP/PS1 amyloid mouse model. From three months of age, mice were on either a vehicle or 4-MU-supplemented diet for 70 days or 52 weeks. Short and long-term 4-MU treatment decreased the soluble parenchymal Aβ 1-42 /Aβ 1-40 ratio. Reductions in insoluble amyloid plaque were observed following 52 weeks of treatment. Extended 4-MU administration also reduced PNN intensity and ameliorated spatial memory deficits in APP/PS1 mice. These findings provide support for targeting brain extracellular matrix (ECM) as a therapeutic strategy for AD.},
}

@article {pmid42245509,
year = {2026},
author = {Wang, Z and Li, L and Dong, Y and Zhang, Y},
title = {The microbiota-tryptophan-brain axis in neurodegenerative diseases: pathogenic mechanisms, disease-specific roles, and translational therapeutics.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1820111},
pmid = {42245509},
issn = {1664-302X},
abstract = {The pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is very complex. Recent studies have shown that gut microbiota and their metabolites play a key role in the progression of these diseases. Tryptophan (Trp) is an essential amino acid, which mainly produces a variety of biologically active compounds in the intestine through the metabolism of indole pathway, Kynurenine pathway (KP) and serotonin pathway, including indole derivatives, Kynurenine (KYN) and serotonin (5-HT). These metabolites affect the central nervous system (CNS) through the Microbiota-gut-brain axis (MGBA) and affect CNS in a variety of mechanisms, including immune regulation, neuroprotection and maintenance of intestinal barrier function. They are involved in key pathological processes such as neuroinflammation, oxidative stress and pathological protein aggregation. This paper systematically reviews the mechanism of the role of Trp metabolites derived from gut microbiota in NDDs, and explores their specific roles in AD, PD, Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD), and summarizes the potential therapeutic value of the current pathway strategy. These strategies include nutritional intervention, targeted microbiome therapy [such as probiotic and fecal microbiota transplantation (FMT)], and metabolite-derived drugs. Future research must clarify its dynamic mechanism in the human body, develop relevant biomarkers, and promote personalized prevention and treatment strategies through clinical transformation, so as to provide a new direction for early intervention and treatment of NDDs.},
}

@article {pmid42247667,
year = {2026},
author = {Yu, J and Chen, Y and Bai, J and Zeng, J and Zhao, J and Fan, Y},
title = {Application of Focused Ultrasound in Alzheimer's Disease: A Bibliometric Analysis.},
journal = {The Journal of craniofacial surgery},
volume = {},
number = {},
pages = {},
pmid = {42247667},
issn = {1536-3732},
abstract = {OBJECTIVE: This study uses bibliometric analysis and knowledge mapping methods to systematically explore the emerging research frontiers and development trajectories of focused ultrasound (FUS) technology in the treatment of Alzheimer's disease (AD), and provides new clues and research directions for future research by exploring hotspots and new topics.

METHODS: A comprehensive literature search was conducted through the Science Citation Index Expanded Core Collection (WoSCC) database to identify relevant articles and reviews published between January 2014 and 2025 on the application of FUS technology in AD. For data analysis and visualization, we used VOSviewer software, CiteSpace, and the R package "bibliometrix" to conduct rigorous bibliometric analysis and build knowledge domain maps.

RESULTS: A total of 1531 papers involving 9220 contributors were identified between 2014 and 2025. The field demonstrated consistent growth (R2=0.9272), peaking in 2025 with 225 publications. China led in total output (475 papers), while the United States achieved the highest academic impact (12,965 citations, H-index: 56). The Chinese Academy of Sciences was the most prolific institution, whereas Harvard Medical School recorded the highest citation impact. The Journal of Alzheimer's Disease and Scientific Reports emerged as the leading publication venues, while Theranostics and Alzheimer's & Dementia provided high-prestige platforms. Tianfu Wang and Baiying Lei were the most productive authors, though Isabelle Aubert garnered the highest total citations. International collaboration analysis revealed a robust, multi-centric network anchored by the USA, China, Canada, and Italy. Co-citation analysis identified Leinenga G (2015) as the foundational study for ultrasound-mediated amyloid-beta clearance. Lipsman N (2018) marked a critical clinical inflection point, exhibiting a strong citation burst (17.3) that catalyzed a shift from preclinical models to human safety trials. Recent bursts extending into 2025 focus on multicenter clinical validation and long-term efficacy. Keywords analysis confirms that non-invasive blood-brain barrier (BBB) opening via microbubble-enhanced focused ultrasound (FUS) is the central research paradigm. Emerging frontiers have shifted from basic technical validation toward neuroinflammation, oxidative stress, tau pathology, and deep-learning-assisted diagnostics, reflecting an evolving focus on molecular mechanisms and precision neurosurgery.

CONCLUSIONS: Focused ultrasound technology has made significant progress in the field of Alzheimer's disease research and has become a research frontier with considerable therapeutic potential. With ongoing technological progress, the clinical translation of FUS is expected to bring new breakthroughs in AD treatment.},
}

@article {pmid42247872,
year = {2026},
author = {Fu, W and Lu, R and Wang, D and Sang, Z},
title = {Shared pathophysiology and therapeutic repurposing in Alzheimer's disease and type 2 diabetes: a critical review of convergent mechanisms and clinical challenges.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110044},
doi = {10.1016/j.bioorg.2026.110044},
pmid = {42247872},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent age-related disorders that share striking pathophysiological similarities, leading to the conceptualization of AD as a metabolic disorder often termed "type 3 diabetes." While numerous reviews have documented the epidemiological association between these diseases, a critical synthesis of the underlying molecular convergence-and its implications for therapeutic repurposing-remains fragmented. This review provides a comprehensive and critical analysis of the shared signaling pathways that underpin both AD and T2DM, including insulin resistance, oxidative stress, the AGE-RAGE axis, amyloidogenic protein misfolding (Aβ in AD and IAPP in T2DM), endoplasmic reticulum stress, and vasculopathy. By systematically examining each pathway, we highlight not only their disease-specific manifestations but also their intricate interconnections and the critical unresolved questions that hinder translational progress. We then critically evaluate the current evidence for repurposing major antidiabetic drug classes-insulin and its analogues, metformin, sulfonylureas, thiazolidinediones, incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors), and amylin receptor modulators-for AD treatment. Through this analysis, we identify key sources of clinical inconsistency, including patient heterogeneity (particularly APOE ε4 genotype), disease stage dependency, blood-brain barrier integrity, and off-target safety concerns. By integrating mechanistic insights with a rigorous assessment of clinical evidence, this review advances the understanding of AD as a metabolic disorder and provides a framework for future precision medicine approaches in cross-disease intervention. The synthesis presented here underscores that realizing the therapeutic potential of antidiabetic drugs in AD will require mechanism-guided patient stratification, early-stage intervention, and the development of brain-selective agents with improved efficacy and safety profiles.},
}

@article {pmid42248234,
year = {2026},
author = {Asmabi, V and Anoop, V},
title = {Multimodal neuroimaging-based deep learning framework for pattern analysis and early prediction of neurodegenerative diseases.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.005},
pmid = {42248234},
issn = {1873-7544},
abstract = {Neurodegenerative diseases, such as Mild Cognitive Impairment (MCI) and Alzheimer's, pose significant challenges due to their progressive nature and late diagnosis. Early detection remains difficult, particularly when using conventional machine learning approaches that fail to capture complex spatial and temporal patterns in multimodal clinical data. Motivated by the need for accurate, scalable, and clinically applicable diagnostic tools, this study proposes a hybrid deep learning framework combining Convolutional Neural Networks (CNN) with Optimized Spatial-Temporal Bidirectional Gated LSTM (O‑SBGC‑LSTM). The framework is evaluated on 1,000 multimodal samples, achieving 94.8% accuracy, 93.9% precision, 94.2% recall, and a 94.0% F1-score, outperforming SVM (82.4%), Random Forest (85.7%), and CNN-LSTM (92.5%). Cross-validation confirms robustness (93.8-95.0% accuracy). The approach balances class performance across cognitively normal, MCI, and Alzheimer's cases. Future work will extend this framework to larger, multi-centre datasets and explore real-time clinical deployment, aiming to enhance early diagnosis, reduce misclassification, and support personalized treatment strategies for neurodegenerative disorders.},
}

@article {pmid42235756,
year = {2026},
author = {Shashwat, P and Kirthi, AV and Selvaraj, M and Karnwal, A and Dutta, J},
title = {Phytochemical engineered quantum dots as potential therapy to counter alpha synuclein aggregation in Parkinson's disease.},
journal = {Neurochemistry international},
volume = {198},
number = {},
pages = {106194},
doi = {10.1016/j.neuint.2026.106194},
pmid = {42235756},
issn = {1872-9754},
abstract = {Parkinson's disease (PD) is a prevalent neurodegenerative disorder that critically impairs human health and presently lacks effective cellular-level therapeutic interventions. The disease is primarily characterized by pathological aggregation of misfolded α-synuclein in presynaptic neurons, leading to dopaminergic neuronal loss. The limited efficacy of current pharmacological treatments stems largely from challenges in crossing the blood-brain barrier. Recent studies suggest that nano-phytomedicine approaches offer promising alternatives for PD management. Specifically, phytochemical-engineered carbon quantum dots (CQDs) show potential to modulate key pathological processes, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuronal degeneration. Evidence from related neurodegenerative models, such as Alzheimer's disease, reveals that multifunctional CQDs can scavenge reactive oxygen species, influence protein aggregation, and mitigate neurotoxicity. The synergistic integration of bioactive phytochemicals into CQDs could enhance drug bioavailability, pharmacokinetic properties, and cellular repair mechanisms while reducing toxicity. This review discusses the design strategies, therapeutic mechanisms, and biological interactions of phytochemical-engineered CQDs, emphasizing their potential as next-generation nanocarriers and intrinsic neurotherapeutic agents for PD treatment.},
}

@article {pmid42236351,
year = {2026},
author = {Hata, M and Miyazaki, Y and Takahashi, S and Ikeda, M},
title = {Temporal pattern of dementia with lewy bodies diagnostic labels around electroconvulsive therapy: A nationwide claims-based study.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100224},
doi = {10.1016/j.inpsyc.2026.100224},
pmid = {42236351},
issn = {1741-203X},
abstract = {BACKGROUND: Electroconvulsive therapy (ECT) is widely used for severe depression. Dementia with Lewy bodies (DLB) may initially present with depressive symptoms, and ECT may be administered in some patients during the course of the disease. However, the timing of DLB diagnosis in relation to ECT treatment has not been well characterized.

METHODS: We conducted a retrospective cohort study using a nationwide administrative claims database in Japan, including records from 564 acute care hospitals between April 2008 and March 2025. Analyses were restricted to patients with a mood disorder diagnosis (ICD-10 F30-F39) recorded in the same month as the first ECT session, and patients with both DLB and Alzheimer disease (AD) diagnostic codes were excluded. The primary analysis examined the timing of recorded DLB diagnostic labels relative to ECT initiation, with AD diagnoses analyzed as a comparator.

RESULTS: Among 3733 patients who underwent ECT, 71 met the analytic criteria for DLB. The median interval between ECT initiation and the first DLB diagnosis was 8 days prior to ECT initiation. Recorded DLB diagnostic labels occurred significantly more often within ±90 and ±180 days of ECT initiation than AD diagnoses, whereas AD diagnoses were distributed more broadly across the observation period.

CONCLUSION: Recorded DLB diagnostic labels showed a distinct temporal pattern around ECT initiation. Clinical evaluation associated with ECT may facilitate recognition of underlying DLB in patients presenting with severe psychiatric symptoms. Clinicians should remain attentive to evolving DLB when treating late-life treatment-resistant mood disorders with ECT, as recognition of DLB may occur several years after treatment initiation.},
}

@article {pmid42236499,
year = {2026},
author = {Kumar, D and Walhekar, V and Shenoy, KM and Kini, SG},
title = {In silico investigation of thiazole-semicarbazide hybrids as dual GSK-3β/Tau inhibitors for Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55932-9},
pmid = {42236499},
issn = {2045-2322},
abstract = {AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects by application of structure-based scaffold hopping and molecular hybridization strategies. Molecular docking was carried out on Glide module; Molecular dynamics simulation of 500 ns was executed employing Desmond and ADMET prediction was achieved by QikProp modules of Schrödinger. Through molecular docking studies targeting the GSK-3β and Tau enzymes, the compounds DVK5 and DVK11 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of - 9.863 and - 8.994 kcal/mol, respectively. Molecular dynamics simulations further revealed that the DVK5 and DVK11 complexes exhibited stable interactions within the active sites of GSK-3β and Tau throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that DVK10 exhibited an excellent human oral absorption rate of 75.175%, outperforming other compounds in the series. These findings strongly suggest the potential of DVK5 and DVK11 as dual inhibitors of GSK-3β and Tau, offering a basis for future drug development studies for the development of new lead compounds for AD treatment.},
}

@article {pmid42239211,
year = {2026},
author = {Patterson, C and Chattopadhyay, T and Thomopoulos, SI and Saykin, AJ and Davatzikos, C and Mormino, EC and Tosun, D and Beecham, GW and Biber, SA and Kukull, WA and Risacher, SL and Montine, TJ and Johnson, SC and Shen, L and Huang, H and Erus, G and Jun, GR and Mukherjee, S and Crane, PK and Cuccaro, ML and Archer, DB and Landman, BA and Toga, AW and Hohman, TJ and Thompson, PM},
title = {Predicting Autopsy-Confirmed Neuropathology across Clinical, Neuroimaging, and CSF Biomarkers using Machine Learning.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.20.726332},
pmid = {42239211},
issn = {2692-8205},
abstract = {Accurate in vivo prediction of neuropathology is critical for advancing diagnosis and treatment of Alzheimer's disease and related dementias (ADRDs). As many individuals with ADRDs have mixed pathologies (β-amyloid, pathologic tau, cerebrovascular disease, vascular brain injury, pathologic TDP-43, hippocampal sclerosis, Lewy bodies), there is interest in determining how accurately we can infer these pathologic changes from clinical data, biofluid assays (e.g., CSF), and neuroimaging. Here we evaluated automated machine learning models trained on data curated by the AD Sequencing Project Phenotype Harmonization Consortium (N=7,894 individuals), to predict 26 autopsy-confirmed neuropathological outcomes. Predictors included in vivo clinical and cognitive composite scores, brain measures from 3D structural MRI and diffusion tensor imaging, image-derived measures of white matter hyperintensities (WMH), and CSF biomarkers. Predictive models were trained using ensemble learning with stratified cross-validation. We assessed performance using Spearman's rank correlation and Matthews correlation coefficient, to accommodate co-occurring pathologic changes. The added value of neuroimaging and CSF versus clinical features alone was quantified. Braak stage was among the most consistently predicted outcomes. CSF biomarkers best predicted β-amyloid and tau pathology, but diffusion MRI metrics best captured vascular brain injury and white matter injury, and outperformed clinical and cognitive measures and anatomical MRI in predicting Lewy body disease. Anatomical measures from structural MRI outperformed standard clinical assessments in assessing neurodegeneration and hippocampal sclerosis, and WMH complemented cognitive measures in predicting TDP-43 pathology. These results establish a baseline for comparing modalities for inferring neuropathology.},
}

@article {pmid42239295,
year = {2026},
author = {Kambali, M and Trushin, S and Wang, M and Nagarajan, R and Lyu, J and Trushina, E and Rudolph, U},
title = {A Small-Molecule Mitochondrial Complex I Modulator Improves Behavioral and Mitochondrial Dysfunction in Schizophrenia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.19.726440},
pmid = {42239295},
issn = {2692-8205},
abstract = {Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimer's and Huntington's diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1α, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.},
}

@article {pmid42239568,
year = {2026},
author = {El-Mokaddem, OK and Elmasry, GF and Mahmoud, WR and Abdel Ghany, LMA},
title = {Bridging the gap in Alzheimer's therapy: strategic design and SAR evolution of coumarin-based hybrids as potent MTDLs.},
journal = {RSC advances},
volume = {16},
number = {32},
pages = {29631-29660},
pmid = {42239568},
issn = {2046-2069},
abstract = {Due to their multitargeting potential, coumarin-based hybrid molecules represent a new and valuable drug development strategy for the treatment of Alzheimer's disease (AD). This review summarizes recent advances in the design, synthesis, and evaluation of coumarin hybrids as multi-target-directed ligands (MTDLs) for AD. This review covers various coumarin hybrid classes, including those incorporating triazole, thiazole, quinoline, chalcone, and other pharmacophores, highlighting their diverse mechanisms of action, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, amyloid-beta (Aβ) aggregation prevention, BACE-1 inhibition, MAO-B modulation, antioxidant activity, and metal ion chelation. Structure-activity relationship (SAR) studies have identified key structural features for optimal activity, including linker length, substitution patterns, and physicochemical properties influencing CNS penetration. Molecular docking and dynamics simulations reveal information about drug-target interactions and demonstrate the ability to engage multiple targets. Coumarin hybrids are already showing ecological in vivo efficacy in animal models, and also the desired safety window and metabolic stability make them potential clinical candidates. Future research directions include incorporating emerging therapeutic targets, advanced computational design, and a focus on the microbiome-gut-brain axis to develop more effective and disease-modifying AD therapeutics.},
}

@article {pmid42240303,
year = {2026},
author = {G, D and K, P and S, R and Vijaya Lakshmi, TR},
title = {Bobcat-Optimized Hybrid Quantum-Classical Spike-Driven Network for MRI-Based Alzheimer's Stage Prediction.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-30},
doi = {10.1080/00207454.2026.2683880},
pmid = {42240303},
issn = {1563-5279},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely affects memory, cognition, and behavioral functions, making early and accurate stage classification essential for timely clinical intervention and treatment planning. Conventional MRI-based diagnostic approaches are often limited by noise sensitivity, manual interpretation, and insufficient capability to model complex non-linear neuroimaging relationships across multiple disease stages. To address these limitations, this paper proposes a novel Hybrid Quantum-Classical Spike-Driven Network optimized with the Bobcat Optimization Algorithm(HQSDNet-BOA)for automated multistage AD classification using MRI data. The suggested framework introduces an integrated architecture that combines Square Root Sage-Husa Adaptive Robust Kalman Filtering(SRS-HARKF)for adaptive noise suppression and covariance stabilization, Graph-Enhanced Fuzzy Clustering(GEFC)for structurally consistent brain tissue segmentation, and a Hybrid Structural Graph Attention Network(HSGAN)for learning discriminative local-global anatomical representations. Moreover, Hybrid Quantum-Classical Spike-Driven Network (HQSDNet), which incorporates quantum convolutional learning, spike-driven transformers, and structural attention schemes, is designed to precisely identify nonlinear and spatial-temporal disease patterns. Bobcat Optimization Algorithm (BOA) is used for optimizing network parameters in real-time to ensure convergence efficiency and computational optimization. This study was performed using two datasets: ADNI (5,300 images representing five disease stages) and OASIS-3 (3,712 images representing three cognitive classes). The suggested HQSDNet-BOA yielded improved classification results with 98.8% accuracy, 98.0% precision, 98.5% recall, and 98.25% F1-score when applied to the ADNI dataset and outperformed the existing techniques in terms of computational speed. The obtained results confirm that the suggested framework provides a robust, efficient, and clinically relevant solution for accurate AD stage prediction and neuroimaging-based diagnostic support.},
}

@article {pmid42243905,
year = {2026},
author = {Qian, L and Cui, M and Wu, M and Song, B and Wang, P and Wu, M and He, T and Zhang, B and He, Y},
title = {Tea-derived natural nanodrug simultaneously enables real-time fluorescent tracking and noninvasive treatment of neuroinflammation in Alzheimer's disease.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04642-5},
pmid = {42243905},
issn = {1477-3155},
support = {BK20240766//Natural Science Foundation of Jiangsu Province/ ; 22504095//National Natural Science Foundation of China/ ; 22393932//National Natural Science Foundation of China/ ; 2023M742532 and 2024T170625//China Postdoctoral Science Foundation/ ; 0002/2022/AKP, 0115/2023/RIA2//Macau University of Science and Technology Foundation/ ; 2023YFB3208202//National Key Research and Development Program of China/ ; },
abstract = {Neuroinflammation and glutamate-induced excitotoxicity are key drivers of synaptic dysfunction and cognitive decline in Alzheimer's disease (AD). However, chemically synthesized small-molecule drugs (e.g., memantine) often cause potential dose-dependent neurotoxicity, limited inflammation-targeting capability, and rapid systemic clearance, resulting in suboptimal therapeutic efficacy. Here, we introduce a tea-derived multifunctional natural nanodrug that enables real time fluorescence tracking and noninvasive treatment of neuroinflammation in AD. The natural nanodrug is derived from Pu-erh tea leaves, formulated with memantine and biomimetic vesicles for intranasal nebulized delivery. The tea-derived biomimetic nanodrug features intrinsic fluorescence, enabling real-time tracking at both cellular and tissue levels, with preferential colocalization in activated microglia and selective accumulation in neuroinflammatory brain regions. Remarkably, under matched nebulization conditions and nominal memantine loading, the tea-derived natural nanodrug shows an improved safety and efficacy relative to free memantine, significantly improving behavioral outcomes and reducing hippocampal damage. This noninvasive strategy enables efficient brain targeting and markedly restores hippocampal structure and cognitive performance in AD mouse models. Together, our study suggests new avenues and exciting opportunities for developing natural nanodrugs for noninvasively and precisely treating brain diseases including but not limited to AD.},
}

@article {pmid41963454,
year = {2026},
author = {Malakar, V and Roy, D and Dugar, N and Mali, PC and Malakar, CC and Gautam, M and Poddar, NK},
title = {Computational investigation of biochanin a targeting DEPTOR in Alzheimer's disease with in vitro cellular validation of neuroprotective activity.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41963454},
issn = {2045-2322},
abstract = {UNLABELLED: Trifolium pratense (TP) L. contains active phytoconstituents such as biochanin A are known to prevent oxidative stress–induced neuronal death in Alzheimer’s disease (AD). This study explored the molecular mechanism of TP phytoconstituents in AD therapy by network pharmacology and computational modelling. Common targets were analyzed via protein–protein interaction (PPI) in STRING and Cytoscape, followed by Gene Ontology (GO). Based on topological parameters DEPTOR (DEP domain–containing mTOR-interacting protein) was selected as a key target. Subsequently, molecular docking, molecular dynamics (MD) simulations, MM-PBSA free energy calculations, and DFT analyses were performed. It revealed that Biochanin A exhibited the highest MM/PBSA energy (− 150.04 kJ/mol) compared to the standard drug (− 24.01 kJ/mol) and formed stable interactions with key residues (Lys131 and Arg138). Moreover, the currently available therapy targeting the cholinesterase enzyme-related pathways is inadequate, as it displays only symptomatic treatment and fails to address the underlying neurodegenerative molecular mechanisms related to AD. In addition to computational analyses, in vitro validation was performed to confirm the neuroprotective effect of biochanin A. Using the MTT assay, increasing concentrations of Aβ1–42 (0.625–20 µM) were shown to reduce SH-SY5Y cell viability in a dose-dependent manner, with 10 µM Aβ1–42 causing ~ 48% reduction. Pretreatment with biochanin A (6.25–100 µM) significantly improved cell survival, with 100 µM restoring viability to ~ 82% of control levels (P < 0.01), indicating a dose-dependent neuroprotective effect without marked cytotoxicity below 100 µM. Overall, this integrative study reveals that biochanin A may target DEPTOR and stabilize mTOR regulatory interactions, suggesting a promising computationally supported and experimentally validated neuroprotective mechanism for Alzheimer’s disease therapy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-47343-7.},
}

@article {pmid42015258,
year = {2026},
author = {Hao, JP and Cheng, ZZ and Wang, MY and Zhu, YP and Chen, N and Zhu, D and Zhang, L and Li, YL and Li, L and Bai, ZF and Xiao, XH and Wang, JB and Zhang, L and Gao, D},
title = {Tet2 deficiency orchestrates Alzheimer's pathogenesis through oxidative mtDNA-driven cGAS-STING activation.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {42015258},
issn = {1742-2094},
support = {82274611//National Natural Science Foundation of China/ ; 82274121//National Natural Science Foundation of China/ ; 7232267//Natural Science Foundation of Beijing Municipality/ ; H2025112023//Natural Science Foundation of Hebei Province/ ; HZ2025PYYX010//Xuanwu Hospital Talent Convergence Program/ ; },
abstract = {UNLABELLED: Emerging evidence underscores the pivotal role of Ten-eleven translocation 2 (Tet2), as an epigenetic regulator with neuroprotective functions, yet its temporal dynamics and pathogenic contributions to Alzheimer’s disease (AD) remain poorly understood. By integrating human longitudinal cohort data with experimental models, we demonstrated that Tet2 deficiency accelerated AD‑like neurodegeneration through oxidative stress-dependent cGAS-STING activation. Clinically, Tet2 loss-of-function carriers among Aβ-positive individuals exhibited significantly accelerated cognitive decline. In mice, Tet2 expression decreased with age and in late‑stage AD models, and constitutive Tet2‑mutant (Tet2[mut]) mice recapitulated AD-like behaviors and pathology by exacerbating neuroinflammation and impairing neurogenesis and synaptic plasticity. Crucially, Tet2 deficiency induced mitochondrial dysmorphology and heightened oxidative stress in the hippocampus, culminating in DNA damage and robust cGAS-STING activation. Mechanistically, integrative epigenomic analyses further revealed that Tet2 deficiency was associated with hypermethylation of antioxidant gene networks, thereby exacerbating oxidative stress and mitochondrial injury. Notably, antioxidant treatment with N-acetylcysteine (NAC) effectively alleviated oxidative damage, restored mitochondrial function and suppressed cGAS-STING signaling in Tet2-silenced microglia. In vivo, NAC administration in Tet2[mut] mice improved cognitive performance and synaptic plasticity while reducing neuroinflammation and neuronal loss through inhibition of cGAS-STING signaling. These findings delineate a previously unrecognized epigenetic-immune axis in AD, highlighting Tet2 enhancement and ROS modulation as promising therapeutic strategies.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03820-4.},
}

@article {pmid42232224,
year = {2026},
author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD},
title = {Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1818660},
pmid = {42232224},
issn = {1663-4365},
abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

METHODS: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs. 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.

RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < 0.0001) and was equally effective in both sexes. Risk reduction was observed for each age-associated disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the greatest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (< 1 year) to 0.25 (> 6 years). Risk reduction was greatest in older participants (75-79 years).

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with significantly reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.},
}

@article {pmid42234329,
year = {2026},
author = {Qi, JW and He, XY and Gu, YC and Luo, ZJ and Duan, R and Zhang, YD and Xie, Y and Jiang, T},
title = {Soluble TREM1 Contributes to Aging-Related Neurodegeneration via ROBO2/ERK Pathway.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42234329},
issn = {1559-1182},
abstract = {Aging is recognized as the most significant risk factor for neurodegenerative diseases. Emerging evidence indicates that inflammation contributes to the progression of aging-related neurodegeneration. As a transmembrane immune receptor, triggering receptor expressed on myeloid cells 1 (TREM1) plays a crucial role in the regulation of inflammatory responses. Previously, our research group and others showed that the levels of a soluble form of TREM1 (sTREM1) were increased in the plasma or cerebrospinal fluid (CSF) of patients with Alzheimer's disease, the most common type of neurodegenerative disease among the elderly. Moreover, the elevated levels of CSF sTREM1 were closely associated with a more rapid rate of hippocampal degeneration in cognitively impaired older adults. However, the precise mechanisms by which sTREM1 contributes to aging-related neurodegeneration remain largely unclear. In this study, by utilizing senescence accelerated mouse prone 8 mice, an animal model of accelerated aging, we confirmed that serum sTREM1 levels were significantly increased during the aging process. Importantly, we demonstrated that roundabout guidance receptor 2 (ROBO2) functioned as a receptor for sTREM1 in hippocampal neurons, and its expression was also upregulated with aging. Additionally, we revealed for the first time that knockdown of neuronal ROBO2 mitigated aging-related hippocampal synaptic degeneration and cognitive impairments. Furthermore, we provided the first evidence that sTREM1 reduced the expression of synaptic proteins via the ROBO2/extracellular signal-regulated kinase pathway. These findings elucidated the mechanisms through which sTREM1 contributed to aging-related neurodegeneration and suggested that the inhibition of sTREM1-mediated signaling might represent a novel therapeutic strategy for the treatment of neurodegeneration and cognitive decline induced by aging.},
}

@article {pmid42234971,
year = {2026},
author = {Zhou, J and Zhu, X and Chen, W and Tan, J and Hong, L and Yang, L and Liu, Y and Zhai, T and Chen, K},
title = {The Dickkopf Protein Family in Non-Neoplastic Disorders: Emerging Roles and Therapeutic Targeting.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1506},
pmid = {42234971},
issn = {2152-5250},
abstract = {The Dickkopf (DKK) family of secreted glycoproteins, comprising DKK1-4, serves as a pivotal regulator of the Wnt signaling pathway. Acting as canonical antagonists of the Wnt/β-catenin cascade, these proteins are indispensable for essential biological processes such as cellular proliferation, differentiation, development, and tissue homeostasis. In recent years, aberrant expressions of DKK proteins has been extensively documented in multiple cancers. Simultaneously, their pathophysiological roles and clinical relevance in non-oncological diseases have garnered growing attention. Disorders such as osteoporosis and arthritis, chronic kidney disease (CKD), myocardial injury, as well as neurodegenerative and dermatological conditions, including Alzheimer's disease (AD) and alopecia, have all been linked to DKK family members. These broad associations emphasize their substantial potential as diagnostic biomarkers and as promising therapeutic targets. This review provides a systematic synthesis of recent research within the past three years on the roles of the DKK protein family in diverse non-oncological diseases, further examining their prospective applications as biomarkers and therapeutic targets while addressing related challenges, with the aim of offering novel insights into diagnosis and treatment.},
}

@article {pmid42235718,
year = {2026},
author = {Oh, JM and Jeong, WK and Son, HJ and Kwon, YJ and Kim, SY and Oh, TW and Ji, M and Baek, M and Shin, WH and Kim, HJ and Choi, B and Kim, SH and Paik, MJ and Kim, H},
title = {Broussochalcone A alleviates cognitive impairment in scopolamine-induced mice as a potent β-amyloid aggregation inhibitor and changes blood and brain metabolite profiles.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121958},
doi = {10.1016/j.jep.2026.121958},
pmid = {42235718},
issn = {1872-7573},
abstract = {Broussonetia papyrifera (BP) has been used for traditional medicine in amelioration of cognitive decline. Accumulation of β-amyloid (Aβ) plaques majorly contributed to the pathogenesis of Alzheimer's disease (AD).

AIM OF THE STUDY: This study aimed to investigate the role of broussochalcone A (BCA), a bioactive constituent of BP, in alleviation of cognitive impairment via Aβ aggregation inhibition in model mice.

METHODS: We screened a potent Aβ aggregation inhibitor from a herbal library and analyzed its effect on improving cognitive functions in model mice and principal protein expression. In addition, we compared the metabolite profiling of blood and tissues. We used the aggregation inhibition assay to screen 960 herbal compounds using Aβ42-, and a leading compound was selected based on drug-like properties. Animal behavioral tests including the Morris water maze were performed using scopolamine (SCO)-treated mice. Western blotting and histopathological analysis were performed. Key compounds in the blood, hippocampus, and cortex were analyzed to compare the metabolic profiles.

RESULTS: BCA was a potent Aβ aggregation inhibitor (IC50 = 1.75 ± 0.021 μM) with a predicted binding energy of -6.405 kcal/mol, and nontoxic to MDCK and SH-SY5Y cells. Molecular dynamics simulation revealed that the atomic contact numbers of BCA with Aβ were highly fluctuated during 100 ns; however, the transient contacts might prevent the aggregation. Cognitive function was significantly improved in BCA-treated mice in behavioral tests. Western blotting and histopathological analysis demonstrated that BCA treatment attenuated apoptosis, preserved hippocampal pyramidal neuron integrity, and alleviated SCO-induced spatial memory impairment. Metabolite profiling demonstrated that BCA modulated the metabolic pathways related to energy metabolism, redox homeostasis, amino acid turnover, and lipid metabolism in the serum and brain tissues, partially attenuating SCO-associated metabolic alterations.

CONCLUSIONS: BCA is a potent Aβ aggregation inhibitor and exhibits significant cognitive improvement, as well as neuroprotective effects, decreasing inflammation, and retaining neuron structures. In addition, BCA induced distinct metabolic alterations in the serum and brain tissues compared to SCO. These results strongly support the use of BCA as a promising candidate for the amelioration of cognitive impairment and application to AD therapeutics.},
}

@article {pmid42228338,
year = {2026},
author = {Chaudhary, B and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and Vellingiri, B and Medhi, B and HariKrishnaReddy, D},
title = {Decoding neuroinflammation: the critical role of NLRP3 inflammasome in Alzheimer's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42228338},
issn = {1568-5608},
abstract = {The hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease, include tau tangles, amyloid-β (Aβ) plaques, cognitive impairment, and severe neuroinflammation. A key molecular mediator linking immunological activation and neurological pathology in AD is the NLRP3 inflammasome. This review explains the intricate role of the NLRP3 inflammasome in AD, including its structure, activation mechanisms, and regulatory signaling pathways. The pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that activate NLRP3 include oxidative stress, Aβ, mitochondrial dysfunction, ion fluxes, gut dysbiosis, and mitochondrial malfunction. Pro-inflammatory cytokines IL-1β and IL-18 are released when the inflammasome assembles with ASC and procaspase-1, leading to caspase-1 activation and pyroptosis. The article investigates both canonical and noncanonical pyroptosis pathways and provides detailed insights into how glial cells-specifically microglia and astrocytes-are involved in NLRP3-mediated neuroinflammation. It has been demonstrated that NLRP3 activation is modulated by several receptor-mediated signaling pathways, including NF-κB, TLR4, TREM2, purinergic, and MAP4K6, which intensify inflammatory responses in the AD brain. Furthermore, the review assesses preclinical and clinical research targeting NLRP3 and its upstream regulators, emphasizing potential treatment options as Simufilam, MCC950, OLT1177, and CY-09. This work highlights the therapeutic potential of the inflammasome and promotes the development of targeted anti-inflammatory treatments to ameliorate AD pathology by elucidating the molecular mechanisms linking NLRP3 to AD progression.},
}

@article {pmid42229579,
year = {2026},
author = {Wang, D and Fan, J and Wang, T and Tang, F and Yao, Q and Ye, X and Qi, X and Tian, M and Lin, X and Shi, J},
title = {Cerebellar rTMS ameliorates cognitive impairment in Alzheimer's disease: A randomized trial.},
journal = {Brain stimulation},
volume = {19},
number = {4},
pages = {103138},
doi = {10.1016/j.brs.2026.103138},
pmid = {42229579},
issn = {1876-4754},
abstract = {BACKGROUND: Developing effective neuromodulatory therapies for Alzheimer's disease (AD) is a critical unmet need. While repetitive transcranial magnetic stimulation (rTMS) shows promise, its optimal targets and mechanisms remain incompletely understood. The cerebellum, a key modulator of large-scale brain network dynamics, represents a novel therapeutic target for addressing the distributed cognitive network dysfunction in AD.

OBJECTIVE: This study aimed to evaluate the cognitive efficacy and safety of cerebellar rTMS in AD and to elucidate its potential mechanism of action through the lens of structural network topology.

METHODS: In this randomized, double-blind, sham-controlled trial, patients with AD were assigned to receive active or sham rTMS targeting the bilateral cerebellar Crus II region. Cognitive assessments were conducted at baseline, post-treatment (4 weeks), and at a 12-week follow-up. Diffusion tensor imaging (DTI) was employed to analyze changes in whole-brain structural network topology.

RESULTS: Compared to the sham group, the active rTMS group demonstrated significantly greater improvement in global and domain-specific cognitive function at 4 weeks, with benefits sustained at the 12-week follow-up. Response rates on the MMSE and MoCA were also significantly higher in the active group. Neuroimaging revealed that active rTMS enhanced global network efficiency, indicated by significant increases in global/local efficiency and clustering coefficient, alongside a decreased characteristic path length, signifying an optimization toward small-world topology. Furthermore, treatment selectively enhanced nodal efficiency within core hubs of the default mode, frontoparietal, and salience networks. Critically, these structural improvements correlated with cognitive gains; increased nodal efficiency in the precuneus and posterior cingulate cortex was associated with improved episodic memory and visuospatial function.

CONCLUSION: Cerebellar rTMS is a safe and effective intervention that confers sustained cognitive benefits in AD. Its therapeutic mechanism likely involves the reinforcement of structural connectivity and enhanced integrative capacity within supraordinate cognitive networks, particularly the default mode network, via cerebello-cortical pathways.},
}

@article {pmid42229590,
year = {2026},
author = {Reddy-Mazzitello, RM and Alexander, J and Skawratananond, S and Sehar, U and Mukherjee, U and Brownell, M and Ballada, S and Reddy, PH},
title = {Associations Between Posttraumatic Stress and Comorbidities of Traumatic Brain Injury and Substance Use Disorders with Alzheimer's Disease in Older Veterans: A Narrative Review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103188},
doi = {10.1016/j.arr.2026.103188},
pmid = {42229590},
issn = {1872-9649},
abstract = {Posttraumatic stress disorder (PTSD) exhibits high rates of comorbidity with Substance Use Disorders (SUDs) and Traumatic Brain Injury (TBI), especially in older adults who are subject to the effects of psychological trauma due to combat exposure, health-related and psychosocial outcomes, and aging. This narrative review explores the associations between PTSD and comorbidities of psychoactive substance abuse and traumatic brain injuries on the incidence of Alzheimer's disease (AD) in veterans aged 55>, according to existing literature. The account of genetic predisposition in reference to the presence of the Apolipoprotein e4 gene was also considered. Biomarkers of AD, including beta-amyloid and phosphorylated tau levels in cerebrospinal fluids (CSF), were analyzed in PTSD, TBI and SUD conditions. This review was conducted as a narrative summary utilizing three separate search engines. Inclusion of data was primarily determined by a single reviewer with a randomized 10 percent of 49 selected studies cross screened by a second reviewer. Two additional independent reviewers incrementally cross- checked the 49 included studies at full-text stages for accuracy and consistency. The literature review found that PTSD and comorbidities of TBI and SUD may share increased incidence of AD and related dementia, however, a causal relationship cannot be implied. Conflicting results on CSF biomarker trends for each comorbidity and complications arising from genetic predispositions indicate a need for future studies to clarify the relationship between PTSD comorbidities on the onset of AD. Expanded biomarker analysis has not yet been assessed. Implications of this review may lead to alternative treatment and care methods for older adults/veterans suffering from psychological impairment to prevent the formation of comorbidities and lower existing elevated risks for AD onset and progression.},
}

@article {pmid42229733,
year = {2026},
author = {Kumari, N and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and HariKrishnaReddy, D},
title = {From capillaries to cognition: decoding neurovascular unit dysfunction and cerebrovascular contributions in Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118107},
doi = {10.1016/j.bcp.2026.118107},
pmid = {42229733},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD), classically defined by abnormal amyloid-β and tau aggregation, is now also understood to profoundly disturb the brain's cerebrovascular system and the integrity of the neurovascular unit (NVU). An ever-growing body of evidence points to NVU dysfunction and neurovascular unit deficits as major contributors to AD pathology. NVU comprises neurons, glial cells, endothelial cells, and pericytes, which together orchestrate cerebral blood flow in the CNS and help maintain the structural and functional integrity of the blood-brain barrier (BBB). Its disruption increases neuronal damage and impairs clearance mechanisms in AD. Interactions between pericytes, astrocytes, smooth muscle cells, neurons, microglia, and NVU endothelial cells support cerebral perfusion, BBB integrity, and metabolic homeostasis. Major pathophysiological events involved in the development of early BBB leakage and neurovascular uncoupling in AD include endothelial impairment, breakdown of tight junctions, thickening of the basement membrane, degeneration of pericytes, and astrogliosis. Activated astrocytes and microglia further exacerbate NVU injury by releasing inflammatory mediators and ROS. Numerous molecular signaling cascades, including PI3K/Akt/mTOR, MAPK/ERK, and NF-κB pathways, are implicated in mechanistic interplay among metabolic perturbations, neuroinflammatory responses, and vascular endothelial damage. Emerging NVU-targeted therapeutic strategies include anti-inflammatory, antioxidant, and vasculoprotective drugs intended to restore BBB integrity, preserving neurovascular coupling, and promoting the removal of amyloid-β. This review synthesizes preclinical and clinical evidence elucidating mechanisms by which capillary-level perturbations lead to cognitive decline, while discussing therapeutic interventions aimed at restoring NVU integrity and preserving BBB architecture. The delineation of cerebral involvement in AD provides support for a potential for timely diagnosis and innovative approaches for treatment.},
}

@article {pmid42229832,
year = {2026},
author = {Singh, VB and Gupta, S and Sella, RN},
title = {Engineered EV-mediated delivery of an anti-amyloid peptide provides neuroprotection in an in vitro Alzheimer's disease model.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {127043},
doi = {10.1016/j.ijpharm.2026.127043},
pmid = {42229832},
issn = {1873-3476},
abstract = {Alzheimer's disease is driven in part by amyloid-β (Aβ) aggregation, oxidative stress, and progressive neuronal dysfunction. Despite various attempts, therapeutic translation remains limited by inefficient delivery of bioactive molecules to neuronal cells. This study presents a surface-engineered extracellular vesicle (EV) platform designed for targeted peptide delivery, assessing its neuroprotective efficacy in an in vitro model of Alzheimer's disease. EVs were obtained from NIH/3T3 cells expressing Lamp2b-RVG and were surface-modified with the β-sheet breaker peptide H102 through CP05-CD63 affinity binding. ATR-FTIR, SERS Raman spectroscopy, high-resolution transmission electron microscopy, nanoparticle tracking analysis, zeta potential measurements, and EV marker profiling demonstrated successful peptide conjugation and vesicle integrity. Aggregated Aβ25-35 was utilized to assess neuronal toxicity in NGF-differentiated PC-12 cells. Peptide-modified EV demonstrated effective, time-dependent cellular uptake and significantly improved cell viability while decreasing membrane damage and intracellular reactive oxygen species levels in comparison to Aβ-treated controls. Treatment with Peptide-modified EV normalized the expression of key genes associated with Alzheimer's, such as APP, Bax, Sirt1, and Stat1, suggesting a coordinated modulation of amyloidogenic, apoptotic, oxidative, and inflammatory pathways. The results indicate that surface-engineered EVs facilitate efficient neuronal delivery of therapeutic peptides and offer multi-level cytoprotection against Aβ-induced neurotoxicity. This study emphasizes the capability of peptide-decorated EV as a multifunctional nanocarrier system for the treatment of Alzheimer's disease.},
}

@article {pmid42230432,
year = {2026},
author = {Liao, Y and Ye, S and Zhao, L and Zhou, M and Wen, Y and Zhu, Y and Huang, J and Zhang, L and Zhang, X and Guo, P and Xie, Y},
title = {Gain-of-function Modulation of TREM2 and its Impact on Amyloid-β and Tau Pathologies in Alzheimer's Disease: A Systematic Review and Meta-analysis of Animal Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42230432},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; Humans ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, hyperphosphorylated Tau accumulation, and chronic neuroinflammation, with microglial function playing a crucial role in modulating these pathological cascades. The microglial receptor TREM2 has emerged as a key regulator of microglial responses to AD-related pathology, and gain-of-function strategies targeting TREM2 have shown substantial therapeutic potential in preclinical models. However, outcomes of these strategies on Aβ and Tau pathologies have exhibited marked heterogeneity across studies, and no systematic integration of the relevant evidence so far. This deficiency has substantially hindered the rational development and clinical translation of TREM2-targeted therapeutic strategies. The objective of this study is to evaluate the effects of TREM2-targeted interventions on Aβ and Tau pathologies in AD animal models. A systematic search of PubMed, Embase, and Cochrane Library identified studies using AD animal models with TREM2-targeted interventions and reporting Aβ or Tau outcomes. This review was registered in PROSPERO (CRD420251131147). A total of 12 studies were included, with overall moderate risk of bias, mainly due to inadequate randomization and blinding. In APP/PS1 mice, TREM2 overexpression significantly reduced Aβ plaque number (SMD = - 0.87; 95% CI, - 1.28 to - 0.47) and plaque area (SMD = - 0.98; 95% CI, - 1.46 to - 0.50), with more pronounced effects observed in younger mice (≤ 7 months), where reductions in insoluble Aβ42 were also observed; phosphorylated Tau levels decreased as well. TREM2 agonist antibodies also reduced Aβ plaque number (SMD = - 2.03; 95% CI, - 2.83 to - 1.24). However, effects on Aβ plaque area, insoluble and soluble Aβ isoforms levels were inconsistent. Antibody treatment also attenuated Tau pathology and Aβ pathology in certain models, including 5XFAD mice or Tau transgenic mice. In addition, both TREM2 overexpression and agonist antibodies could reverse the cognitive impairment of AD animal models. This systematic review and meta-analysis provides the first comprehensive synthesis of preclinical evidence supporting TREM2 gain-of-function modulation as an AD therapeutic strategy targeting both Aβ and Tau pathologies. Our findings reveal that therapeutic efficacy is governed by disease stage, model pathological complexity, and intervention mode. These insights highlight the need for developing stage-specific and pathology-stratified strategies in translational research, establishing TREM2 as a condition-dependent yet promising immunotherapeutic target for AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
Humans
Disease Models, Animal

@article {pmid42230965,
year = {2026},
author = {Jörg, M and Walz, L and Nathal, S and Kristen, M and Lietz, C and Müller, M and Nguyen, VTT and Ruffini, N and Winz, ML and Gerber, S and Endres, K and Helm, M and Friedland, K},
title = {Sex-specific regulation of angiogenin in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42230965},
issn = {1476-5578},
support = {TRR319 RMaP (Project Id 439669440) TPB05//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; TRR319 RMaP (Project Id 439669440) TP A05//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder, highlighting the need to identify novel molecular regulators for effective treatment development. Angiogenin (ANG), a stress-responsive ribonuclease that inhibits apoptosis by generating 5'-tRNA fragments, is a candidate whose expression and regulation in AD is not understood. Here, we investigated ANG expression and regulation using AD cell and animal models, postmortem human brain tissue, and transcriptomic datasets (n = 645). We found that ANG is dysregulated in AD in a sex-dependent manner, altering downstream levels of 5'-tiRNA[Gly-GCC]. Our analysis revealed female-specific molecular subtypes, absent in males: Subtype 1 featured low ANG levels with increased inflammation and neuronal death; subtype 2 exhibited higher ANG expression and intermediate pathology; subtype 3, marked by the highest ANG levels, showed reduced inflammation, slower cognitive decline, and extended survival. These findings position ANG as a key modulator of neuroinflammation and apoptosis in AD, highlighting its potential as a treatment strategy.},
}

@article {pmid42231842,
year = {2026},
author = {Wiechmann, D and Günes, A and Kerz, E and Qiao, Y and Köhne, M and Sprick, U},
title = {Connected-speech digital biomarkers for monitoring transcranial pulse stimulation in Alzheimer's disease: A pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261456294},
doi = {10.1177/13872877261456294},
pmid = {42231842},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) lacks effective disease-modifying therapies and scalable, ecologically valid biomarkers to monitor treatment response. Transcranial pulse stimulation (TPS) is an emerging non-invasive neuromodulation technique with potential to attenuate cognitive decline. Sensitive digital endpoints are needed to quantify intervention-related changes.ObjectiveTo develop and validate connected-speech-derived digital biomarkers as a longitudinal framework for monitoring TPS treatment response in AD.MethodsIn this open-label, single-arm pilot study, 32 patients with AD were compared to cognitively healthy controls. A three-stage framework was implemented: (1) machine-learning classification using linguistic features to derive a parsimonious biomarker panel; (2) construction of a Speech Composite Index (SCI) calibrated against the CERAD total score (CTS); and (3) longitudinal SCI tracking in a sub-cohort receiving TPS.ResultsThe classifier discriminated AD from controls with an AUROC of 0.879 and an F1-score of 0.825. The SCI showed strong convergent validity with global cognition (CTS: r = 0.76, p < 0.001; MMSE: r = 0.76, p < 0.001) and executive function (Stroop interference: r = -0.51, p = 0.015). Longitudinal modeling demonstrated a significant positive deviation from a CERAD-based progression reference (β_time = 0.057 z-units/month, p = 0.013), indicating relative stabilization of speech performance. Individual trajectories were heterogeneous (range -0.053 to +0.336) without significant demographic associations.ConclusionsConnected-speech-derived digital biomarkers can serve as scalable longitudinal endpoints for neuromodulatory interventions in AD. The SCI captures treatment-related dynamics and may support response stratification. Further validation in larger, sham-controlled multicenter studies is needed to establish clinical utility and specificity to TPS.},
}

@article {pmid42231857,
year = {2026},
author = {Rashidi-Ranjbar, N and Churchill, NW and Jerkic, M and Zomorrodi, R and Rotstein, O and Schneider, R and Andreazza, AC and Rajji, TK and Graham, SJ and Munoz, DG and Fornazzari, L and Lim, L and Norris, M and Schweizer, TA and Fischer, CE},
title = {A multimodal evaluation of transcranial photobiomodulation in mild cognitive impairment: Cognitive, metabolic, and neuroimaging outcomes of a pilot randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453911},
doi = {10.1177/13872877261453911},
pmid = {42231857},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration.ObjectiveWe hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default mode network (DMN) functional connectivity (FC).MethodsWe conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults ≥50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 min per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks.ResultsAdherence was high (active 96.9%; sham 94.2%). Adverse events (AEs) were reported by 10 of 20 participants (4 active, 6 sham). No serious AEs occurred. Compared with sham, active tPBM produced greater improvement in global cognition (Mini-Mental State Examination; p = 0.03, d = 1.05) and episodic memory (California Verbal Learning Test-II long-delay recognition; p = 0.02, d = 1.09). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate (L/P) ratio (p = 0.007, d = -1.37). DMN FC increased (p = 0.014, d = 1.25), and plasma IL-6 declined (p = 0.02, r = -0.52).ConclusionsHome-based tPBM was safe, well tolerated, and feasible, with high adherence and mild AEs. Cognitive, metabolic, and network-level findings are consistent with enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind, multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.},
}

@article {pmid42231859,
year = {2026},
author = {Tsutsui, S and Stepanchuk, AA and Stys, JP and Black, SAG and Templeton, GW and Greiner, R and Stys, PK},
title = {Fluorescence spectroscopy and machine learning methods for detection of Alzheimer's disease from circulating white blood cells.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453512},
doi = {10.1177/13872877261453512},
pmid = {42231859},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common cause of dementia whose prevalence is projected to increase significantly in the coming decades. The recent advent of disease modifying therapies is a welcome development; however, it is also now apparent that early treatment maximizes the benefits of these drugs. Therefore, it is important to develop reliable methods of disease detection, preferably from an easily accessible matrix such as blood.ObjectiveTo develop a method for detecting AD from circulating white blood cells using spectral confocal microscopy.MethodsUsing K114-stained wild type and 5xFAD transgenic mouse cortical sections as proof-of-principle, spectral imaging of K114 fluorescence coupled with a signal processing/machine learning pipeline (spectral wavelet decomposition, dimensionality reduction, support vector machine classifier) can reliably distinguish non-plaque background parenchyma in the two strains. We then performed immunoprecipitation of Aβ from peripheral blood mononuclear cells (PBMCs) obtained from non-neurological controls and histopathologically-proven AD cases. We spectrally imaged the immunobeads labeled with K114, then used similar machine learning methods to classify control versus AD samples.ResultsNormal-appearing non-plaque 5xFAD background was reliably distinguished from wild type mouse brain. We could also classify AD with a high degree of reliability (area under the receiver operating curve = 0.95, p = 6.1e-5) and predict neuropathological scores from these blood elements (R = 0.89).ConclusionsOur spectral imaging method, together with automated machine learning analysis of spectral micrographs, using readily obtainable PBMCs from blood, represents a potentially useful approach for detection of AD in living subjects.},
}

@article {pmid42231879,
year = {2026},
author = {Nibila, Y and Sivagami, M},
title = {Artificial intelligence techniques for classification of Alzheimer's disease using neuroimaging data: a review.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1748985},
pmid = {42231879},
issn = {2624-8212},
abstract = {Alzheimer's disease (AD) is a gradually advancing brain disorder marked by memory impairment. The incurable, progressive nature of the disease leads to the dementia stage. Treatment is effective in the early stage, and it can be controlled but not cured. Artificial Intelligence (AI) learning models are used in medical science to detect and classify diseases into specific categories. Features are extracted from medical images and trained using AI learning models to perform an accurate diagnosis of AD. Recent advancements in machine learning (ML) and deep learning (DL) models have demonstrated significant potential in identifying AD across various data modalities, including neuroimaging, genetic information, and clinical assessments. This study focuses on the application of advanced ML and DL techniques in the identification and classification of AD, including regression models, decision trees, random forests, support vector machines (SVMs), k-nearest neighbors (KNNs), ensemble models, convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). Each model is analyzed for its strengths, limitations, and performance metrics, with particular emphasis on the importance of data preprocessing and augmentation techniques to improve model accuracy and robustness. The review highlights that multimodal approaches, particularly the fusion of MRI and PET data, enhance classification accuracy compared to single-modality models. Additionally, transfer learning techniques have shown promise in overcoming data limitations by leveraging pretrained models. The review also highlights the critical role of evaluation metrics in assessing model performance, emphasizing the need for a diverse set that includes accuracy, precision, recall, F1-score, and Cohen's Kappa. The study identifies gaps in the current literature, including underreporting of certain metrics and the need for more comprehensive evaluations, and provides recommendations for future research. Finally, this study discusses the challenges and opportunities in the field, including improving model generalizability, enhancing interpretability, advanced data preprocessing and augmentation, integration with clinical workflows, and multimodal data fusion. This review provides consolidated information that may be useful for researchers, clinicians, and data scientists, offering insights into current trends, challenges, and future research directions in AI-driven AD detection.},
}

@article {pmid42221153,
year = {2026},
author = {Nitrini, R},
title = {Diagnosis of Alzheimer's disease in asymptomatic individuals: a historical perspective.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e2026487},
pmid = {42221153},
issn = {1980-5764},
abstract = {The diagnosis of Alzheimer's disease (AD) based on biomarkers of the pathological process represents a significant change from previous criteria, which required the presence of dementia for AD diagnosis. These new criteria create difficulties in disclosing the diagnosis of AD to asymptomatic individuals. A similar example exists in the history of cognitive and behavioral disorders, where the risk of developing dementia paralytica (DP), a form of neurosyphilis (NS), could be detected even in the asymptomatic phase. Treatment in this phase of DP or in its early symptomatic phase was successful due to the discovery of new therapeutic modalities and new evolutionary biomarkers, which are not yet widely available in AD. This type of biomarker was very important in NS and will certainly be in AD, allowing for faster and less expensive clinical trials.},
}

@article {pmid42221535,
year = {2026},
author = {Kogan, M and Frame, LA and Fahim Devin, M and Prather, C and Alchalabi, T and Ashraf, U and Darling Luczak, B and Fine, H and Ifateyo, A and Ledenac, M and Novak, SS and Yakel, J},
title = {The Integrative Personalized Functional Medicine Approach to Reverse Cognitive Decline: Academic Experience of the First 51 Patients Case Series.},
journal = {Global advances in integrative medicine and health},
volume = {15},
number = {},
pages = {27536130261452680},
pmid = {42221535},
issn = {2753-6130},
abstract = {Background: Alzheimer's disease (AD) and related dementias remain major public health challenges with limited treatment options. Personalized, multimodal integrative approaches have emerged as potential strategies for patients with mild cognitive impairment (MCI) and early-stage AD. Purpose: To describe outcomes from the first 51 participants enrolled in an academic integrative functional medicine program for cognitive decline. Research Design: Retrospective case series, chart analysis. Study Sample: Participants with MCI or AD enrolled at the GW Center for Integrative Medicine (n=51, 2017-2025); 22 remained in the program for ≥2.5 years for long-term cognitive analyses. Data Collection and/or Analysis: Participants underwent serial cognitive assessments [Montreal Cognitive Assessment (MoCA) and/or Boston Cognitive Assessment (BOCA), subset also completing CNS-Vitals and SLAMs at variable intervals]. MoCA was the prespecified primary outcome. Interventions included dietary modification, time-restricted eating, exercise, cognitive training, sleep optimization, individualized supplementation, hormonal management, and 40 Hz gamma-frequency sensory stimulation. Exploratory measures included volumetric brain MRI and Alzheimer's blood biomarkers (Aβ42/Aβ40, p-tau217, NfL) in a subset. Outcomes were summarized descriptively without formal statistical analyses. Results: Among participants with ≥2.5 years of follow-up, mean MoCA increased from 21.7 to 22.5, and 73% (16/22) demonstrated improvement (≥2-point increase) or stabilization (-1 to +1 points). Attrition was high; 29/51 discontinued within the first year, most commonly due to cost, program complexity, and lack of caregiver support. Conclusions: This program demonstrated encouraging preliminary findings of cognitive stabilization or improvement in participants with MCI or AD who remained enrolled. Controlled prospective trials are needed to determine efficacy and mechanisms.},
}

@article {pmid42221706,
year = {2026},
author = {Rangasamy, SB and Raha, S and Dasarathi, S and Pahan, K},
title = {Corrected Version: Sodium Benzoate, A Metabolite of Cinnamon and A Food Additive, Improves Cognitive Functions in Mice After Controlled Cortical Impact Injury.},
journal = {Journal of clinical & experimental immunology},
volume = {11},
number = {1},
pages = {11-26},
pmid = {42221706},
support = {I01 BX005002/BX/BLRD VA/United States ; IK6 BX004982/BX/BLRD VA/United States ; },
abstract = {Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults, and war veterans. Although the research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of effective therapy to halt the pathogenesis of brain injury. Earlier we have reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson's disease and Alzheimer's disease. This study was undertaken to examine the therapeutic efficacy of NaB in controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and inhibits the expression of inducible nitric oxide synthase (iNOS) in hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displayed substantial reduction in depression like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.},
}

@article {pmid42222332,
year = {2026},
author = {Pluta, R and Ułamek-Kozioł, M},
title = {Genomic and proteomic conversion of brain ischemia to Alzheimer's disease.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1804251},
pmid = {42222332},
issn = {2296-634X},
abstract = {Despite many years of extensive research into the etiology and treatment of Alzheimer's disease, based on the importance of amyloid and tau protein as causative factors, these studies have stalled, have not brought any breakthroughs and, most importantly, have not led to any final conclusions. Therefore, the ineffectiveness of the above-mentioned actions and the pressure from the community of people affected by Alzheimer's disease forced the scientific community to change its way of thinking about the etiopathogenesis of this disease. This situation has prompted a group of scientists who have been studying the effects of brain ischemia for years to focus on post-ischemic changes, which-similarly to Alzheimer's disease-predominate in the hippocampus, leading to the development of amyloid plaques, neurofibrillary tangles and ultimately to dementia. In this context, it has been proposed that brain ischemia may play an important role in driving amyloid and tau protein pathology in the development of Alzheimer's disease. In this review, we present an update of extensive experimental and clinical studies conducted over several years on the role of brain ischemia in the neuropathogenesis of Alzheimer's disease. Current advances in understanding the ischemic etiology of Alzheimer's disease have revealed dysregulation of Alzheimer's disease-associated genes, including secretases, amyloid precursor protein, apoptosis, autophagy, mitophagy, tau protein, α-synuclein, apolipoproteins, LRP1, and RAGE. This article presents the relationship between genes which dysregulation is a result of brain ischemia and the cellular and tissue neuropathology characteristic of Alzheimer's disease and their proteins. These observations clearly indicate that, following brain ischemia, changes occur in the expression of Alzheimer's disease-associated genes and in the folding of disease-associated proteins such as amyloid, tau protein, and α-synuclein. This leads to massive neuronal death and disruption of the neuronal network, ultimately leading to the development of Alzheimer's disease-like dementia. Data indicate common genomic and proteomic factors in brain ischemia and Alzheimer's disease. It seems that the brain ischemia model may be useful in determining the role of folding proteins and their genes dysregulation in Alzheimer's disease. In the future, manipulation of genes and proteins associated with ischemia and ischemia-induced Alzheimer's disease will likely provide new hope for developing causal therapies that are urgently needed to prevent or treat Alzheimer's disease. The innovative/novel approach to the etiology of Alzheimer's disease presented in this review will provide stakeholders with a glimpse into the future.},
}

@article {pmid42222363,
year = {2026},
author = {Roamcharern, N and Yubolphan, R},
title = {Overcoming the blood-brain barrier in Alzheimer's disease: translational perspectives on advanced drug delivery platforms.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1810486},
pmid = {42222363},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide and represents a growing public health challenge in aging societies. Despite extensive research efforts, currently approved therapies provide only limited symptomatic benefit and do not halt disease progression. A major obstacle to effective treatment is the blood-brain barrier (BBB), which severely restricts the brain delivery of most therapeutic agents. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome BBB-related limitations by enabling precise control over physicochemical properties such as size, surface characteristics, and material composition. These properties can improve drug solubility, stability, pharmacokinetics, and targeted brain accumulation while reducing systemic toxicity. However, efficient BBB penetration and clinically feasible translation remain major challenges. This review summarizes key design principles for nanoparticles intended for AD therapy and highlights representative platforms with translational considerations, particularly lipid-based and polymer-based nanoparticles. In addition, alternative delivery strategies-including nose-to-brain nanoparticle systems and nanoparticles exploiting receptor-mediated and adsorptive-mediated transcytosis, as well as synaptic dysfunction targeting-are discussed. Collectively, this review outlines current advances and future directions for nanoparticle-mediated therapeutic delivery in AD.},
}

@article {pmid42222852,
year = {2026},
author = {Kale, D and Ramachandran, I and Lakshmi, S and Elumalai, P},
title = {In-vivo evaluation of neuroprotective effect of methanolic extract of Turbinaria ornatacombined with AKG against aluminium chloride-induced Alzheimer's in Wistar rats.},
journal = {3 Biotech},
volume = {16},
number = {6},
pages = {240},
pmid = {42222852},
issn = {2190-572X},
abstract = {UNLABELLED: The progressive neurodegenerative disease known as Alzheimer's disease (AD) is typified by behavioral abnormalities and cognitive deterioration. In the current investigation, the preventive potential of a combination formulation of alkyl glycerol (AKG) and Turbinaria ornata methanolic extract against aluminum chloride (AlCl3)-induced neurotoxicity in Wistar rats was examined. Groups 1 (control), 2 (AlCl3, 100 mg/kg), 3 and 4 (AlCl3 + T. ornata methanolic extract at low and high doses, respectively), and 5 and 6 (AlCl3 + T. ornata methanolic extract + AKG at low and high dosages, respectively) were the six groups that were part of the experimental design. Compared with the AlCl3-treated group, animals receiving the combined treatment, particularly Group 6, showed a significant restoration of antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH), along with a significant reduction in the lipid peroxidation marker malondialdehyde (MDA) in brain and liver tissues. Exposure to AlCl3 caused learning and memory deficits and markedly hampered spontaneous locomotor and exploratory behavior; these effects were mitigated with combination therapy. Additionally, both the cortex and the hippocampus showed changed expression of important genes involved in the amyloid precursor protein (APP) processing pathway, according to qRT-PCR study. The combined treatment groups demonstrated significant modulation of APP pathway-related gene expression relative to the AlCl3 group, indicating an association between the observed biochemical and behavioral improvements and molecular changes in this experimental model. Overall, the results imply that AlCl3-induced neurobehavioral, biochemical, and molecular changes may be lessened by administering T. ornata methanolic extract and AKG together. To identify the independent or synergistic impacts of each component, more research including individual treatment groups is necessary, as the study is restricted to assessing the effects of the combination treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04872-2.},
}

@article {pmid42223785,
year = {2026},
author = {Özkurt, Ç and Köse, S and Karasu, Ç and Kortholt, A and Kelicen-Uğur, P},
title = {Taliglucerase Alfa Reduces Amyloid-β Burden by Restoring Autophagic Pathways in a Neuronal Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42223785},
issn = {1573-6903},
mesh = {Animals ; *Autophagy/drug effects/physiology ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Glucosylceramidase/pharmacology/therapeutic use ; Mice ; *Neurons/drug effects/metabolism ; Humans ; Hippocampus/drug effects/metabolism ; Peptide Fragments ; Cell Line ; Lysosomes/metabolism/drug effects ; Signal Transduction/drug effects ; Recombinant Proteins/pharmacology ; },
abstract = {Intraneuronal amyloid-beta (Aβ) accumulation and autophagic dysfunction are key pathological features of Alzheimer's disease (AD). Mutations in GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are linked to several neurodegenerative disorders, but the role of GCase in AD remains incompletely understood. In this exploratory, proof-of-concept study, we investigated whether taliglucerase alfa (TAL), a recombinant human GCase, may influence intracellular Aβ accumulation by modulating autophagy pathways in a neuronal AD model. Endogenous Aβ accumulation was induced in mouse hippocampal neuronal cells (HT-22) by exposure to low-molecular-weight Aβ1-42 oligomer-enriched assemblies (oAβ1-42), followed by treatment with TAL. Soluble Aβ levels and selected components of the autophagy-lysosome pathway, including GCase, cathepsin B, p62/sequestosome-1 (p62/SQSTM1), and mammalian target of rapamycin (mTOR), were evaluated using Western blotting, ELISA, and RT-PCR. In this in vitro model, TAL treatment was associated with a reduction in intracellular monomeric Aβ levels. This observation was accompanied by changes in mTOR signaling and p62 levels, suggestive of modulation of autophagy-related processes. Overall, these results provide preliminary, hypothesis-generating evidence supporting a potential association between lysosomal GCase augmentation and Aβ-related and autophagy-associated processes in AD. Further studies, including expanded experimental validation and in vivo investigations, are required to clarify the underlying mechanisms and translational relevance.},
}

Animals
*Autophagy/drug effects/physiology
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/metabolism/drug therapy/pathology
*Glucosylceramidase/pharmacology/therapeutic use
Mice
*Neurons/drug effects/metabolism
Humans
Hippocampus/drug effects/metabolism
Peptide Fragments
Cell Line
Lysosomes/metabolism/drug effects
Signal Transduction/drug effects
Recombinant Proteins/pharmacology

@article {pmid42226198,
year = {2026},
author = {Lee, HJ and Hoe, HS},
title = {The CDK4/6 inhibitor abemaciclib attenuates cognitive impairment and neuroinflammation via DYRK1A in human tau transgenic mice.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01318-x},
pmid = {42226198},
issn = {1756-6606},
support = {RS-2024-00357857//National Research Foundation of Korea/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2024-00343370//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)/ ; H0501-25-1001//NIPA (National IT Industry Promotion Agency) to support digital medical devices for AI-based Neurodevelopmental disorders/ ; RS-2026-25492172//NRF/ ; },
abstract = {We recently demonstrated that abemaciclib treatment modulates cognitive function, Alzheimer's disease (AD) pathology, and neuroinflammatory responses in wild-type mice treated with lipopolysaccharide and in 5xFAD mice. In this study, we investigated the influence of abemaciclib treatment on neuroinflammation and cognitive function in 6- or 9-month-old PS19 mice, a P301S mutant tauopathy model. We found that abemaciclib administration suppressed microglial activation in 6-month-old PS19 mice, whereas astrocytic activation was partially attenuated in the entorhinal cortex but not in the hippocampus. In addition, abemaciclib treatment improved short-term and recognition memory and the dendritic spine formation in 6- and 9-month-old PS19 mice. More importantly, abemaciclib administration enhanced short-term and recognition memory in a DYRK1A-dependent manner in 6-month-old PS19 mice. Collectively, our results suggest that abemaciclib treatment alleviates neuroinflammatory responses and cognitive impairment through DYRK1A in 6- or 9-month-old human tau transgenic PS19 mice, highlighting how this multi-kinase-targeting drug could be leveraged for the treatment of neurodegenerative diseases.},
}

@article {pmid42227120,
year = {2026},
author = {Gillet, JN},
title = {Overinvestment in ultra‑rare APOE variants and highly speculative apoE-inhibitor docking risks undermining translational progress in sporadic Alzheimer's disease.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/07391102.2026.2671163},
pmid = {42227120},
issn = {1538-0254},
abstract = {Misclassification of ultra-rare and isoform-defining APOE variants, together with unsupported attempts to dock small-molecule 'inhibitors' to apolipoprotein E (apoE), continues to appear in the structural bioinformatics literature. Such inconsistencies stem from a broader misunderstanding of apoE as a highly flexible, two-domain protein with extensive intrinsically disordered regions (IDRs), a context essential for interpreting sequence variation. A recurring issue is the treatment of the pathogenic ε4 and protective ε2 substitutions as independent rare variants rather than as the canonical APOE isoform-defining polymorphism, a misinterpretation arising, for instance, from inconsistent minor-allele-frequency filtering and leading to overinterpretation of ultra-rare substitutions lacking established clinical relevance. Likewise, no experimental evidence supports stable interactions between apoE and small 'inhibitors' such as donepezil or other acetylcholinesterase drugs that provide only symptomatic benefit in Alzheimer's disease (AD). Docking such small ligands to apoE-frequently using incompatible homology models and outdated molecular-dynamics force fields ill-suited for proteins with large IDRs (e.g. AMBERff03)-tends to generate simulation-artifact cavities and non-biological ligand poses; compounding this, ligand protonation is frequently misassigned, such as the neutral state often attributed to donepezil, leading to meaningless structure-activity relationships. Collectively, these issues risk obscuring the well-established genetic architecture of APOE-associated AD and highlight the need for methodological rigor in in-silico structural modeling.},
}

@article {pmid42227129,
year = {2026},
author = {Andreev, AI and Neganova, ME and Aleksandrova, YR and Salikhova, DI and Belousova, EV and Shedenkova, MO and Sudina, AK and Maksimov, YM and Orlova, EA and Lapshina, MA and Popov, VS and Ahremenko, EA and Goldshtein, DV and Ustyugov, AA and Nebogatikov, VO},
title = {[Glial Progenitor Cell Therapy Improves Mitochondrial Function in the Hippocampus of 5xFAD Mice, but Does Not Restore the Multiscale Structure of Behavioral Stress Response].},
journal = {Molekuliarnaia biologiia},
volume = {60},
number = {2},
pages = {328-344},
doi = {10.7868/S3034555326020096},
pmid = {42227129},
issn = {0026-8984},
abstract = {Cell therapy is increasingly used to treat a variety of medical conditions, including cancer, immune system disorders, and neurodegeneration. Stem cells secrete growth factors, signaling molecules, and extracellular vesicles, that can be used to treat neurological diseases and promote neuronal regeneration. Transgenic 5xFAD mice, which are a model for Alzheimer's disease (AD), were used in this study. The mice were 7 months old and received retro-orbital injections of glial progenitor cells (GPCs) once a week for 4 months. At 11 months, their behavior was analyzed using a multichannel actigraphy system. Brain tissues from the cortex, hippocampus, and midbrain were collected for postmortem analysis of mitochondrial respiratory chain enzyme activity. The results showed that the GPCs injection significantly improved the response of the hippocampal p2 mitochondrial fraction in 5xFAD mice to succinate, reaching a level observed in control animals. A similar trend was also observed for the cytochrome c oxidase complex. The oxygen consumption rate of mitochondria did not differ from that of clinically healthy mice after ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride administration. A similar decrease in the efficiency of the electron transport chain was detected in the midbrain of 5xFAD mice, but no recovery was observed after GPCs treatment. Behavioral differences between non-transgenic and transgenic groups were observed in a multiparameter analysis using the actigraphy system. The behavior of transgenic mice in the treated and untreated groups was similar, while the behavior of non-transgenic mice varied. Additional analysis of locomotor activity and transient events in particular revealed that the activity of the GPCs-treated 5xFAD mice was differed fundamentally compared to other groups. Specifically, GPCs-treated mice exhibited greater number of transitions between intermediate activity states. In contrast, untreated mice showed transitions between extreme activity states, such as from low to high activity or vice versa. These findings suggest that changes in behavior and activity of the AD mice may be associated not only with hippocampal dysfunction, but also with disruptions in midbrain structures.},
}

@article {pmid42227398,
year = {2026},
author = {Wu, X and Zhang, K and Kan, C and Sheng, S and Jing, D and Han, F and Sun, X},
title = {Transmembrane Proteins in Neurodegeneration: Pathophysiology from Alzheimer's to Parkinson's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X451846260403084025},
pmid = {42227398},
issn = {1875-6190},
abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), represent a growing global health burden due to aging populations. These disorders are characterized by progressive neuronal dysfunction, protein aggregation, synaptic impairment, and neuronal loss. Transmembrane proteins, which regulate signal transduction, material transport, and cell communication, have emerged as key contributors to disease pathogenesis. In AD, amyloid precursor protein processing, N-methyl-D-aspartate receptor overactivation, and microglial receptor signaling drive β-amyloid accumulation, excitotoxicity, and neuroinflammation. In PD, α-synuclein aggregation, dopamine receptor dysregulation, mitochondrial dysfunction, and impaired iron homeostasis disrupt neuronal and synaptic integrity. Despite differences in clinical manifestations, both AD and PD share common mechanisms involving abnormal protein folding, altered calcium signaling, and oxidative and endoplasmic reticulum stress, largely mediated by transmembrane proteins. These shared pathways highlight the interconnected nature of these devastating conditions. These proteins also provide opportunities for therapeutic targeting and biomarker development. Current strategies include secretase inhibitors, N-methyl-D-aspartate receptor modulators, dopamine agonists, and emerging approaches targeting α-synuclein and other misfolded proteins. While challenges remain in achieving selectivity, delivery, and clinical efficacy, advances in molecular biology underscore the potential of transmembrane proteins as critical targets for diagnosis and treatment. Ongoing research continues to unravel their complex roles, and future studies will further elucidate their precise involvement in disease progression, offering hope for new interventions. This comprehensive review summarizes current knowledge on the structural and functional roles of transmembrane proteins in AD and PD, their contributions to shared pathological mechanisms, and their potential as biomarkers and therapeutic targets.},
}

@article {pmid42227403,
year = {2026},
author = {Yang, Z and Hou, X and Tan, Y and Tang, L and Ke, Z and Hu, Z and Ye, Q and Meng, H and Xu, Y and Chen, H},
title = {Neuro-navigated rTMS Targeting Left Angular Gyrus Promotes White-Gray Matter Remodelling to Improve Cognitive Function in Amnestic Mild Cognitive Impairment Patients: Evidence for Early Alzheimer.s Intervention.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438627260121063828},
pmid = {42227403},
issn = {1875-6190},
abstract = {INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive neuromodulation technique, has been increasingly applied in early intervention for amnestic Mild Cognitive Impairment (aMCI). However, the mechanism of changes in brain structure after rTMS treatment remains unclear.

METHODS: A total of 54 aMCI patients received neuro-navigation rTMS targeting the left angular gyrus for 4 weeks (rTMS group: n=28; sham group: n=26). All participants received multimodal MRI and cognitive assessments before and after rTMS. A white matter network was constructed, and Local Diffusion Homogeneity (LDH) was calculated to analyse white matter differences. Surface-based morphometry was used to detect cortical changes. In addition, the correlation between these structural alterations and improved cognitive function was analysed.

RESULTS: After rTMS, general cognitive function and episodic memory of aMCI patients significantly improved. Assortativity improved (P=0.039) while hierarchy decreased (P=0.036). Lower LDH was detected in the right hippocampus cingulum fasciculus, left inferior longitudinal fasciculus, right inferior/superior cerebellar peduncle, and right cingulum gyrus. The sulcus depth of the left medial orbitofrontal cortex, left superior frontal/parietal cortex, left middle/inferior temporal cortex, and right lateral occipital cortex was decreased. Improved general cognition was negatively correlated with decreased sulcus depth in left inferior temporal cortex (R=-0.585, P=0.001) and left superior parietal cortex (R=-0.447, P=0.017). Improved memory was negatively correlated with altered LDH in the right inferior cerebellar peduncle (R=-0.427, P=0.037).

DISCUSSION: Our study shows that neuro-navigated rTMS targeting the left angular gyrus can improve cognitive function and mood symptoms in aMCI patients by impacting brain structures, offering new biological evidence for its potential as an early AD intervention.

CONCLUSION: Neuro-navigated rTMS targeting the left angular gyrus improves aMCI cognition, linked to specific brain structural changes, supporting its early intervention value.},
}

@article {pmid42227483,
year = {2026},
author = {Shankar, M and Tiwari, P and Dubey, S},
title = {Phosphodiesterase-5 Inhibitors in Neurodegenerative Diseases: A Path to Cognitive Rescue.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037397181251204145349},
pmid = {42227483},
issn = {1875-5550},
abstract = {Phosphodiesterase type 5 inhibitors (PDE5-Is) have emerged as potential therapeutic agents for neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Originally developed for cardiovascular disorders, PDE5-Is have gained significant attention for their neuroprotective effects due to their ability to modulate intracellular signaling pathways. These inhibitors exert their effects by increasing nitric oxide synthase expression, elevating cyclic guanosine monophosphate (cGMP) levels, and activating protein kinase G (PKG), leading to improved synaptic plasticity, neuronal survival, and cognitive enhancement. By targeting these molecular pathways, PDE5-Is help regulate neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuronal apoptosis, which are key pathological features of neurodegenerative disorders. Several preclinical studies have demonstrated that PDE5-Is can reduce neuroinflammation, enhance neurogenesis, and improve mental performance in animal models of AD, PD, and MS. Additionally, these agents have shown promise in mitigating β-amyloid and tau pathology in AD, improving dopamine signalling in PD, and exerting immunomodulatory effects in MS. Furthermore, emerging research suggests that PDE5-Is may protect against neuronal cell death and improve cognitive function following cerebral ischemia by enhancing cerebral blood flow, reducing excitotoxicity, and promoting neurovascular coupling. Despite these promising findings, the clinical translation of PDE5-Is for neurodegenerative diseases remains in its early stages. Challenges, such as blood-brain barrier permeability, optimal dosing strategies, and long-term safety, must be addressed through further research. Nevertheless, given their multifaceted mechanisms of action, PDE5-Is represent a novel and exciting therapeutic approach that warrants deeper investigation in both preclinical and clinical settings for the treatment of neurodegenerative diseases.},
}

@article {pmid42227779,
year = {2026},
author = {Sharma, DK and Prasad, CS},
title = {Chitosan-based nanocarriers in Alzheimer's disease therapy: Recent developments and future perspectives.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-32},
doi = {10.1080/1061186X.2026.2683967},
pmid = {42227779},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD) is a neurological condition that worsens with time and causes behavioral problems, memory loss, and cognitive decline. It is a major global health concern. Alzheimer's complexity and the blood-brain barrier (BBB) limit effective disease-modifying treatments despite extensive research. The primary goal of conventional pharmacotherapies is to relieve symptoms; however, they frequently have low absorption, a short half-life, and peripheral adverse effects. The use of anti-Alzheimer medications in nanoparticles (NPs) is a potential remedy for these issues. Although many NPs are biocompatible and nontoxic, many are not biodegradable, making them unsuitable for CNS targeting. Chitosan (CS)-based NPs stand out among polymeric nanocarriers as stable, biodegradable delivery systems for central nervous system drugs. In this review, we examine the design, mechanisms of BBB penetration, drug-loading capacity, controlled-release behaviour, and therapeutic efficacy of CS-based delivery platforms, including nanoparticles, nanogels, lipid nanoparticles, polymeric micelles, nanoemulsions, and acetylcholinesterase inhibitor-loaded systems. Furthermore, the benefits of CS-based systems, including improved brain bioavailability, reduced toxicity, intranasal delivery, and support for multifunctional and stimuli-responsive therapeutics, are highlighted. All things considered, chitosan-based drug delivery systems offer a flexible and promising strategy for enhancing AD treatment results.},
}

@article {pmid42216640,
year = {2026},
author = {Kong, Y and Lv, X and Yang, Y and Li, Q and Dai, C and Lin, X and Liu, J and Li, J},
title = {Lactobacillus mucosae Reduces Neuronal Oxidative Stress in Alzheimer's Disease via the Regulation of CB2 Signaling.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {5},
pages = {48598},
doi = {10.31083/JIN48598},
pmid = {42216640},
issn = {0219-6352},
support = {Y20240038//Science and Technology Funds of Wenzhou/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects/physiology ; *Alzheimer Disease/metabolism/drug therapy ; Male ; *Probiotics/pharmacology/administration & dosage ; *Signal Transduction/drug effects ; Disease Models, Animal ; *Receptor, Cannabinoid, CB2/metabolism/drug effects ; Mice, Transgenic ; Mice ; *Neurons/metabolism/drug effects ; *Lactobacillus ; },
abstract = {BACKGROUND: The probiotic Lactobacillus mucosae has been widely shown to have many positive effects. However, its neuroprotective effects and underlying mechanism in Alzheimer's disease (AD) remain elusive.

METHODS: Male APP/PS1 mice were treated for 4 weeks with L. mucosae WMU007, followed by the evaluation of cognitive function, neuronal damage, amyloid-β (Aβ) deposition, and Tau phosphorylation. RNA-seq coupled with Gene Ontology (GO) enrichment analysis implicated L. mucosae WMU007 in modulating oxidative stress in this AD model. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and qPCR were performed to identify the specific mechanism by which this probiotic suppresses oxidative stress in the pathogenesis of AD. In addition, we quantified the levels of classical oxidative stress markers, such as superoxide dismutase 2 (SOD2) and glutathione peroxidase 4 (GPX4). We also examined the expression of cannabinoid receptor type 2 (CB2) and its key downstream regulators in the redox pathway, namely nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), in both animal and cellular models.

RESULTS: Our results showed that treatment with L. mucosae WMU007 significantly decreased cognitive impairment, neuronal damage, Aβ deposits, and Tau phosphorylation in APP/PS1 mice. Activation of CB2 was identified as the key mechanism by which L. mucosae WMU007 reduces oxidative stress in AD. In addition, L. mucosae WMU007 reduced oxidative stress and increased the levels of CB2 pathway-related proteins in vivo and in vitro.

CONCLUSIONS: These results indicate that L. mucosae WMU007 confers neuroprotection in AD by targeting CB2-mediated oxidative pathways, highlighting its therapeutic potential as a novel probiotic intervention.},
}

Animals
*Oxidative Stress/drug effects/physiology
*Alzheimer Disease/metabolism/drug therapy
Male
*Probiotics/pharmacology/administration & dosage
*Signal Transduction/drug effects
Disease Models, Animal
*Receptor, Cannabinoid, CB2/metabolism/drug effects
Mice, Transgenic
Mice
*Neurons/metabolism/drug effects
*Lactobacillus

@article {pmid42216664,
year = {2026},
author = {Wen, T and Zhu, T and Zhou, LY and Ran, Z and Chen, L and Wang, WJ},
title = {Bibliometric analysis of natural medicine in the treatment of Alzheimer's disease: Trends, hotspots, and emerging research fields.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451887},
doi = {10.1177/13872877261451887},
pmid = {42216664},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder whose global prevalence continues to rise, yet treatment options are still limited. Natural medicines, with their potential for multi-target intervention, have become a key direction in AD drug development. However, a systematic overview of research trends in this field based on bibliometric methods is currently lacking.ObjectiveThis study aims to summarize research progress on natural medicines for AD treatment using bibliometric analysis and to identify future research hotspots and trends.MethodsRelevant publications were retrieved from the Web of Science Core Collection. Data visualization and analysis were conducted using VOSviewer, CiteSpace, and R.ResultsA total of 3800 publications were included, involving contributions from 108 countries/regions, 4024 institutions, 18,729 authors, and 706 journals. Publication output showed steady growth, with China and India as the leading contributing countries. Institutions such as the Chinese Academy of Sciences and Kyung Hee University demonstrated high productivity and influence. The research focus has shifted from initial clinical pharmacology and molecular pathology to exploring multi-target mechanisms of natural medicines through network pharmacology and molecular docking. Promising natural agents include Ginkgo biloba, ginseng, curcumin, resveratrol, and Centella asiatica.ConclusionsResearch on natural medicines for AD has progressed steadily over the past two decades, with current emphasis on elucidating multi-target mechanisms using emerging technologies. However, clinical evidence remains limited. Future studies should strengthen multi-omics integration and clinical translation to foster innovative AD prevention and treatment strategies.},
}

@article {pmid42216879,
year = {2026},
author = {Pyun, J and Noor, A and Runwal, P and Mawal, C and Fuller, OK and Egan, CL and Febbraio, MA and Donnelly, PS and Short, JL and Bush, AI and Nicolazzo, JA},
title = {Cu(ATSM) Restores Blood-Brain Barrier Abundance of P-Glycoprotein and Improves Cognitive Function in the APP/PS1 Mouse Model of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00252},
pmid = {42216879},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) peptides in the brain. P-glycoprotein (P-gp), a key efflux transporter at the blood-brain barrier (BBB), plays a crucial role in the clearance of Aβ. Using the APP/PS1 mouse model of familial AD, this study investigated the effect of copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) on brain microvascular abundance and function of P-gp and the associated effects on exogenous Aβ clearance, brain amyloid burden, and cognitive function. Compared to vehicle-treated 10 month-old APP/PS1 mice, Cu(ATSM) (30 mg/kg/day for 56 days) restored brain microvascular P-gp abundance (24.1%) and Cu concentrations (229.8%) as well as significantly reduced brain cortical concentrations of human Aβ42 (hAβ42) (42.1%) in APP/PS1 mice. Cu(ATSM) treatment led to a trend toward improved brain clearance (11.9%) of [125]I-Aβ42 that was cortically injected into APP/PS1 mice compared to vehicle-treated APP/PS1 mice. Importantly, Cu(ATSM) treatment led to significantly improved (43.8% p = 0.0087) learning and long-term spatial memory in APP/PS1 mice, assessed by the Barnes maze paradigm. Inductively coupled plasma mass spectrometric analysis revealed increased Cu concentrations in brain microvessel-enriched fractions. In APP/PS1 mice, Cu(ATSM) restored brain microvascular P-gp abundance, which was associated with lowered cortical hAβ42, and improved long-term spatial memory, indicating neurovascular target engagement accompanied by amyloid lowering and behavioral benefit. Together with established BBB penetration and ongoing safety and tolerability evaluation in neurodegenerative populations, these findings propose Cu(ATSM) as a potential therapeutic application of biometal modulation targeting neurovascular dysfunction and Aβ burden in AD.},
}

@article {pmid42217307,
year = {2026},
author = {Sharma, S and Kumar, V and Arulsamy, S and Kumar, S and Wadhwa, P},
title = {An integrated in silico approach to identify pyridine-based AChE and BChE inhibitors for Alzheimer's disease.},
journal = {Computers in biology and medicine},
volume = {212},
number = {},
pages = {111765},
doi = {10.1016/j.compbiomed.2026.111765},
pmid = {42217307},
issn = {1879-0534},
abstract = {Among all the neural diseases Alzheimer's disease (AD) represents a major and critical global health challenge, along with limited diseases-altering therapeutic interventions efficacy. This study deploys collective approaches of in silico study which includes molecular docking, ADMET profiling, density functional theory (DFT), and MD simulations simulation to evaluate pyridine-based dual inhibitors which can target acetylcholinesterase (AChE PBD ID: 4EY7) and butyrylcholinesterase (BChE PDB ID: 6I0B). From a curated library of 55 ZINC-derived compounds, virtual screening using AutoDock Vina identified lead candidates exhibiting superior binding affinities (-11.5 to - 8.0 kcal/mol for AChE; - 10.9 to - 7.4 kcal/mol for BChE) compared to marketed drugs donepezil and tacrine. Compound 46 emerged as the top AChE inhibitor, while compound 49 demonstrated optimal BChE inhibition. DFT analysis at the B3LYP/6-31G(d) level revealed distinct electronic properties: compound 46 exhibited a wider HOMO-LUMO gap (5.32 eV) correlating with enhanced kinetic stability, whereas compound 49 displayed a narrower gap (5.10 eV) and elevated dipole moment, supporting target-selective binding. Extended MD simulations with 200 ns of total duration confirmed that compounds 46 and 49 (two complexes) have structurally stable conformations compared with each other; however, compound 49 was found to be thermodynamically more stable according to MM-PBSA predicted binding free energy (-54.96 ± 4.36 kcal/mol) than compound 46 (-44.73 + 4.85 kcal/mol). ADMET predictions showed good intestinal absorption and CNS permeability; however, it will be necessary to improve both the solubility of these compounds as well as their CYP3A4-related liability. This multi-tiered computational strategy was able to identify both compounds 46 and 49 as highly promising candidates for further experimental validation as dual cholinesterase inhibitors that will be incorporated into efforts to develop new AD treatment approaches.},
}

@article {pmid42217970,
year = {2026},
author = {Toma, C and Vujosevic, S},
title = {Optical coherence tomography and OCT-angiography in neurologic and neuro-ophthalmologic diseases: Current applications and future perspectives.},
journal = {Handbook of clinical neurology},
volume = {218},
number = {},
pages = {13-32},
doi = {10.1016/B978-0-443-22212-2.00022-7},
pmid = {42217970},
issn = {0072-9752},
mesh = {Humans ; *Tomography, Optical Coherence/methods/trends ; *Nervous System Diseases/diagnostic imaging ; *Eye Diseases/diagnostic imaging ; Retina/diagnostic imaging ; },
abstract = {Optical coherence tomography (OCT) and OCT-angiography (OCTA) have emerged as useful tools for noninvasive imaging in the neurologic field. This chapter elucidates their utility in detecting biomarkers for the diagnosis and monitoring of progression and response to treatment in different prevalent neurologic conditions. The retina, an extension of the central nervous system, presents a unique opportunity for monitoring brain pathology due to its accessibility. Through highly resolved scans of the retina and optic nerve, OCT and OCTA facilitate the identification of subtle clinical changes occurring during neuroinflammatory, neurodegenerative, and ischemic processes in disorders like multiple sclerosis, Alzheimer and Parkinson disease, anterior ischemic optic neuropathies, and papilledema. Peripapillary nerve fiber layer and macular internal retinal layer thickness on OCT, and vessel density in the superficial retina on OCTA seem to be the most sensitive parameters in detecting axonal injury and neurodegeneration. These metrics hold promise as surrogate markers for cerebral alterations. While OCT and OCTA show considerable potential, continued research is necessary to validate their reliability and clinical significance, considering potential confounding factors such as concurrent ophthalmic pathologies. Nonetheless, these advancements represent significant progress toward enhancing the diagnosis, management, and prediction of outcomes in various neuro-ophthalmic disorders.},
}

Humans
*Tomography, Optical Coherence/methods/trends
*Nervous System Diseases/diagnostic imaging
*Eye Diseases/diagnostic imaging
Retina/diagnostic imaging

@article {pmid42218511,
year = {2026},
author = {Lin, H and Zhang, Y and Ni, R and Wang, M and Men, J and Ge, J and Lu, J and Wang, J and Zhang, H and Yang, Y and Zhang, Z and Zhu, Y and Zhao, H and Yen, TC and Wang, J and Shi, K and Rominger, A and Guan, Y and Fang, M and Yu, J and Jiang, J and Zuo, C},
title = {White matter [18]F-florbetapir retention predicts cognitive decline and treatment response in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02098-1},
pmid = {42218511},
issn = {1758-9193},
support = {2022ZD0211606//STI2030-Major Projects/ ; 82021002, 82272039, and 82394434//National Natural Science Foundation of China/ ; },
abstract = {PURPOSE: White matter (WM) signal on [18]F-florbetapir positron emission tomography (PET) is often regarded as nonspecific, yet its biological significance remains unclear. This study aimed to characterize the trajectory, clinical significance, and biomarker correlates of normal-appearing white matter (NAWM) [18]F-florbetapir retention across the Alzheimer's disease (AD) continuum.

METHODS: We analyzed NAWM ¹⁸F-florbetapir retention in 672 participants across the AD continuum from the Alzheimer's Disease Neuroimaging Initiative and two Chinese cohorts. Longitudinal PET, plasma, and cerebrospinal fluid (CSF) biomarkers, as well as lecanemab treatment effects, were evaluated.

RESULTS: NAWM retention followed a distinct trajectory from cortical amyloid, increasing during preclinical stages and plateauing in symptomatic phases. Elevated NAWM ¹⁸F-florbetapir retention independently predicted cognitive decline, correlated with plasma p-tau217 and CSF p-tau/Aβ42 ratio, and showed significant reductions following lecanemab therapy. Combined assessment of cortical and NAWM PET improved diagnostic accuracy for amyloid positivity to 92%. NAWM retention also correlated strongly with plasma and CSF biomarkers in preclinical stages, and mediation analyses indicated that these fluid markers partly explained NAWM-cognition associations.

CONCLUSION: NAWM ¹⁸F-florbetapir retention represents a biologically valid and dynamic biomarker of AD progression, with potential utility for early detection, prognostication, and therapeutic monitoring.},
}

@article {pmid42218670,
year = {2026},
author = {Dong, Y and Xiao, X and Zhuang, XX and Wu, W and Fang, EF and Yang, G and Niu, Z and Lu, JH},
title = {AI-Driven discovery of brain-penetrant mTOR-independent autophagy enhancers for Alzheimer's disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/15548627.2026.2679639},
pmid = {42218670},
issn = {1554-8635},
abstract = {Current Alzheimer's disease therapies offer limited efficacy and are often accompanied by significant side effects, underscoring the urgent need for new treatment strategies. Enhancing autophagy represents a promising therapeutic approach, yet most known autophagy inducers act through the mTOR-dependent pathway, which broadly affects cellular metabolism and proliferation, and their clinical potential is further limited by poor blood-brain barrier (BBB) penetration. To address these twin challenges, an artificial intelligence (AI)-driven platform named DeepDrugDiscovery was developed, shifting the focus from traditional structure-based screening toward a mechanism-centric strategy for identifying mTOR-independent autophagy enhancers with brain penetrability. The platform screened over one million molecules and identified two lead compounds, Ombuin and 2-Hydroxycinnamic acid, which were experimentally shown to clear pathogenic tau and amyloid-β aggregates and restore memory function in both worm and mouse models of Alzheimer's disease. Notably, Ombuin exhibited robust brain exposure, confirming accurate BBB prediction. Released as an open-source resource, DeepDrugDiscovery demonstrates a scalable, AI-powered pipeline for discovering mechanism-based therapeutics.},
}

@article {pmid42220121,
year = {2026},
author = {Zhao, J and Tian, G and Qu, Y and Liu, Y and Wu, W and Dai, L and Zhang, G and An, F},
title = {Research Progress on Alzheimer's Disease with Classical Traditional Chinese Medicine Formulas.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672018401009251117113526},
pmid = {42220121},
issn = {1875-5704},
abstract = {Alzheimer's disease (AD) is caused by complex pathological changes and is a problem that cannot be ignored by the global public health system. Its main clinical manifestations include progressive cognitive impairment, mental and psychological changes, and, in advanced stages, paralysis and loss of self-care ability. The economic and psychological burdens imposed on AD patients and their caregivers have been progressively exacerbating, while the annual expenditures on AD treatment by nations worldwide and by the United Nations have demonstrated a consistent upward trend rather than a decline. The treatment of AD remains challenging, with currently limited therapeutic options available. The advantages of the multi-target, multi-component, safe, and low-toxicity characteristics of Traditional Chinese Medicine (TCM) have attracted public attention, providing ideas for the prevention and treatment of AD and for the development of new drugs. In this study, 27 TCM formulas reported to exhibit preventive and therapeutic effects on AD in basic or clinical research were identified and summarized. TCM can intervene in the progression of AD by clearing Aβ deposition, inhibiting Tau phosphorylation, reducing neuroinflammation, mitigating mitochondrial dysfunction and oxidative stress, and regulating gut microbiota. This review aims to provide evidence for further exploring the role and potential mechanisms of TCM in the prevention and treatment of AD, and to offer insights for the development of new anti-AD drugs.},
}

@article {pmid42220134,
year = {2026},
author = {Singh, I and Dheek, M and Usmani, A and Chauhan, SB and Sinha, A},
title = {Development, Optimization, and Characterization of Donepezil Hydrochloride-loaded Emulsomes with Nigella Sativa Oil for the Treatment of Alzheimer's Disease.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026444242260514094253},
pmid = {42220134},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease is a progressive neurodegenerative disorder where conventional oral delivery of donepezil hydrochloride is limited by poor bioavailability and restricted brain access due to the blood-brain barrier. This study aims to develop an alternative nanocarrier-based delivery system to enhance therapeutic efficacy.

METHOD: Trestearin, phosphatidylcholine, and cholesterol formed a solid lipid core that was used to make emulsomes. TEM was used to characterize emulsomes, while FTIR spectroscopy was used for compatibility tests. The formulation was optimized using the 3-factor, 3-level Central Composite Design.

RESULT: The optimized emulsome formulation demonstrated a stable formulation with a mean particle diameter of 124 ± 3.25 nm, an entrapment efficiency of 74 ± 0.67%, a PDI of 0.209 ± 0.03, with a zeta potential of -0.130 mV. In vitro release study demonstrated a consistent drugrelease pattern, with 84 ± 1.24% of the medication released during the investigation.

DISCUSSION: Based on insights from the thesis, emulsomes incorporating Nigella sativa oil show enhanced neuroprotective potential due to the antioxidant and anti-inflammatory actions of thymoquinone. The intranasal route further supports improved brain targeting by bypassing the blood-brain barrier. The consistency of particle size, strong entrapment efficiency, and sustained drug release align with the reported advantages of emulsome-based formulations discussed in the thesis, reinforcing their promise as an effective approach for Alzheimer's treatment.

CONCLUSION: The central composite design optimization ensures a stable and effective delivery system for the donepezil hydrochloride-loaded emulsomes containing Nigella sativa oil with great potential for novel drug delivery in Alzheimer's disease.},
}

@article {pmid42220141,
year = {2026},
author = {Ahmed, I and Ansari, YA and Parveen, G and Shukla, K and Bhise, M and Singh, S and Shaikh, UP and Ahmed, R and Ansari, I and Kumar, A},
title = {Neuroprotective Phytochemicals Targeting Amyloid and Tau Pathologies.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266446356260226085409},
pmid = {42220141},
issn = {1873-4294},
abstract = {The prevalence of Alzheimer's disease stands at more than 55 million individuals in the world, with estimates showing that the figure will increase to 152 million in 2050. Existing treatment methods are mostly symptomatic and do not address the underlying molecular disruptions, such as oxidative stress, mitochondrial dysfunction, and neuroinflammation. Neurodegeneration mediated by convergent pathways of these processes occurs through Aβ and hyperphosphorylated Tau. This is an overall review summarizing evidence from the PubMed, Scopus, and Web of Science databases as of 2025 on phytochemicals that can address both amyloid and tau pathologies simultaneously. This study presents a comprehensive assessment of more than 100 bioactive compounds across 7 chemical families with dual anti-amyloid and anti-tau effects, without prior reviews that address separate pathological targets or isolated classes of compounds with bioactivity. Major phytochemicals, such as curcumin, resveratrol, and epigallocatechin-3- gallate, suppress the activity of the beta-secretase, prevent the formation of amyloid fibrils, inhibit glycogen synthase kinase-3beta-mediated tau phosphorylation, and promote autophagy-lysosomal clearance. These molecules regulate NF-erythroid-2-related factor 2 signaling to inhibit reactive oxygen species and inhibit NF-κB-mediated neuroinflammation. Preclinical models show reductions in cognitive and neuropathological burden, but bioavailability and blood-brain barrier penetration pose barriers to clinical translation. Developed nanotechnology-based systems of delivery and structural modifications have potential in overcoming pharmacokinetic constraints. This represents a multi-target candidate therapy, a paradigm shift from the single-pathway therapeutics of the past, which may provide disease-modifying strategies beyond symptom management of Alzheimer's disease.},
}

@article {pmid42220203,
year = {2026},
author = {Eyre, B and Bonney, SK},
title = {EXPRESS: A perivascular perspective on the immune impacts in cerebral amyloid angiopathy.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261454165},
doi = {10.1177/0271678X261454165},
pmid = {42220203},
issn = {1559-7016},
abstract = {Cerebral amyloid angiopathy (CAA) is one of the most common small vessel diseases. With the deposition of amyloid beta within the walls of cerebral blood vessels, CAA can result in damage to blood vessels over time and ultimately intracerebral haemorrhage (ICH). Not only is CAA a leading cause of ICH but CAA is commonly observed in Alzheimer's disease (AD), yet there are still no effective treatments for CAA. The pathophysiology of CAA has yet to be fully elucidated but we know the perivascular environment is heavily impacted by the deposition of amyloid within blood vessels. In recent years, there has been an increased interest in the role that perivascular clearance may play in the development of the disease. Additionally, the role of the immune system has also come into question, especially regarding CAA-related inflammation. In this review, we aim to discuss the immune impacts of CAA within the perivascular environment, and probe how specific cells within this environment may be involved in the pathogenesis of CAA. Importantly, we also consider how some of these immune cells may be key treatment avenues to explore.},
}

@article {pmid42220275,
year = {2026},
author = {Ou, J and Hou, K and Fu, Y and Luo, Y and Yu, Q and Shen, M and Jiang, S and Zhu, J and Wang, Y and Lin, K and Lin, Z and Fang, M},
title = {EXPRESS: Brain Microvascular Endothelial Cells: Beyond a Barrier.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261454263},
doi = {10.1177/0271678X261454263},
pmid = {42220275},
issn = {1559-7016},
abstract = {The blood-brain barrier (BBB) has long been regarded as a passive, protective filter for the brain. This review re-evaluates the role of brain microvascular endothelial cells (BMECs)-from viewing them as static structural components to recognizing them as dynamic immunoregulatory sentinels within the neurovascular unit. BMECs actively sense inflammatory and pathogenic signals through pattern recognition receptors, integrate competing pathways such as Wnt/β-catenin and NF-κB, and make context-dependent decisions to balance barrier integrity with immune defense. In response to activation, they orchestrate neuroimmune communication by secreting chemokines, modulating adhesion molecules, and facilitating immune cell trafficking. Dysregulation of these functions contributes to the pathogenesis of various central nervous system disorders, including stroke, Alzheimer's disease, and multiple sclerosis, where BMECs dysfunction drives neuroinflammation and barrier breakdown. Further progress is required to resolve endothelial heterogeneity, develop precise tools for barrier function assessment, and define targeted interventions that modulate the immunoregulatory functions of BMECs in order to explain the mechanistic heterogeneity observed in neurological disorders. These efforts will deepen our understanding of the BBB's role in physiology and pathology, offering new strategies for the prevention and treatment of neurological diseases, and highlight BMECs as active participants in brain immunity and potential therapeutic targets.},
}

@article {pmid42221048,
year = {2026},
author = {Han, Y and Zhou, C and Wang, P and Karako, K and Song, P},
title = {The skin as a sentinel organ for neurodegeneration: An underrecognized target for dementia prevention.},
journal = {Intractable & rare diseases research},
volume = {15},
number = {2},
pages = {156-165},
pmid = {42221048},
issn = {2186-3644},
abstract = {Dementia prevention increasingly requires attention to modifiable systemic inflammatory stressors. In older adults, bullous pemphigoid (BP), herpes zoster (HZ), psoriasis, atopic dermatitis (AD), rosacea, prurigo nodularis (PN), and chronic pruritus are not merely disorders limited to the skin; they may signal or amplify neuroimmune vulnerability. Observational studies link BP with dementia and Alzheimer's disease, HZ with incident dementia and vascular cognitive injury, and psoriasis, AD, rosacea, or PN with smaller but biologically plausible cognitive risks. The proposed skin-brain axis integrates cytokine spillover, endothelial activation, blood-brain barrier dysfunction, BP180/ BP230 autoantigen sharing, varicellazoster virus neurotropism and vasculopathy, barrier failure, dysbiosis, itching-induced fragmented sleep, and medication or frailty-related cognitive toxicity. Clinically, cognitive impairment also worsens skin surveillance, hygiene, topical adherence, and recognition of pain, itching, infection, or blistering. Although causality and dementia prevention remain unproven, the evidence justifies proactive dermatological care in older adults and greater cognitive vigilance in older patients with severe inflammatory or pruritic dermatoses. Recombinant zoster vaccination, prompt antiviral therapy, steroid-sparing BP strategies, modern anti-inflammatory treatment for AD, psoriasis, and PN, and systematic attention to sleep, itching, caregiver capacity, and the medication burden are practical, low-regret steps while prospective brain-relevant trials are developed. This translational framework highlights mechanisms clinicians can now interrupt and endpoints investigators can soon measure. We propose that the skin should be recognized as a sentinel organ for neurodegeneration and that dermatological disease represents a potentially modifiable contributor to cognitive decline.},
}

@article {pmid42212431,
year = {2026},
author = {Kim, JP and Lee, H and Kim, BH and Kang, H and Shin, D and Yim, S and Kim, S and Seo, SW and Kim, HN},
title = {Genetically prioritized druggable targets for amyloid-β pathology highlight ACE as a therapeutic candidate in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261454540},
doi = {10.1177/13872877261454540},
pmid = {42212431},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by a neuropathological cascade that begins with amyloid-β (Aβ) deposition. The recent success of disease-modifying drugs targeting Aβ has demonstrated that modulating amyloidopathy can yield clinical benefits, underscoring the need for additional drugs affecting amyloid pathology.ObjectiveTo identify novel drug targets associated with Aβ accumulation in AD using Mendelian randomization (MR) analysis of the druggable genome.MethodsWe performed MR analysis on expression quantitative trait loci (eQTLs) of the druggable genome in relation to Aβ accumulation using summary-data-based MR (SMR). Blood eQTL data were obtained from the eQTLGen consortium, and brain eQTL data from BrainMeta and PsychENCODE, while Aβ positron emission tomography (PET) genome-wide association study data were derived from 11,816 non-Hispanic White participants across 13 cohorts. Co-localization analysis was conducted to enhance the reliability of the MR results, and additional validation was performed using blood and brain protein quantitative trait loci (pQTLs) as instrumental variables.ResultsThe SMR and co-localization analyses revealed causal associations between the druggable genome and Aβ accumulation, with APH1B identified in blood eQTL data and ACE, APH1B, and CR1 identified in brain eQTL data. Further analysis using pQTL data confirmed causal associations for ACE and CR1, with ACE showing a negative association with Aβ PET uptake.ConclusionsThese findings highlight potential target genes for AD treatment, and the protective effect of ACE against amyloid pathology suggests that alternative medications to ACE inhibitors may be preferred for blood pressure management in the context of AD. Overall, our study demonstrates the potential of MR to facilitate drug repurposing for AD.},
}

@article {pmid42213912,
year = {2026},
author = {Wilson, S and Beswick, E and Popp, Z and Rahman, S and Bhogal, S and Whitfield, T and Low, S and Khan, R and Tolley, C and Walker, Z and Au, R and Slight, SP},
title = {Acceptability of Technologies to Support Early Dementia Detection: Qualitative Study With the Boston University Alzheimer's Disease Center Cohort.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e84004},
pmid = {42213912},
issn = {1438-8871},
mesh = {Humans ; Aged ; Female ; *Dementia/diagnosis ; Male ; Boston ; *Alzheimer Disease/diagnosis ; Digital Health ; Cognitive Dysfunction/diagnosis ; Cohort Studies ; Aged, 80 and over ; Early Diagnosis ; Qualitative Research ; *Patient Acceptance of Health Care ; },
abstract = {BACKGROUND: Dementia is on the rise globally due to increasing life expectancies and population growth. Digital technologies may help detect early signs, enabling timely interventions to slow or reverse cognitive decline. However, to support the successful implementation of these digital technologies into health care settings, they must be acceptable to target users. Older adults and those with mild cognitive impairment (MCI) are at risk of developing dementia in later life and need to be able to use these technologies in order for this intervention to be approved and implemented in clinical practice.

OBJECTIVE: This study explored the perspectives of older adults and those living with a clinical diagnosis of MCI on the acceptability of using various digital technologies that have the potential to support early dementia detection.

METHODS: Participants were recruited from Boston University's Alzheimer's Disease Research Center. Participants selected at least 2 technologies from 9 different wearables and software to use for 2 weeks, at 3-month intervals, over a total duration of 2 years. A subgroup of self-selecting participants was interviewed after the first 2 weeks of use to gather initial perspectives regarding the acceptability of using the digital technologies. An inductive framework thematic analysis approach was used, assisted by NVivo (version 14.23.2; QSR International).

RESULTS: In total, 13 individuals living with a clinical diagnosis of MCI and 11 adults aged 65 years and older were interviewed. Our analysis identified five key themes: (1) gamification, (2) wearability, (3) user guidance, (4) burden of use, and (5) usefulness. Gamified apps were generally liked, although users with little experience of digital games needed time to adjust. Wearables resembling everyday accessories (eg, watches) were preferred, but complaints about tight or uncomfortable straps were frequently reported. Clear instructions were critical to support correct use, but many participants would have liked more troubleshooting support when technical issues arose. The use of 5 or more devices led to a high burden, especially when devices had practicality issues such as not being waterproof. Devices offering personal feedback were perceived as useful to satisfy personal interests, though some questioned their usefulness within health care. Participants raised concerns about losing valued personal interactions with health care professionals and questioned how their existing health conditions and treatment for such conditions may affect the validity of the data collected by the devices.

CONCLUSIONS: These findings can guide researchers in choosing appropriate devices and minimizing burden. Future work should explore the views of those experiencing digital exclusion to ensure equitable access to dementia-detection technologies.},
}

Humans
Aged
Female
*Dementia/diagnosis
Male
Boston
*Alzheimer Disease/diagnosis
Digital Health
Cognitive Dysfunction/diagnosis
Cohort Studies
Aged, 80 and over
Early Diagnosis
Qualitative Research
*Patient Acceptance of Health Care

@article {pmid42214568,
year = {2026},
author = {Zhong, RF and Chen, ZQ and Li, SF and Jiang, JG},
title = {Neuroprotective effects of Uncaria rhynchophylla alkaloid extracts against amyloid-β toxicity via regulation of oxidative stress pathways.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121918},
doi = {10.1016/j.jep.2026.121918},
pmid = {42214568},
issn = {1872-7573},
abstract = {Uncaria rhynchophylla is a important medicinal plant in Chinese traditional medicine for the treatment of neurological disorders, its alkaloid-rich constituents are considered the primary bioactive components responsible for its effects on the central nervous system.

AIM OF THE STUDY: This study aimed to investigate the neuroprotective effects of U. rhynchophylla alkaloid extract (URAs) against amyloid-β (Aβ)-induced neurotoxicity and oxidative stress, and elucidate underlying molecular mechanisms.

MATERIALS AND METHODS: URAs was prepared and characterized by LC-MS/MS for chemical profiling. The neuroprotective effects were evaluated using transgenic C. elegans CL2006 and CL2355, and H2O2-induced PC12 cells. In C. elegans, paralysis assay, Aβ deposition, and chemotaxis behavior were assessed. Oxidative stress markers including reactive oxygen species (ROS), lipofuscin accumulation, lipid peroxidation (MDA), and antioxidant enzyme activities (SOD, CAT) were measured. Quantitative real-time PCR was performed to examine the expression of genes of related signaling pathways. In PC12 cells, cell viability, ATP levels, and oxidative stress were evaluated.

RESULTS: URAs treatment significantly delayed Aβ-induced paralysis, reduced Aβ deposition, and improved chemotaxis behavior in transgenic C. elegans, while decreasing ROS, lipofuscin, and MDA, and increasing SOD and CAT activities. Furthermore, URAs modulated the expression of genes involved in Aβ metabolism, proteasome function, and antioxidant defense, and significantly suppressed the expression of p38 MAPK signaling pathway components.

CONCLUSION: Our findings demonstrate that URAs exert neuroprotective effects against Aβ toxicity and oxidative stress through multi-target mechanisms involving enhanced antioxidant defense, regulated proteostasis, highlighting their therapeutic potential for AD intervention.},
}

@article {pmid42214747,
year = {2026},
author = {Long, X and Shen, R and Yang, Y and Xu, Y and Wang, Y and He, Y and Xie, Y and Xie, X and Gao, D and Pang, X and Du, L},
title = {Isoquercetin-ligustrazine co-polymorph attenuates hypoxia-accelerated Alzheimer's disease by suppressing PERK-CHOP-mediated ER stress.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115856},
doi = {10.1016/j.expneurol.2026.115856},
pmid = {42214747},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD), a neurodegenerative disorder predominantly affecting the elderly population, is frequently associated with hypoxic conditions, including obstructive sleep apnea and other age-related comorbidities. Arising from various pathological conditions, chronic hypoxia may contribute to the acceleration of AD progression. However, the precise mechanisms underlying hypoxia-induced cellular stress responses, particularly those involving ER stress and the PERK pathway, remain insufficiently explored. In this study, the therapeutic effects of a co-polymorph combining Isoquercetin and Ligustrazine (ILCP) on AD-related pathologies aggravated by chronic hypoxia were investigated. ApoE3/4 transgenic mice were exposed to hypoxic conditions for four weeks; results on oxidative stress levels, β-amyloid (Aβ) deposition, and neuronal apoptosis were assessed. Chronic hypoxia was found to intensify PERK pathway activity, elevate neuronal damage, and further aggravate AD-associated cognitive deficits. ILCP administration was associated with reduced PERK pathway activation, resulting in reduced oxidative stress, alleviated neuronal damage, and preserved synaptic plasticity. These findings support a role for PERK-CHOP signaling in hypoxia-driven AD pathology and suggest a potential link between ILCP treatment and modulation of this pathway.},
}

@article {pmid42216035,
year = {2026},
author = {Ibrahim, KS and Albaker, A and Abd-Elrahman, KS and Ferguson, SSG},
title = {Blocking estrogen receptors restores surface mGluR5 but not downstream signaling in female APP/PS1 Mice.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01314-1},
pmid = {42216035},
issn = {1756-6606},
support = {195977/CAPMC/CIHR/Canada ; 148656/CAPMC/CIHR/Canada ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. Deposition of β-amyloid (Aβ), a hallmark of AD pathology, disrupts metabotropic glutamate receptor-5 (mGluR5) regulation of autophagy and accelerates disease progression in male AD mouse models. Yet, mGluR5 contribution to Aβ pathology is not observed in female AD mice, suggesting a distinct sex-selective profile. Given that estrogen receptors (ERs) form functional complexes with mGluR5 selectively in females, we assessed the role of ER activity in mGluR5 expression and downstream signaling in APPswe/PS1ΔE9 (APP/PS1) mice. We report here that mGluR5 cell surface expression is elevated in male but reduced in female APP/PS1 cortex relative to sex-matched wildtype controls, with total receptor expression remaining unchanged in both sexes. Treatment with the ER blocker, ICI 182,780, restored mGluR5 cell surface expression in female APP/PS1 mice but failed to rescue GSK3β and ULK1-regulated autophagy signaling. These findings indicate that male and female mGluR5 are embedded within intrinsically distinct signaling interactomes that are independent of ER regulation.},
}

@article {pmid41963989,
year = {2026},
author = {Digma, LA and Young, CB and Winer, JR and Cody, KA and Younes, K and Sheng, J and Insel, PS and Rissman, RA and Sperling, R and Mormino, EC},
title = {Continuum of Core 1 biomarkers in preclinical Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41963989},
issn = {1758-9193},
support = {K99AG071837/NH/NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; K99AG071837/NH/NIH HHS/United States ; AARFD-21-849349/ALZ/Alzheimer's Association/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Biological Staging for Alzheimer’s disease (AD) in clinically unimpaired (CU) individuals is critical for early detection efforts. In this study, we evaluated whether Core 1 biomarkers (plasma p-tau217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predict progression of downstream biomarkers and cognition.

METHODS: We used baseline plasma p-tau217 and amyloid-PET, and longitudinal tau-PET, atrophy, and cognition data from the recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. PET data were used to identify participants within AD Biological Stage A (amyloid-PET positive and medial temporal tau-PET negative). Within these Stage A participants, linear mixed effects models were used to examine associations between baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether p-tau217 and amyloid-PET burden within this group were associated with higher risk of progression to Biological Stage B+ (tau-PET positive in the medial temporal lobe). In our statistical models, we included covariates for age, sex, and APOE4 carriage.

RESULTS: Of 335 A4 participants with complete biomarker data, 222 were identified as being in Biological Stage A. Among Biological Stage A CU, baseline plasma p-tau217 and amyloid-PET burden were associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean [SD] follow-up time for tau-PET: 4.2 [2.1] years and MRI: 4.2 [1.9] years), as well as faster cognitive decline (mean [SD] follow-up time for PACC: 5.7 [1.6] years) (all p < 0.05). Plasma p-tau217 and amyloid-PET burden were also associated with higher risk of progression to Biological Stage B+.

DISCUSSION: In CU individuals in the initial stage of AD (Biological Stage A), early changing AD biomarkers provide prognostic information of downstream markers of disease. Evaluation of the utility of these measures in a real-world setting is warranted.

TRIAL REGISTRATION: The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2013. The study is registered with ID NCT02008357. Screening and data collection for the study began in April 2014.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02044-1.},
}

@article {pmid42001005,
year = {2026},
author = {Bayar, E and Cengiz, T and Erdoğan, F and Coşkun, HS and Tomak, Y},
title = {Impact of comorbidities on preoperative and postoperative outcomes in hip fracture patients.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {42001005},
issn = {1471-2318},
abstract = {BACKGROUND: Hip fractures represent a major public health concern due to their increasing incidence in the aging population and their association with significant morbidity and mortality. Comorbidities are known to complicate both the surgical management and rehabilitation process, yet their specific impact on outcomes remains variable across studies.

OBJECTIVE: This study aimed to determine the prevalence and distribution of comorbidities in patients who presented with hip fractures and underwent surgical treatment, to evaluate perioperative and postoperative risk factors retrospectively, and to compare these findings with the existing literature.

METHODS: A retrospective descriptive analysis was conducted on 589 patients aged ≥ 60 years who were surgically treated for hip fractures between 2013 and 2024 at a tertiary university hospital. Demographic characteristics, surgical protocols, anesthesia types, revision rates, infection, dislocation, mobilization outcomes, hospital stay, intensive care admissions, and mortality were systematically analyzed in relation to comorbidity profiles and the number of comorbidities. Statistical analyses included chi-square, Fisher’s exact test, Mann-Whitney U, and Kruskal-Wallis tests, with p < 0.05 considered significant.

RESULTS: Hypertension (59.1%), diabetes mellitus (33.6%), coronary artery disease (21.4%), and Alzheimer’s disease (21.4%) were the most frequent comorbidities. Revision surgery was significantly associated with diabetes mellitus and congestive heart failure. Diabetes mellitus, coronary artery disease, and chronic renal failure were strong predictors of postoperative infection. While the mean hospital stay was significantly prolonged in patients with ≥ 3 comorbidities, mortality was significantly associated only with oncological diseases and chronic renal failure. Contrary to expectations, no significant association was found between overall mortality and the number of comorbidities.

CONCLUSION: Comorbidities, particularly diabetes mellitus, congestive heart failure, oncological diseases, and chronic renal failure, substantially influence surgical outcomes, postoperative complications, and hospitalization in hip fracture patients. However, the number of comorbidities alone was not a predictor of mortality, highlighting the importance of the type rather than the quantity of comorbid conditions. These findings underscore the need for individualized perioperative planning and comprehensive patient counseling to reduce risks and improve postoperative outcomes.},
}

@article {pmid42210804,
year = {2026},
author = {Devanand, DP and Huey, ED and Qian, M and Wei, R and Motter, JN and Nedic, L and Andrews, HF and Deliyannides, DA and Maayan, L and Graff, J and Deehan, E and Acosta, EP and Zanderigo, F and Goldberg, TE},
title = {Valacyclovir Treatment in Mild Cognitive Impairment: The VALMCI Randomized Clinical Trial.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000735},
pmid = {42210804},
issn = {1546-4156},
abstract = {BACKGROUND: Evidence from neuroscience, epidemiology, and electronic health records studies implicates herpes simplex viruses (HSV) as potentially etiologic for Alzheimer disease (AD).

METHODS: The VALMCI study was conducted in a research outpatient clinic specializing in memory disorders. The efficacy and side effects of valacyclovir 4 g/day were compared with placebo in a 12-month pilot, randomized, double-blind trial of participants with mild cognitive impairment (MCI), seropositivity to HSV1 or HSV2, and positive 18F-florbetapir PET scan.

RESULTS: Totally, 42 of 50 participants (84%) completed the trial. In linear mixed-effects model analyses with age, sex, and apolipoprotein E e4 genotype as covariates, change in the primary outcome of 18F-florbetapir PET mean SUVR was not significant with least-squares mean difference -0.01 (95% CI: -0.12 to 0.10; P=0.82). For secondary cognitive and functional outcomes, PACC composite z-score showed the least square mean difference 0.16 (95% CI: -0.17 to 0.49; P=0.32), and ADCS-ADL-PI score showed the least square mean difference 1.96 (95% CI: -0.43 to 4.34; P=0.11).

CONCLUSION: The results do not support the use of valacyclovir in the treatment of individuals with MCI with HSV seropositivity and PET amyloid positivity.},
}

@article {pmid42211120,
year = {2026},
author = {Song, H and Yang, M and Wu, S and Dai, Q and Qin, W and Xie, W and Chen, Y and Jiang, X and Zhang, X and Deng, X and Ouyang, C and Zhang, Y and Liu, X and Zhu, Y and Huang, G},
title = {Andrographolide attenuates microglial senescence in Alzheimer's disease mice by suppressing the STAT3 signaling.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116033},
pmid = {42211120},
issn = {2589-0042},
abstract = {Andrographolide (AP), a diterpenoid extracted from Andrographis paniculata, has emerged as a promising treatment for Alzheimer's disease (AD) in preclinical studies, but the underlying mechanisms remain incompletely defined. Here, we demonstrated that AP treatment improved cognition performance and reduced amyloid-β (Aβ) plaque accumulation in 5×FAD transgenic mice of both sexes, by mitigating microglial senescence. Proteomic analysis revealed that AP markedly decreased cholesterol content in the cerebral cortex. Using an in vitro low-density lipoprotein-induced senescence model, we found that AP significantly alleviated senescence in BV2 microglia while enhancing their phagocytic capacity. Mechanistically, AP mitigated microglial senescence by inhibiting STAT3 signaling. Overall, these findings identify a previously unrecognized immunometabolic mechanism for AP in the treatment of AD.},
}

@article {pmid41928225,
year = {2026},
author = {Kato, M and Isazawa, A and Ohki, A and Fujita, A and Araki, M and Yanaizu, M and Kino, Y},
title = {Functional sQTLs regulating PTK2B exon 31 splicing uncover an RNA-dependent modulation of its kinase activity and cellular phenotype.},
journal = {Cell communication and signaling : CCS},
volume = {24},
number = {1},
pages = {},
pmid = {41928225},
issn = {1478-811X},
support = {19J15024//Ministry of Education, Culture, Sports, Science and Technology/ ; 19K07982//Ministry of Education, Culture, Sports, Science and Technology/ ; },
abstract = {BACKGROUND: Genome-wide association studies have shown that polymorphisms in PTK2B (Protein Tyrosine Kinase 2 Beta), encoding the calcium-sensitive tyrosine kinase PYK2 (Proline-rich tyrosine kinase 2), are associated with an increased risk of Alzheimer’s disease (AD). However, it remains unclear which genetic variants of PTK2B are functionally important. A recent transcriptome-wide association study has identified alternative splicing of exon 31 in PTK2B as being associated with AD, and proposed rs2251430 as the relevant splicing quantitative trait locus (sQTL). Here, we aimed to elucidate the regulatory mechanisms and functional significance of exon 31 splicing.

METHODS: Alternative splicing of exon 31 was evaluated using publicly available RNA-seq data. To investigate the regulation of exon 31 splicing, we performed RT-PCR, RNA pull-down assays, Liquid Chromatography–Tandem Mass Spectrometry, and RNA immunoprecipitation. Western blotting, immunofluorescence, and co-immunoprecipitation analyses were conducted to examine the effects of exon 31 and its polymorphisms on PYK2 protein expression and function. The impact of exon 31 on cellular phenotypes was further assessed using antisense oligonucleotide (ASO) treatment in HeLa and HMC3 cells.

RESULTS: We detected exon 31 skipping in certain human cell types, but not in mice, and observed its increase in microglia during AD progression. We then identified rs751019 and rs751018, both located near rs2251430, as sQTLs that affect exon 31 splicing, with rs751019 having a greater impact. Among RNA-binding proteins that interact with the surrounding sequence of rs751019, PCBP1 and PCBP2 were found to redundantly regulate exon 31 inclusion. PYK2 lacking exon 31 exhibited reduced protein expression and kinase activity, which in turn resulted in diminished phosphorylation of its substrate, GSK3β, with little change in calmodulin binding and intracellular localization. Moreover, ASO-induced exon 31 skipping decreased cell migration in a wound healing assay. It also increased multinucleation in human microglia-like HMC3 cells, a process recently identified in protective microglia.

CONCLUSIONS: Our study validates rs751019 and rs751018 as functional sQTLs that influence PTK2B exon 31 splicing. It also identifies species-specific alternative splicing of exon 31 as a modulator of PYK2 expression and kinase activity, thereby linking sQTL-associated genetic variants to molecular and cellular changes that may underlie AD pathogenesis.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-026-02835-x.},
}

@article {pmid42167701,
year = {2026},
author = {Hou, P and Li, X and Yan, Y and Lu, Q and Wang, J and Yuan, M and Wang, X and Wang, X},
title = {Polyethylene terephthalate microplastics activate AKT1 signaling and induce neurotoxic responses in SH-SY5Y cells.},
journal = {Toxicology and applied pharmacology},
volume = {513},
number = {},
pages = {117873},
doi = {10.1016/j.taap.2026.117873},
pmid = {42167701},
issn = {1096-0333},
abstract = {Microplastic exposure has emerged as a growing environmental health concern, with increasing evidence suggesting potential effects on the nervous system. However, the molecular basis by which polyethylene terephthalate (PET) contributes to Alzheimer's disease (AD)-related neurotoxicity remains unclear. This study examined whether PET induces neuronal injury by activating the AKT1 signaling pathway. Network toxicology integrating PubChem, STITCH, SwissTargetPrediction, OMIM, TTD, and GeneCards was used to identify PET-associated targets relevant to AD. Core targets were analyzed with Cytoscape, followed by GO and KEGG enrichment using R and clusterProfiler. Molecular docking and molecular dynamics simulations characterized the interaction between PET and AKT1. For in vitro validation, SH-SY5Y cells were treated with 100 μg/mL PET for 24 h or 48 h to detect cytotoxicity and molecular alterations. Four experimental groups were set in this study: Control, PET, PET + MK2206 (1 μM) and MK2206 (1 μM) single treatment groups. PET exposure reduced cell viability, increased intracellular reactive oxygen species (ROS) levels, and enhanced AKT phosphorylation at Ser473, while MK2206 attenuated these effects. These research results show that PET microplastics can induce neurotoxic reactions by activating the AKT1 pathway.},
}

@article {pmid42201342,
year = {2026},
author = {Aydın, Ş and Dalkılınç, E and Özdemir, S and Küçükler, S and Çomaklı, S and Adıgüzel, A},
title = {Neuroprotective effects of luteolin against aluminum-induced brain injury via chelation and antioxidant pathways.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42201342},
issn = {1432-1912},
abstract = {Aluminum (Al) is a widespread environmental neurotoxin linked to several neurodegenerative conditions through oxidative stress, inflammation, and apoptosis. Because it is present in food, water, pharmaceuticals, and consumer products, chronic exposure is nearly unavoidable and poses a public health concern. Luteolin (LUT), a natural flavone with antioxidant, anti-inflammatory, and metal-chelating properties, has emerged as a potential neuroprotective agent. This study investigated the protective effects of LUT against aluminum chloride (AlCl3)-induced neurotoxicity in rats. Sprague-Dawley rats received AlCl3 (4.2 mg/kg, i.p.) alone or together with LUT (25 or 50 mg/kg, p.o.) for 30 days. Behavioral performance was evaluated using novel object recognition and open-field tests. ICP-MS was employed to quantify brain Al levels, and complementary analyses were conducted to assess oxidative stress, neuroinflammation, apoptosis-related gene expression, neuroplasticity markers (BDNF, c-Fos), and cholinergic function (AChE). AlCl3 exposure significantly increased brain Al accumulation and induced oxidative stress, inflammation, apoptosis, and behavioral deficits. Although LUT co-treatment led to an apparent increase in total brain Al, this rise is likely attributable to the formation of Al-LUT complexes. This interpretation is supported by the marked reduction in Al-induced oxidative stress, apoptosis, and inflammation, accompanied by improved behavioral outcomes. This evaluation reveals that LUT provides protection in an environmental Al neurotoxicity model, offering insights beyond classical Alzheimer's disease contexts. Although its antioxidant and anti-inflammatory effects are well documented, evidence for its efficacy against environmentally induced Al neurotoxicity is still lacking.},
}

@article {pmid42202469,
year = {2026},
author = {Jessen, F and Dell'Agnello, G and Zimmer, JA and Sapin, C and Dichter, S and Doty, E and Epelbaum, S and Evans, CD and Hauck, PM and Khanna, R and Brooks, DA and Sims, JR and Agosta, F and , },
title = {Efficacy and safety of donanemab in the European eligible population: TRAILBLAZER-ALZ 2 post-hoc analyses.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100605},
doi = {10.1016/j.tjpad.2026.100605},
pmid = {42202469},
issn = {2426-0266},
abstract = {BACKGROUND: In the European Union (EU), donanemab is indicated in adults with early symptomatic Alzheimer's disease who are apolipoprotein E ε4 non-carriers or heterozygotes. Among these, patients without superficial siderosis at baseline, uncontrolled hypertension, or anticoagulant use are eligible.

OBJECTIVE: To assess efficacy and safety of donanemab in the EU-eligible population.

METHODS: A post-hoc conservative hybrid imputation method was implemented for clinical efficacy analyses during the TRAILBLAZER-ALZ 2 placebo-controlled period. In the 78-week long-term extension (LTE) participants in the early-start (randomised to donanemab) and delayed-start (randomised to placebo with donanemab initiation during the LTE) groups were compared to a propensity-weighted external control. Participants were switched to placebo after meeting amyloid-based treatment course completion criteria.

RESULTS: By 76 weeks, donanemab-treated participants in the EU-eligible population had a mean Clinical Dementia Rating Scale (CDR)-Sum of Boxes change from baseline difference from placebo of -0.7 points (95% confidence interval, -1.0, -0.4) and a 40.3% lower risk of disease progression to the next stage (per CDR-Global score). Treatment benefit increased over 154 weeks for non-carriers and heterozygotes, including those meeting treatment course completion criteria by 52 or 76 weeks. In the placebo-controlled period, 119 (19.5%) and 49 (8.0%) donanemab-treated eligible participants experienced amyloid-related imaging abnormalities-edema/effusion and infusion-related reactions, respectively. Safety findings were similar among donanemab-treated participants in the placebo-controlled period and LTE delayed-start group.

CONCLUSIONS: Consistent with previous TRAILBLAZER-ALZ 2 and LTE findings, donanemab significantly slowed disease progression compared to controls with a manageable safety profile in non-carriers and heterozygotes.},
}

@article {pmid42202980,
year = {2026},
author = {Sánchez-Valle, R and Alcolea, D and Ferrer, GA and Balasa, M and Naranjo, IC and Fortea, J and Lladó, A and Lleó, A and Montes, AM and Lozano, LM and Martínez-Lage, P and Matias-Guiu, JA and Mendioroz, M and Martinez, DAP and Ripoll, GP and Riverol, M and Sanchez-Juan, P and Bondía, HV and , },
title = {Appropriate use recommendations of the Spanish Society of Neurology's Behavioural Neurology and Dementia Study Group on anti-amyloid antibodies in the treatment of Alzheimer disease.},
journal = {Neurologia},
volume = {},
number = {},
pages = {502075},
doi = {10.1016/j.nrleng.2026.502075},
pmid = {42202980},
issn = {2173-5808},
abstract = {INTRODUCTION: Two anti-amyloid monoclonal antibodies (mAb) have recently been approved by the European Commission for the treatment of Alzheimer disease (AD). In this context, the Spanish Society of Neurology's Behavioural Neurology and Dementia Study Group decided to issue a consensus statement gathering the recommendations of national experts on the appropriate use of anti-amyloid mAb. The document provides recommendations on practical aspects of the use of these drugs in Spain, which are intended to complement the indications described by regulators.

DEVELOPMENT: Fifty-seven members of the study group participated in the consensus process (January-September 2025), which includes recommendations on criteria for selecting candidates, adverse reactions, monitoring, criteria for suspension of treatment, shared physician-patient decision-making, and requirements of prescribing centres. All participants were invited to revise the complete document, specifically asked whether they agreed with the content of each section, and invited to share their comments.

CONCLUSIONS: The introduction of the first anti-amyloid mAb represents a paradigm shift in the management of AD, but is not free of challenges. The participating experts showed a high level of consensus on basic clinical and practical considerations, with the requirements of prescribing centres and criteria for treatment suspension being the areas that generated the most debate. Participants noted concerns about equity of access and implementation into current care, particularly if insufficient resources are allocated to this implementation. This document will require updates in line with new knowledge and/or approval of new drugs in this class.},
}

@article {pmid42203570,
year = {2026},
author = {Ho, NCW and Zhukovsky, P and Rajji, TK and Bowie, CR and Brooks, H and Butters, MA and Chen, Y and Fischer, CE and Flint, AJ and Herrmann, N and Lanctôt, KL and Lee, A and Mah, L and Marawi, T and Pollock, BG and Ryan, JD and Schoer, N and Ma, C and Voineskos, AN and Mulsant, BH and , },
title = {Brain Structures and Cognitive Decline: Moderation Analysis of the PACt-MD Randomized Clinical Trial of Brain Stimulation Plus Cognitive Remediation in Older Adults With Remitted Depression or Mild Cognitive Impairment.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.04.008},
pmid = {42203570},
issn = {1545-7214},
abstract = {OBJECTIVE: To identify which patients with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI) benefit from cognitive remediation (CR) plus transcranial direct current stimulation (tDCS).

DESIGN: We conducted a moderator analysis to examine the effects of baseline brain magnetic resonance imaging (MRI) measures on the impact of CR + tDCS on cognitive decline in Prevention of Alzheimer's dementia with CR plus tDCS in MCI and Depression (PACt-MD), a double-masked randomized two-arm controlled trial with assessments at baseline, two months, and yearly for three to seven years.

SETTING: Five academic hospitals in Toronto, Canada.

PARTICIPANTS: A total of 246 participants with rMDD, MCI, or both, with an analyzable baseline MRI.

INTERVENTION: CR + tDCS or sham CR + sham tDCS.

MEASUREMENTS: Overall cortical thickness, overall fractional anisotropy, and cortical thickness in an a-priori composite region of interest (ROI); changes in global cognition, executive function, or verbal memory.

RESULTS: Overall cortical thickness moderated decline in global cognition (Χ² = 10.43, df = 3, p = 0.015); ROI cortical thickness moderated treatment-related changes in global cognition (Χ² = 29.05, df = 3, p <0.001), executive function (Χ² = 11.57, df = 3, p = 0.009), and verbal memory (Χ² = 16.08, df = 3, p = 0.001).

CONCLUSION: Future work needs to confirm that cortical thickness can be used to select adults at risk for dementia who are the most likely to benefit from CR + tDCS. CLINCIALTRIALS.

GOV IDENTIFIER: NCT02386670.},
}

@article {pmid42204876,
year = {2026},
author = {Khorsand, B and Teichrow, D and Ghanbarian, E and Zheng, L and Sajjadi, SA and Glover, CM and Grill, JD and Rabin, LA and Ezzati, A},
title = {Scalable markers for early cognitive decline: Plasma p-tau217, subjective cognitive concerns, and digital testing: Results from the A4/LEARN studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71505},
doi = {10.1002/alz.71505},
pmid = {42204876},
issn = {1552-5279},
support = {//public-private philanthropic partnership/ ; //National Institutes of Health/National Institute on Aging/ ; //Eli Lilly and Company/ ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; //Avid and Cogstate/ ; },
mesh = {Humans ; Aged ; *Cognitive Dysfunction/diagnosis/blood ; *tau Proteins/blood ; Biomarkers/blood ; Female ; Male ; Aged, 80 and over ; Neuropsychological Tests ; Positron-Emission Tomography ; *Alzheimer Disease/blood ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers confirm Alzheimer's disease (AD) pathology but are impractical for large-scale screening. Plasma phosphorylated tau at threonine 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We assessed their separate and combined predictive value for cognitive decline.

METHODS: We analyzed 1064 cognitively unimpaired adults (ages 65-85 years) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4; amyloid-positive) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN; amyloid-negative) studies. Baseline assessments included apolipoprotein E (APOE) ε4 status, hippocampal volume, amyloid PET, plasma p-tau217, Cognitive Function Index (CFI), and Cogstate Computerized Battery (CCB). Cognitive impairment was defined as conversion from a Clinical Dementia Rating Global Score (CDR-GS) of 0 to ≥0.5 over 240 weeks.

RESULTS: During the follow-up, 34.1% developed cognitive impairment. Higher p-tau217, higher CFI, and lower CCB were associated with higher odds of converting to CDR-GS >0 across all cohorts.

DISCUSSION: P-tau217, CFI, and CCB each independently predict cognitive decline, offering practical, non-invasive tools for early AD risk stratification and trial enrichment.},
}

Humans
Aged
*Cognitive Dysfunction/diagnosis/blood
*tau Proteins/blood
Biomarkers/blood
Female
Male
Aged, 80 and over
Neuropsychological Tests
Positron-Emission Tomography
*Alzheimer Disease/blood
Longitudinal Studies

@article {pmid42206050,
year = {2026},
author = {Deng, HX and Cao, JL and Wu, Y and Jiang, SJ and Fang, QQ and Zhu, BY and Jiang, YJ},
title = {AI-driven insights into protein misfolding and innate immunity in neurodegenerative diseases.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1814357},
pmid = {42206050},
issn = {1664-3224},
mesh = {Humans ; *Neurodegenerative Diseases/immunology/metabolism ; *Immunity, Innate ; *Protein Folding ; Animals ; *Artificial Intelligence ; *Proteostasis Deficiencies/immunology ; },
abstract = {Neurodegenerative diseases encompass a diverse group of disorders ranging from adult-onset conditions such as Alzheimer's and Parkinson's disease to pediatric forms including neuronal ceroid lipofuscinoses (NCLs), Niemann-Pick type C (NPC), and infantile neuroaxonal dystrophy (INAD), all of which are characterized by protein misfolding and chronic neuroinflammation. During their occurrence and development, the innate immune system, especially the immune responses mediated by microglia in the central nervous system, plays a crucial regulatory role. Increasing evidence indicates that misfolded and abnormally aggregated proteins, such as β-amyloid (Aβ), Tau, α-synuclein, and TDP-43, are not only neurotoxic factors but can also act as damage-associated molecular patterns (DAMPs) recognized by innate immune receptors, thereby triggering persistent neuroinflammatory responses. However, traditional experimental and computational methods still have significant limitations in systematically analyzing the "protein misfolding-innate immune activation" mechanism. In recent years, artificial intelligence has made breakthrough progress in protein structure prediction, multi-conformation modeling, and integration of multi-omics data, providing a new research paradigm for revealing the intrinsic relationship between protein misfolding and innate immunity across the spectrum of neurodegenerative diseases. This article systematically reviews the latest applications of artificial intelligence in predicting the conformational characteristics of misfolded proteins, simulating the protein aggregation process, revealing the mechanism of innate immune perception, and reconstructing the regulatory network of neuroinflammation. It focuses on discussing the significance of deep learning models such as AlphaFold, I-TASSER, RoseTTAFold, Phyre2, and ESMFold in the field of protein structure prediction, as well as the related research on multi-modal AI technology in revealing the complex molecular mechanisms behind neurodegenerative diseases, such as combining AI with mathematical models to simulate the spread of misfolded proteins and further exploring the association with disease progression. The review also highlights the potential of AI to address the diagnostic challenges unique to pediatric neurodegenerative disorders, which, despite their rarity, collectively impose devastating lifelong burdens. In summary, AI tools not only deepen our understanding of the molecular mechanisms underlying both adult and childhood neurodegenerative diseases but also open up new avenues for developing innovative diagnostic tools and treatment methods.},
}

Humans
*Neurodegenerative Diseases/immunology/metabolism
*Immunity, Innate
*Protein Folding
Animals
*Artificial Intelligence
*Proteostasis Deficiencies/immunology

@article {pmid42207225,
year = {2026},
author = {Ed-Day, S and Kacimi, FE and El Gui, R and Didou, L and Ibouzine-Dine, L and El Kourchi, C and Boulbaroud, S and Haddan, A and Harhar, H and Azzaoui, FZ},
title = {Erythrina caffra extract restores memory, modulates cholinergic dysfunction, neuroinflammation, and attenuates oxidative stress in cadmium-induced alzheimer's disease-like pathology in rats.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42207225},
issn = {1573-4978},
mesh = {Animals ; Oxidative Stress/drug effects ; *Plant Extracts/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Rats ; Rats, Wistar ; Cadmium/toxicity ; Male ; *Erythrina/chemistry/metabolism ; *Memory/drug effects ; Antioxidants/pharmacology ; Hippocampus/drug effects/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; Acetylcholine/metabolism ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND: Cadmium (Cd) is a well-established neurotoxic heavy metal. Several epidemiological studies have highlighted its involvement in the pathogenesis of Alzheimer's disease (AD). AD is a multifactorial disorder influenced by environmental factors such as heavy metals. Erythrina caffra (E. caffra) is a medicinal plant rich in bioactive compounds with anti-inflammatory, antioxidant, and anticholinesterase properties. However, its protective potential against Cd-induced neurodegeneration remains insufficiently explored. This study investigated the effects of Cd on memory, cholinergic function, oxidative stress, and neuroinflammation, as key AD-related pathophysiological features, and evaluated the therapeutic potential of E. caffra seeds ethanolic extract.

METHODS AND RESULTS: AD-like alterations were induced in Wistar rats by intracerebroventricular (ICV) administration of cadmium chloride (CdCl2). Animals were treated with E. caffra ethanolic extract (2.5 mg/kg) or memantine (20 mg/kg) by oral gavage. Behavioral, neurobiochemical, and histological analyses were performed to assess memory, cholinergic function, oxidative stress, neuroinflammation, and neuronal integrity. Cd exposure significantly impaired memory and disrupted cholinergic function, as evidenced by reduced acetylcholine (ACh) levels in the hippocampus. Moreover, it induced oxidative stress, marked by decreased catalase (CAT), superoxide dismutase (SOD), and non-protein thiols (NPSH), alongside increased proinflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and hippocampal neuronal loss. Treatment with E. caffra and memantine significantly ameliorated these alterations.

CONCLUSIONS: E. caffra extract demonstrates neuroprotective effects against Cd-induced AD-like pathology by modulating oxidative stress, neuroinflammation, and cholinergic dysfunction. These findings suggest its potential as a promising therapeutic candidate for mitigating neurodegenerative processes associated with AD.},
}

Animals
Oxidative Stress/drug effects
*Plant Extracts/pharmacology
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Rats
Rats, Wistar
Cadmium/toxicity
Male
*Erythrina/chemistry/metabolism
*Memory/drug effects
Antioxidants/pharmacology
Hippocampus/drug effects/metabolism
Neuroinflammatory Diseases/drug therapy/metabolism
Disease Models, Animal
Acetylcholine/metabolism
Neuroprotective Agents/pharmacology

@article {pmid42207606,
year = {2026},
author = {Papamicaël, C and Gembus, V and Gourand, F and Levacher, V},
title = {Redox Heterocyclic Platforms Engineered for Brain Drug Delivery and Beyond.},
journal = {Chemical record (New York, N.Y.)},
volume = {},
number = {},
pages = {e70162},
doi = {10.1002/tcr.70162},
pmid = {42207606},
issn = {1528-0691},
abstract = {Overcoming the blood-brain barrier remains one of the most formidable challenges in the diagnosis and treatment of central nervous system disorders. In this account, we showcase our contributions to the field of redox-responsive heterocycles, most notably 1,4-dihydroquinolines and 1,4-dihydropyridines, designed as powerful platforms for targeted brain delivery. Our work builds on the chemical delivery system and bioprecursor prodrug strategies pioneered by Bodor et al. We have focused on the development of redox-activated drug carriers and "bio-oxidizable" prodrugs, which enable efficient transport of neurotransmitters, neuropeptides, and radiotracers for advanced brain imaging, as well as cholinesterase and kinase inhibitors for the treatment of Alzheimer's disease. Last but not least, these versatile heterocyclic systems offer unprecedented perspectives in synthetic methodology, driving breakthrough advances in peptide synthesis and atroposelective amide bond construction.},
}

@article {pmid42207745,
year = {2026},
author = {Bhat, KMR and Lc, P and Thonse, NK and Potu, BK and Kateel, R},
title = {Neuroprotective Effects of Ginkgo biloba Extract in Neurological Disorders: Integrating Anti-Inflammatory and Antioxidant Mechanisms.},
journal = {Complementary medicine research},
volume = {},
number = {},
pages = {1-40},
doi = {10.1159/000552633},
pmid = {42207745},
issn = {2504-2106},
abstract = {BACKGROUND: Neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic stroke are major causes of global disability and mortality. Neuroinflammation and oxidative stress play central roles in their pathogenesis. Ginkgo biloba extract (GBE), particularly the standardized formulation EGb 761, contains flavonoids and terpenoids that exert antioxidant, anti-inflammatory, and mitochondrial-protective effects. These pleiotropic actions position GBE as a promising candidate for neuroprotection.

SUMMARY: This narrative review synthesizes evidence from preclinical and clinical studies on the neuroprotective actions of GBE. Experimental data demonstrate that GBE attenuates oxidative stress by scavenging reactive oxygen species and enhancing endogenous antioxidant defenses, while simultaneously downregulating pro-inflammatory mediators through NF-κB inhibition and NLRP3 inflammasome suppression. Additional benefits include stabilization of mitochondrial function, modulation of neurotransmission, and prevention of apoptosis. Preclinical models consistently show improvements in cognition, motor function, and neuronal survival across diverse disease contexts. Clinical findings, however, are mixed: some randomized trials report improved cognition and functional outcomes in dementia and Parkinsonism, whereas others show no superiority over placebo. Variability in study design, extract standardization, and treatment regimens contribute to these discrepancies.

KEY MESSAGES: GBE exerts multifaceted neuroprotective effects through combined antioxidant, anti-inflammatory, mitochondrial, and neurotransmitter-modulating actions. Preclinical evidence strongly supports its role in mitigating pathological processes underlying Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic injury. But clinical outcomes remain inconsistent. GBE holds potential as a safe, multi-target adjunctive therapy for complex central nervous system disorders, but translation into consistent clinical practice requires further validation.},
}

@article {pmid42208269,
year = {2026},
author = {Saxena, S and Kaur, J and Singh, TG and Kumar, M and Awasthi, A},
title = {Beyond the brain barrier: Hybrid nanoparticles orchestrating intelligent neuro-theranostics.},
journal = {Advances in colloid and interface science},
volume = {356},
number = {},
pages = {103954},
doi = {10.1016/j.cis.2026.103954},
pmid = {42208269},
issn = {1873-3727},
abstract = {Hybrid nanoparticles (HNPs) that integrate organic and inorganic components have been recognized as one of the most sophisticated solutions in the field of nanomedicine to surpass the physiological limitations of the blood-brain barrier (BBB). By the combination of biocompatibility, flexibility, and the capacity of functionalization of the organic shells with the magnetic, optical, or structural precision of the inorganic cores, HNPs provide receptor-mediated transport, controlled drug release, and multimodal imaging with high efficiency. This review details the molecular mechanisms of HNPs crossing the BBB, such as receptor-mediated, adsorptive, carrier-mediated, and biomimetic transcytosis, and also points to the role of the advanced conjugation chemistries like EDC/NHS coupling, thiol‑gold anchoring, click reactions, and redox-cleavable linkers in enhancing targeting fidelity. The therapeutic improvements in the major neurological diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease, and glioblastoma, are discussed with the help of figures, which illustrate enhanced bioavailability, gene silencing, mitochondrial targeting, and integrated photothermal or magnetic responsiveness. Moreover, the review discusses potential diagnostic applications such as multimodal MRI/PET/NIR-II imaging, molecular biosensing, and theranostic nanoplatforms, which link the real time visualization with the targeted treatment. To conclude, we point out the upcoming directions comprising biomimetic coatings, AI guided nanoparticle design, stimuli responsive logic-gated systems, and clinically scalable biodegradable hybrids. In sum, HNPs embody a radically different strategy to precision neuro-nanomedicine, thereby providing a seamless avenue for diagnosis, targeted therapy, and continuous disease monitoring within a single intelligent nanosystem.},
}

@article {pmid42208565,
year = {2026},
author = {Serrano-Pozo, A and Escott-Price, V and Grinberg, LT and Pascoal, T and Suárez-Calvet, M and Dubois, B and Sperling, RA},
title = {Alzheimer's disease.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2241-2262},
doi = {10.1016/S0140-6736(26)00198-4},
pmid = {42208565},
issn = {1474-547X},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology/prevention & control ; Biomarkers ; },
abstract = {Alzheimer's disease is the leading cause of dementia and among the top ten leading causes of death in high-income countries. Exponential advances in epidemiology, genetics, diagnostic imaging and fluid biomarkers, treatment, and prevention in the last decade reinforce the notion that we are entering a new era in the clinical management of Alzheimer's disease. However, far from triumphalism, this momentum should be accelerated to achieve the goals of preventing Alzheimer's disease and arresting its progression. In this Seminar, we summarise this progress and highlight unmet needs and areas of research priority.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/epidemiology/prevention & control
Biomarkers

@article {pmid42210357,
year = {2026},
author = {Behzad, F and Leili, FR and Ebrahimi, MJ and Moafi, M and Kenari, PB and Alizadeh, A and Adeli, S and Khosravani, M and Jadidi Kouhbanani, MA and Fahanik-Babaei, J},
title = {Plant-mediated green nanoparticles: combining nanometal and biometabolite potential for Alzheimer's treatment.},
journal = {Biomedical engineering online},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12938-026-01572-z},
pmid = {42210357},
issn = {1475-925X},
abstract = {Alzheimer's disease (AD) can cause cognitive and memory dysfunction due to insufficient acetylcholine (ACh). In principle, acetylcholinesterase (AChE) hydrolyzes ACh into acetic acid and choline, rendering the latter inactive. Acetylcholinesterase inhibitors (AChEI) are currently the main treatment strategy used to increase ACh availability and decrease the effects of cholinergic loss. The FDA has currently approved donepezil, rivastigmine, and galantamine (GAL) as AchEI drugs to treat AD. Among these drugs, only the alkaloid galantamine is found naturally among the AChEIs. The synergistic effect of plant metabolites and metal nanoparticles (MNPs) presents a promising avenue for AD treatment. Green synthesis approach leverages the unique properties of MNPs combined with the therapeutic potential of plant-derived compounds. In the present review, recent developments in nanotechnology, including the green synthesis of MNPs, have been discussed in relation to the treatment of AD. Given the recent advancements, we hope that the combination of nanotechnology and medicinal plants will eventually result in the development of highly successful strategies for the treatment of AD.},
}

@article {pmid41963962,
year = {2026},
author = {Li, Y and Wu, H and Yang, J and Weedor, JG and Ding, H and Cui, W and Cui, B and He, Z and Zhang, W and Xing, Y and Zeng, F and Huang, X and Zheng, K and Shen, Y and Yu, Y and Pan, W and Yang, X},
title = {Clostridium butyricum ameliorates Toxoplasma gondii-induced neuropsychiatric disorders by attenuating glial-mediated synaptic pruning via the gut-brain axis.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41963962},
issn = {1742-2094},
support = {Nos. 202310313083Y//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313020//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313017//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; No. JC20250007//the Faculty Development Grant of Basic Medical Sciences in Xuzhou Medical University/ ; Nos. 82372283//the National Natural Science Foundation of China/ ; No. QL-YB022//the XZHMU-QL Joint Research Fund/ ; No. 2022M710120//China Postdoctoral Science Foundation/ ; },
abstract = {UNLABELLED: Gut microbiota dysbiosis contributes to Toxoplasma gondii (T. gondii)-induced neuropsychiatric disorders (TNDs); however, the underlying mechanisms remain largely elusive. Here, we identified the critical role of butyrate-producing bacteria in TNDs in mice. Decreased abundance of butyrate-producing bacteria was consistently observed in patients with Alzheimer’s disease and T. gondii-infected mice. Dietary supplementation with Clostridium butyricum (C. butyricum), a gut commensal butyrate-producing bacterium, reversed gut microbiota dysbiosis, ameliorated intestinal barrier disruption and inflammation, and reduced endotoxemia. Coincidentally, C. butyricum administration suppressed microglial and astrocytic activation, rescued synaptic ultrastructure damage and synaptic loss, thus alleviating cognitive impairment and anxiety/depression-like behaviors. Mechanistically, C. butyricum treatment mitigated the abnormal synaptic pruning mediated by glial cells and C1q to prevent the neuropathology induced by T. gondii infection. Importantly, fecal microbiota transplantation from C. butyricum-supplemented mice into antibiotic-treated recipients recapitulated the therapeutic effects on gut and brain pathology observed in infected mice. Together, our findings suggest that C. butyricum ameliorates TNDs by modulating glial cell-mediated abnormal synaptic pruning via the gut-brain axis, highlighting the therapeutic potential efficacy of butyrate-producing bacteria against TNDs.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03761-y.},
}