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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

EXPOSURE: c-hGH contaminated with Aβ amyloid seeds.

MAIN OUTCOMES AND MEASURES: Clinical and histopathological description.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

GRAPHICAL ABSTRACT: [Image: see text]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid41892131,
year = {2026},
author = {Kasabov, NK and Yang, A and Wang, Z and Abouhassan, I and Kassabova, A and Lappas, T},
title = {eXCube2: Explainable Brain-Inspired Spiking Neural Network Framework for Emotion Recognition from Audio, Visual and Multimodal Audio-Visual Data.},
journal = {Biomimetics (Basel, Switzerland)},
volume = {11},
number = {3},
pages = {},
doi = {10.3390/biomimetics11030208},
pmid = {41892131},
issn = {2313-7673},
abstract = {This paper introduces a biomimetic framework and novel brain-inspired AI (BIAI) models based on spiking neural networks (SNNs) for emotional state recognition from audio (speech), visual (face), and integrated multimodal audio-visual data. The developed framework, named eXCube2, uses a three-dimensional SNN architecture NeuCube that is spatially structured according to a human brain template. The BIAI models developed in eXCube2 are trainable on spatio- and spectro-temporal data using brain-inspired learning rules. Such models are explainable in terms of revealing patterns in data and are adaptable to new data. The eXCube2 models are implemented as software systems and tested on speech and video data of subjects expressing emotional states. The use of a brain template for the SNN structure enables brain-inspired tonotopic and stereo mapping of audio inputs, topographic mapping of visual data, and the combined use of both modalities. This novel approach brings AI-based emotional state recognition closer to human perception, provides a better explainability and adaptability than existing AI systems. It also results in a higher or competitive accuracy, even though this was not the main goal here. This is demonstrated through experiments on benchmark datasets, achieving classification accuracy above 80% on single-modality data and 88.9% when multimodal audio-visual data are used, and a "don't know" output is introduced. The paper further discusses possible applications of the proposed eXCube2 framework to other audio, visual, and audio-visual data for solving challenging problems, such as recognizing emotional states of people from different origins; brain state diagnosis (e.g., Parkinson's disease, Alzheimer's disease, ADHD, dementia); measuring response to treatment over time; evaluating satisfaction responses from online clients; cognitive robotics; human-robot interaction; chatbots; and interactive computer games. The SNN-based implementation of BIAI also enables the use of neuromorphic chips and platforms, leading to reduced power consumption, smaller device size, higher performance accuracy, and improved adaptability and explainability. This research shows a step toward building brain-inspired AI systems.},
}

@article {pmid41892340,
year = {2026},
author = {Cohen, BM and Koh, E and Levental, KR and Levental, I and Sonntag, KC},
title = {Inherent Lipid Composition Abnormalities in Astrocytes Associated with Late-Onset Alzheimer's Disease (LOAD).},
journal = {Cells},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/cells15060549},
pmid = {41892340},
issn = {2073-4409},
support = {N/A//Steele Fund SUNDRY/ ; R35GM134949/GM/NIGMS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; Lipidomics ; Fatty Acids/metabolism ; *Lipid Metabolism ; Mitochondria/metabolism ; *Lipids/chemistry ; Aged ; Male ; Cholesterol Esters/metabolism ; },
abstract = {Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived brain cells. These cells lack markers associated with aging and environmental exposures. The iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Astrocytes are crucial to neural activity and health, and altered astrocyte functions are associated with LOAD pathology. Lipidomics analyses were performed on whole-cell and mitochondria-enriched fractions. Large reductions in cholesterol esters (CEs) and imbalances in fatty acids (FAs) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. The findings identify abnormalities in CEs, as well as in FAs, as inherent abnormalities and likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Astrocytes/metabolism/pathology
Induced Pluripotent Stem Cells/metabolism
Lipidomics
Fatty Acids/metabolism
*Lipid Metabolism
Mitochondria/metabolism
*Lipids/chemistry
Aged
Male
Cholesterol Esters/metabolism

@article {pmid41892608,
year = {2026},
author = {Zhang, T and Sun, F and Stang, A and Ayoub, G},
title = {Peripheral Sensory Stimulation for Long-Term Improvement in Mild Cognitive Decline: A Prospective Interventional Study.},
journal = {Brain sciences},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/brainsci16030265},
pmid = {41892608},
issn = {2076-3425},
support = {grant in aid//Nova Palm Foundation/ ; },
abstract = {BACKGROUND: Despite recent breakthroughs in pharmacological treatment for Alzheimer's disease, high costs and the complex procedure to monitor safety have limited access for many patients. Less invasive and more accessible non-pharmacological therapies that support neuroplasticity and slow cognitive decline are needed. Processing Inner Strength Toward Actualization (PISTA) stimulation applies structured tactile input to promote cortical-subcortical activation. This study evaluated the long-term effects of PISTA on cognition and pain in older adults with mild cognitive impairment or early dementia.

METHODS: This single-arm, prospective trial enrolled 100 outpatients aged 47-70 years at outset (50 women, 50 men) with no control group. Participants received clinician-supervised PISTA stimulation three times weekly for 48 months. Each 30 min session delivered rhythmic tactile input calibrated to individual sensory thresholds. Cognitive performance was assessed monthly using the Mini-Mental State Examination (MMSE). Perceived pain was measured monthly with the Numeric Pain Rating Scale. Outcomes were analyzed using ANCOVA, adjusting for age, sex, and baseline cognitive status.

RESULTS: Cognitive scores improved significantly across all age strata, with a mean annual MMSE increase of 0.75 points (95% CI: 0.26-1.21; p < 0.0025). Pain intensity decreased in parallel (mean reduction: 0.56 points; 95% CI: 0.34-0.78; p < 0.001). Improvements in cognition and pain were moderately correlated (r = 0.38). The greatest combined benefits occurred in participants aged 55-62 years. No serious adverse events were observed during the 48-month trial.

CONCLUSIONS: PISTA stimulation produced sustained improvement in cognition and reduced perceived pain, supporting its promising role as a safe, non-invasive adjunct for neurodegenerative cognitive decline. These findings suggest peripheral sensory activation as a promising driver of functional neuroplasticity and warrant verification in randomized, controlled trials.},
}

@article {pmid41893324,
year = {2026},
author = {Bientinesi, E and Vignoli, A and Ristori, S and Salobehaj, M and Bertoni, G and Monti, D and Tenori, L},
title = {An NMR-Based Protocol for Profiling the Endo- and Exo-Metabolomes in Aβ1-42 Treated Human Astrocytes from Healthy and Alzheimer's Disease Donors.},
journal = {Metabolites},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/metabo16030173},
pmid = {41893324},
issn = {2218-1989},
support = {M4C2 Investment 1.3 - Research Program PE8 Project Age-It: "Ageing Well in an Ageing Society" (CUP B83C22004800006)//Ministero dell'università e della ricerca/ ; },
abstract = {Background/Objectives: Astrocytes play a critical role in maintaining brain homeostasis and are increasingly recognized as active contributors to neurodegenerative processes. Metabolic dysfunction in astrocytes has been implicated in the onset and progression of Alzheimer's disease (AD), yet the underlying metabolic alterations remain poorly characterized. Methods: We used an optimized protocol for untargeted metabolomic profiling of both intracellular and extracellular compartments of primary human astrocytes derived from AD patients and healthy subjects (HS) using [1]H nuclear magnetic resonance (NMR) spectroscopy. Cells were treated with oligomeric Aβ1-42 to model pathological conditions. Results: Aβ1-42 treatment induced intracellular metabolic alterations in both AD and HS astrocytes, including a consistent reduction in phosphocreatine, potentially indicating impaired energy-buffering capacity. Notably, a decrease in β-alanine was observed only in AD astrocytes, suggesting alterations in carnosine-related antioxidant defence. Analysis of conditioned media revealed differential responses between groups: AD astrocytes showed increased extracellular levels of 2-oxoglutarate, citrate, and glycine, whereas HS astrocytes exhibited reduced extracellular levels of leucine and isoleucine, suggesting distinct adaptive metabolic responses to Aβ-induced stress. However, none of these differences remained statistically significant after correction for multiple testing. Conclusions: These findings suggest that NMR-based metabolomics can detect subtle metabolic shifts in human astrocyte models of AD and HS exposed to amiloidogenic challenge. Given the limited sample size and the exploratory design adopted, the results should be interpreted as preliminary and require validation in larger, better-matched cohorts. Nevertheless, this study provides a methodological framework and generates biologically plausible hypotheses regarding astrocyte metabolic responses relevant to AD pathophysiology.},
}

@article {pmid41893345,
year = {2026},
author = {Yang, D and Guo, W and Guo, L},
title = {Exercise Reprograms the Spatial Function of Phosphoglycerate Dehydrogenase of a Pathogenic Nuclear Transcription Factor (PHGDH): A Narrative Review.},
journal = {Metabolites},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/metabo16030196},
pmid = {41893345},
issn = {2218-1989},
abstract = {Background: Alzheimer's disease (AD) represents a significant therapeutic challenge, largely attributed to the complex interplay of genetic and non-genetic mechanisms. Among the latter, metabolic dysregulation has emerged as a critical factor influencing disease progression. This study proposes a paradigm shift in our understanding of the role of phosphoglycerate dehydrogenase (PHGDH), a key metabolic enzyme, which, under pathological conditions associated with AD, transitions from a protective role to a pathogenic influence through alterations in its cellular localization and function. Methods: To elucidate the impact of exercise on PHGDH dynamics, a narrative review methodology was employed. We conducted comprehensive searches across bibliographic databases, including PubMed, Scopus, and Web of Science, focusing on peer-reviewed articles that detail the relationship between exercise, PHGDH activity, and AD-related neuroinflammation. The review was structured around specific inclusion criteria, which prioritized studies elucidating the mechanisms underlying PHGDH's dual role in AD pathology and the influence of exercise on this process. Results: Our findings reveal that under AD-associated stress, PHGDH translocates to the nucleus, facilitating the activation of pro-inflammatory genes such as IKKα and HMGB1, while simultaneously suppressing autophagy and enhancing amyloid beta (Aβ) deposition. However, exercise induces the release of the myokine irisin, which inhibits PHGDH nuclear translocation through AMPK/PGC-1α signaling pathways. Additionally, peripheral effects of exercise are observed in hepatic Kupffer cells, where exercise attenuates PHGDH activity, leading to reduced systemic IL-1β release and neuroinflammation. Conclusions: This study underscores the potential of exercise as a precision intervention in AD management, highlighting its capacity to modulate PHGDH activity and mitigate neuroinflammatory processes. The therapeutic implications of these findings are profound, paving the way for novel diagnostic tools, such as PET probes for assessing PHGDH compartmentalization, and promoting a synergistic approach to "exercise-pharmacotherapy" in the treatment of Alzheimer's disease. Future research should aim to further delineate the mechanisms by which exercise influences metabolic pathways in the context of neurodegeneration.},
}

@article {pmid41893846,
year = {2026},
author = {Lin, Z and Sun, R and Ross, JS and Lau, K and Stumpf, S and Chen, X},
title = {Racial and Ethnic Reporting and Representation in US Alzheimer Clinical Trials: A Systematic Review.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e262427},
doi = {10.1001/jamanetworkopen.2026.2427},
pmid = {41893846},
issn = {2574-3805},
mesh = {Humans ; *Alzheimer Disease/drug therapy/ethnology ; United States ; *Ethnicity/statistics & numerical data ; *Racial Groups/statistics & numerical data ; *Clinical Trials, Phase III as Topic/statistics & numerical data ; Clinical Trials as Topic ; },
abstract = {IMPORTANCE: Alzheimer disease (AD) disproportionately affects racial and ethnic populations underrepresented in US clinical research, raising concerns about the generalizability of AD trial findings and the evaluation of treatment safety and efficacy for populations most affected by AD.

OBJECTIVE: To examine patterns and trends in the reporting and representation of patient race and ethnicity in US-based phase 3 AD clinical trials.

EVIDENCE REVIEW: This systematic review examined US-based phase 3 AD drug trials identified through the Trialtrove trial database between 1997 and 2023. Trials were cross-referenced with peer-reviewed publications, ClinicalTrials.gov, pharmaceutical company reports, and conference abstracts. Completed trials were eligible for inclusion if they were designated as phase 3 drug trials targeting AD and recruited patients exclusively in the US. Primary outcomes included reporting of race and ethnicity, the number of racial and ethnic groups reported, and their representation among trial populations. Secondary outcomes included terminology used, reporting of safety or efficacy differences by race and ethnicity, and discussion of racial and ethnic representation in trial reports. Temporal trends in reporting and representation were assessed. Methodologic quality was evaluated using the Quality Rating Scheme for Studies and Other Evidence. Data collection was completed May 2024.

FINDINGS: Among 88 US-based phase 3 AD clinical trials conducted between 1997 and 2023, 71 (80.7%) had publicly available results, including 52 (59.1%) published in peer-reviewed journals. Nearly half of published trials (35 [49.3%]) did not report patient race or ethnicity. Among published trials, reporting was inconsistent and focused predominantly on White (36 [50.7%]) patients, with substantially fewer trials reporting data on Asian or Pacific Islander (11 [15.5%]), Black (20 [28.2%]), Hispanic (13 [18.3%]), or Native American (2 [2.8%]) patients. Median (IQR) enrollment of White patients was 91.3% (87.3%-93.6%), whereas enrollment of underrepresented patient populations was markedly lower, with median (IQR) enrollment of 0.9% (0.6%-1.6%) for Asian or Pacific Islander, 4.5% (3.6%-6.6%) for Black (ethnicity unspecified), 7.2% (3.7%-9.1%) for Black (non-Hispanic), 5.2% (3.1%-6.6%) for Hispanic, and 0.4% (0%-0.8%) for Native American patients. Few trials (3 of 71 [4.2%]) conducted subgroup analyses by race or ethnicity, and none reported detailed subgroup characteristics or safety or efficacy outcomes by patient race and ethnicity. Reporting practices and representation showed little improvement over time.

CONCLUSIONS AND RELEVANCE: US-based phase 3 AD trials showed substantial gaps in racial and ethnic reporting and representation from 1997 to 2023, limiting the evaluation of treatment safety and efficacy across diverse populations. These findings suggest that stronger reporting standards and more inclusive trial design and recruitment strategies are needed to improve the equity and generalizability of AD trials.},
}

Humans
*Alzheimer Disease/drug therapy/ethnology
United States
*Ethnicity/statistics & numerical data
*Racial Groups/statistics & numerical data
*Clinical Trials, Phase III as Topic/statistics & numerical data
Clinical Trials as Topic

@article {pmid41894159,
year = {2026},
author = {Suemoto, CK and Custodio, N and Aguilar, D and Avila-Funes, JA and Baez, S and Bagnati, PM and Barnes, LL and Brucki, SMD and Calandri, IL and Caramelli, P and Cornejo-Olivas, M and Derio, CD and Ferreira, ST and García, AM and Grinberg, LT and Ibanez, AM and Isasi, R and Josephy-Hernández, SE and Porras, ML and Llibre-Guerra, JJ and Llibre-Rodriguez, JJ and Lourenco, MV and Meza, BMM and Migeot, J and Miranda, JJ and Miranda-Castillo, C and Mummery, CJ and Parodi, JF and Castro, NP and Contreras, RMS and Santamaría-García, H and Slachevsky, A and Souza-Talarico, JN and Surace, EI and Takada, LT and Tsoy, E and Pilalumbo, MU and Zimmer, ER and Fontana, IC and Mahinrad, S and Snyder, HM and Carrillo, MC},
title = {The landscape of dementia research, diagnosis, treatment, and care in Latin America.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71309},
doi = {10.1002/alz.71309},
pmid = {41894159},
issn = {1552-5279},
support = {//Global Brain Health Institute/ ; //ANID/FONDEF/ ; //ANID/Fondecyt/ ; //ANID/Fondap/ ; //NIH D43 Fogarty/ ; //ANID Millennium Science Initiative Program/ ; //National Institute for Health and Care Research/ ; //ANID/PIA/ANILLOS/ ; //Multi-partner Consortium to Expand Dementia Research in Latin America (ReDLat)/ ; //DICYT-USACH/ ; //Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; //National Institute for Translational Neuroscience (INNT-Brazil)/ ; //Agencia Nacional de Investigación y Desarrollo/ ; //Consejo Nacional de Desarrollo Científico y Tecnológico/ ; //Pilot Awards for Global Brain Health Leaders (Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society)/ ; /NH/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Agencia Nacional de Promoción Científica y Tecnológica/ ; //Takeda/ ; //National Institutes of Aging/ ; },
mesh = {Humans ; *Dementia/diagnosis/therapy/epidemiology ; Latin America/epidemiology ; *Biomedical Research ; Congresses as Topic ; },
abstract = {Latin America is undergoing rapid population aging alongside a rising burden of dementia. While the region holds substantial potential for dementia risk reduction, challenges remain, such as delayed diagnoses, limited access to specialized care and biomarker testing, persistent stigma, and deep-rooted structural inequities. To address these gaps and foster regionally informed solutions, the Alzheimer's Association convened the 2025 Alzheimer's Association International Conference (AAIC) Satellite Symposium in Lima, Peru, on May 14-15, in collaboration with the Global Brain Health Institute (GBHI) and the Atlantic Fellows for Equity in Brain Health. The meeting aimed to bring core elements of the global AAIC meeting to regional Latin American settings, recognizing that national and cultural contexts demand tailored approaches to dementia prevention, risk reduction, treatment and care all aimed at promoting brain health in the region. This manuscript synthesizes the symposium's key discussions, scientific advances, and opportunities for collaboration across the region.},
}

Humans
*Dementia/diagnosis/therapy/epidemiology
Latin America/epidemiology
*Biomedical Research
Congresses as Topic

@article {pmid41894949,
year = {2026},
author = {Brem, AK and Khan, Z and Radermacher, J and Georgiadis, K and Lazarou, I and Grammatikopoulou, M and Pickering, E and Mitterreiter, J and Aakre, JA and Ashton, NJ and Baquero, M and Beser-Robles, M and Braboszcz, C and Brandt, S and Brown, J and Cacciamani, F and Campill, S and Collins, C and Deshpande, P and Diaz, A and Durrleman, S and Engelborghs, S and Ferré-González, L and Frisoni, GB and Gjestsen, MT and Gove, D and Honigberg, L and Huang, B and Hudak, A and Kaushik, S and Letoha, T and Marquardt, G and Mendes, AJ and Müllenborn, M and Paletta, L and de Barros, NP and Pszeida, M and Vik-Mo, AO and Rostamipour, H and Perneczky, R and Rauchmann, BS and Russegger, S and Schirmer, T and Shadmaan, A and Solana, AB and Soria-Frisch, A and Tegethoff, P and Ribbens, A and De Witte, S and van der Giezen, M and Nikolopoulos, S and Corbett, A and Fröhlich, H and Aarsland, D and , },
title = {Screening for Alzheimer's disease in the community using an AI-driven screening platform: design of the PREDICTOM study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100545},
doi = {10.1016/j.tjpad.2026.100545},
pmid = {41894949},
issn = {2426-0266},
abstract = {BACKGROUND: Recent developments in physiological, imaging and digital biomarkers combined with the approval of new disease-modifying drugs against Alzheimer's disease (AD) and diagnostic blood tests provide an opportunity to shift the first diagnostic steps to the home-setting. While these novel biomarkers enable scalable screening and earlier detection and treatment of AD, they require an evaluation of their accuracy, feasibility, and safety in primary care and the community setting.

OBJECTIVES: The aim of PREDICTOM is to develop and test the accuracy of an artificial intelligence (AI) driven screening platform for the risk assessment and early detection of AD to extend the clinical pathway to home-based screening using established and novel biomarkers.

DESIGN/SETTING: PREDICTOM is a European (Norway, UK, Belgium, France, Switzerland, Germany, Spain) observational, prospective cohort study using a cloud-based platform that stores a digitalised journey for each participant and provides a collection of artificial-intelligence (AI) algorithms and tools for risk assessment and early diagnosis and prognosis.

PARTICIPANTS: Cohort 1 consists of 4000 adults aged 50 years or older at risk of developing AD. Cohort 2 consists of 615 participants selected from Cohort 1 based on estimates indicating high (N = 415) or low (N = 200) risk of AD. Data from existing cohorts will guide the analytic strategy of the study.

MEASUREMENTS: Cohort 1 will undergo home-based assessments (Level 1), Cohort 2 will undergo in-clinic assessments (Levels 2 and 3). Level 1 includes at-home screening, collecting digital and physiological data (questionnaires, cognition, hearing, eye-tracking) and biofluids (capillary blood via finger-stick and saliva) for biomarker analysis. Level 2 comprises a more complex biomarker collection, most of which can be completed in primary care, including EEG, MRI, venous blood, microbiome from stool, cognition, hearing, and eye-tracking. Level 3 includes a diagnostic evaluation to confirm or rule out AD pathology using established biomarkers (cerebrospinal fluid, or amyloid PET).

CONCLUSIONS: PREDICTOM will develop AI-driven algorithms for the early detection of AD using biomarkers that can be collected at home or in the community care setting, and evaluate their integration into a well-defined and comprehensive clinical pathway.},
}

@article {pmid41895394,
year = {2026},
author = {Xia, X and Yi, F and Zhang, R and Wu, R and Zhang, X and Zhang, Y and Liu, J and Qin, H and He, B and Duan, Y and Xu, Y and Huang, XF and Yu, Y and Hu, M},
title = {Senolytic therapy ameliorates high-fat diet-induced hippocampal senescence and cognitive decline in mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115745},
doi = {10.1016/j.expneurol.2026.115745},
pmid = {41895394},
issn = {1090-2430},
abstract = {Obesity is a recognized risk factor for cognitive decline and neurodegenerative diseases, including Alzheimer's disease (AD). Obese individuals typically consume high-fat diet (HFD), particularly those rich in palmitate. However, the potential for HFD to induce neurodegeneration and their underlying mechanisms remain poorly understood. In this study, we demonstrate that HFD exposure induced significant deficits in hippocampal-dependent behaviors in mice and decreased synaptic protein expression. Transcriptomic analysis revealed differentially expressed genes in the hippocampus of HFD-fed mice, with enrichment predominantly in senescence-associated pathways. Furthermore, HFD-fed mice exhibited elevated hippocampal senescence markers, including increased SA-β-gal-positive cells, upregulated p16/p21 expression, elevated SASP factors and reduced Lamin B1. Remarkably, a palmitate-enriched diet recapitulated the hippocampal senescence phenotype and cognitive deficits induced by HFD, indicating that palmitate-the principal saturated fatty acid in HFD-served as a key mediator of cellular senescence. Finally, treatment with the senolytic cocktail dasatinib plus quercetin significantly reduced senescent cell burden, suppressed p16 protein expression, and normalized SASP factor levels. This intervention effectively restored cognitive function and synaptic protein expression. This work uncovers a novel HFD-induced cognitive impairment mechanism and suggests potential therapeutic strategies for mitigating obesity-associated neurodegeneration.},
}

@article {pmid41895668,
year = {2026},
author = {Jung, H and Hyun, G and Kim, S and Jeon, Y and Han, KA and Lee, KJ and Ko, J and Um, JW},
title = {Somatostatin-induced modulation of microglial activity contributes to mitigating Alzheimer's disease pathology.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106563},
doi = {10.1016/j.bbi.2026.106563},
pmid = {41895668},
issn = {1090-2139},
abstract = {Somatostatin (SST) is a neuropeptide widely expressed in the central nervous system, known to exert inhibitory effects through activation of G protein-coupled somatostatin receptors (SSTRs). Although its synaptic and network-level functions have been implicated in various neurological disorders, the direct peptidergic actions of SST-particularly on microglia-remain poorly understood. Given that SST levels are reduced in Alzheimer's disease (AD) and microglia predominantly express SSTR2, we hypothesized that SST modulates microglial function both in physiological and AD-related contexts. In this study, we demonstrate that SST treatment enhances phagocytic capacity and suppresses pro-inflammatory cytokine release in cultured microglia. Furthermore, SST overexpression in an AD mouse model reduced microglial density and amyloid-β plaque burden and improved hippocampus-dependent cognitive performance, indicating a protective effect mediated through microglial modulation. Our findings suggest a previously unrecognized role of SST in regulating microglial behavior and highlight the therapeutic potential of targeting the SST-SSTR signaling axis in neuroinflammatory and neurodegenerative diseases.},
}

@article {pmid41895681,
year = {2026},
author = {Iwao, T and Takata, F and Tanaka, Y and Aridome, H and Mizoguchi, J and Dohgu, S},
title = {Docosahexaenoic and eicosapentaenoic acids differentially enhance the blood-brain barrier function via distinct PPAR-dependent upregulation of tight junction proteins in brain endothelial cells.},
journal = {Microvascular research},
volume = {},
number = {},
pages = {104948},
doi = {10.1016/j.mvr.2026.104948},
pmid = {41895681},
issn = {1095-9319},
abstract = {Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are unsaturated omega-3 fatty acids that reduce the risk of Alzheimer's disease and dementia by protecting blood-brain barrier (BBB) function. However, the mechanisms through which DHA and EPA regulate BBB function remain unclear. DHA and EPA act as ligands for the peroxisome proliferator-activated receptor (PPAR), which is a nuclear receptor superfamily member, with three isoforms: α, β, and γ. Tight junctions (TJs) formed between brain endothelial cells play a central role in restricting the paracellular passage of substances across the BBB. In this study, we aimed to investigate whether DHA and EPA regulate TJ protein expression via PPARs. Primary cultured rat brain endothelial cells (RBECs) isolated from Wistar rats were used for in vitro analysis. TJ protein (ZO-1, occludin, and claudin5) and PPARα, β, and γ expression levels in RBECs were measured using western blot analysis. Additionally, to verify PPAR involvement in TJ protein expression regulation, RBECs were treated with DHA or EPA in combination with PPARα, β, or γ inhibitors. The DHA-induced ZO-1 upregulation was suppressed by PPARβ inhibition. Either PPARβ or PPARγ inhibition suppressed the DHA-induced occludin increase, whereas both PPAR inhibitors suppressed the DHA-induced claudin-5 increase. In contrast, the EPA-induced increase in claudin-5 expression was suppressed via PPARγ inhibition. Conclusively, DHA and EPA regulate TJ protein expression via different PPARs in brain endothelial cells, revealing potential targets for the prevention or treatment of neurodegenerative diseases.},
}

@article {pmid41895957,
year = {2026},
author = {Ma, W and Wang, S and Yang, X and Chen, YB and Li, Y and Cui, YL},
title = {Gastrodin and gastrodigenin: advancing neurogenesis in neurological disease management.},
journal = {Food research international (Ottawa, Ont.)},
volume = {232},
number = {},
pages = {118882},
doi = {10.1016/j.foodres.2026.118882},
pmid = {41895957},
issn = {1873-7145},
mesh = {*Benzyl Alcohols/pharmacology/therapeutic use ; *Neurogenesis/drug effects ; *Glucosides/pharmacology/therapeutic use ; Humans ; Animals ; Gastrodia/chemistry ; *Nervous System Diseases/drug therapy ; Neural Stem Cells/drug effects ; },
abstract = {Neurogenesis, the creation of new neurons from neural stem cells (NSCs) in the brain, plays a crucial role in neurological diseases when disrupted. Herbal medicine components, especially those with dual applications in disease treatment and food, like those from Gastrodia elata Blume, have gained attention for their ability to influence neurogenesis. Notably, gastrodin and gastrodigenin from this herb influence neurogenesis and affect conditions like Alzheimer's, depression, stroke, and amnesia. Understanding these processes and mechanisms is essential for addressing neurological disorders. We also discuss gastrodin's potential in aiding peripheral nerve regeneration and its therapeutic effects on neurological diseases through neurogenesis regulation. This review offers insights into gastrodin's therapeutic potential, encouraging further research to boost its efficacy in neurological diseases.},
}

*Benzyl Alcohols/pharmacology/therapeutic use
*Neurogenesis/drug effects
*Glucosides/pharmacology/therapeutic use
Humans
Animals
Gastrodia/chemistry
*Nervous System Diseases/drug therapy
Neural Stem Cells/drug effects

@article {pmid41555522,
year = {2026},
author = {Lahiri, D and Cooper, J and Seixas-Lima, B and Roncero, C and Wellington, C and Cherktow, H},
title = {CAPS Plus: A Clinical Biomarker Scoring System to Predict Aβ Positivity and Facilitate Enrollment in Anti-Amyloid Clinical Trials.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/cjn.2026.10530},
pmid = {41555522},
issn = {0317-1671},
abstract = {BACKGROUND: A critical step toward determining eligibility for experimental and clinical treatment with anti-amyloid therapies in Alzheimer's disease (AD) is to select appropriate subjects having a high likelihood of being Aβ+. We propose a clinical biomarker composite score, named Clinical β-Amyloid Positivity Prediction Score Plus (CAPS Plus), for Aβ+ prediction in people presenting with clinical Alzheimer's syndrome including both prodromal and mild AD.

METHODS: The original CAPS incorporated scores from the neuropsychiatry inventory questionnaire, mini-mental state examination score loss per year and Fazekas score. Plasma p-tau-217, a novel addition to CAPS, was measured using the Simoa HD-X with the AlzPATH p-tau217 Advantage Plus assay. To incorporate p-tau-217 into CAPS Plus, an intra-cohort cut-off (>0.698 pg/ml) for p-tau217 was generated using logistic regression and Yoden's index. CAPS Plus had a maximum score of 5, with those ≥4 indicating a high probability of being Aβ+. The accuracy of CAPS Plus was computed through logistic regression and area under the receiver operating characteristic curve (AUROC) analysis.

RESULTS: Of n = 44 patients, n = 25 (57%) were Aβ+. Plasma p-tau-217 was significantly higher in the Aβ+ subgroup (1.36 vs 0.46 pg/mL, p < 0.0001). The AUROC was 0.89 for a CAPS Plus score of 4 or more, suggesting excellent discrimination and improving the accuracy of the original CAPS (0.86). CAPS Plus has a notably better specificity (89%) than the original CAPS (80%) and p-tau-217 alone (74%).

CONCLUSION: CAPS Plus is potentially a useful screening tool for enrollment in anti-Aβ therapy and clinical trials for AD, specifically addressing people with prodromal and mild AD.},
}

@article {pmid41691301,
year = {2026},
author = {Penny, LK and Arastoo, M and Lofthouse, R and Abdallah, A and Imoesi, PI and Schwab, K and Shiells, H and Melis, V and Riedel, G and Harrington, CR and Wischik, CM and Porter, A and Palliyil, S},
title = {Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {},
pages = {},
pmid = {41691301},
issn = {1758-9193},
abstract = {INTRODUCTION: Immunotherapy is an attractive proposition for preventing the spread of pathologic tau in Alzheimer’s disease and other tauopathies. Given that tau is heavily truncated in tauopathies, it is hypothesised that directly targeting the repeat domain which forms the core of pathological filaments will improve the likelihood of success. S1D12, a chimeric IgG2a isolated via phage display, recognises 2N4R tau341-353 with high affinity (200 pM) and has previously been shown to prevent tau aggregation and propagation in vitro. We further explored the pharmacokinetics and biodistribution of S1D12 as well as its efficacy in a tauopathy mouse model. We also verified its efficacy in vitro against tau seeding species from multiple human tauopathies.

METHODS: Single dose S1D12 intraperitoneal injections (30 mg/kg) were performed in wild-type mice followed by tissue harvest at multiple time points. For efficacy studies, four-weekly doses followed by four-fortnightly doses of S1D12 (30 mg/kg) or negative control antibody were administered intraperitoneally to Line 66 tau transgenic mice. Two cohorts, beginning from 2 months and 4.5 months of age were utilised. Endpoints included quantification of aggregated tau, seed-competent tau and insoluble phosphorylated tau in brain homogenates, as well as neurofilament light (NfL), tau phosphorylated at Thr-217 (pTau217) and core tau in plasma.

RESULTS: S1D12 was detected in plasma and in brain with a tmax of 24/48 h respectively, and a slow washout over 7 days (t1/2 > 230 h), with 0.35% CNS bioavailability. S1D12 inhibited the generation of aggregated tau, seed-competent tau and insoluble phosphorylated tau in transgenic mice. This was associated with a reduction in NfL and pTau217, and an increase in core tau in plasma. In the 4.5-month cohort, S1D12 did not remove already established tau aggregates below baseline. Additionally, S1D12 inhibited seeding tau species from different tauopathies to a similar degree, independent of structural diversity.

CONCLUSIONS: S1D12, a high-affinity antibody targeting the R4 repeat domain of tau offers potential for halting progression of tau pathology through inhibition of tau aggregation rather than removal of established aggregates. These findings support the notion that both early diagnosis and intervention are key for the treatment of AD and other tauopathies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01985-x.},
}

@article {pmid41881052,
year = {2026},
author = {Noguchi-Shinohara, M and Ono, K},
title = {Successful Amyloid Removal by Donanemab Treatment in a Female Patient With Alzheimer Disease: A Case Report.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214817},
doi = {10.1212/WNL.0000000000214817},
pmid = {41881052},
issn = {1526-632X},
}

@article {pmid41882255,
year = {2026},
author = {Yan, Y and Song, D and Li, G and Li, J and Tang, Y and Li, D and Mao, J and Li, H and Liu, X and Yu, D and Ma, F and Pang, Y and Jin, Y and Deng, Y and Qiu, Y and Quan, Z and Ni, J and Cheng, Y and Wang, Z and Dong, Z and Hong, Q},
title = {The dynamic impairment of synaptic transmission in the PCx-IL engram circuit contributes to early olfactory memory decline in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41882255},
issn = {1476-5578},
support = {82371446//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer's disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood. We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits. Clinical functional magnetic resonance imaging (fMRI) data revealed that connectivity between the piriform cortex (PCx) and the infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations. Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Impairment of PCx-IL functional connectivity may represent a new target for the diagnosis and treatment of early-stage AD.},
}

@article {pmid41882372,
year = {2026},
author = {Hajjar, IM and Neal, R and Singh, N and Yang, Z and Obideen, M and Shah, AM and Dammer, EB},
title = {Adhesion molecules provide an endothelial protein signature in preclinical and clinical Alzheimer's disease and predict clinical progression.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01519-4},
pmid = {41882372},
issn = {2730-664X},
abstract = {BACKGROUND: Cardiometabolic and inflammatory pathways may play important roles in Alzheimer's disease (AD) pathogenesis contributing to neuronal dysfunction even in the absence of cognitive symptoms. Our objective is to characterize proteomic signatures of these pathways in AD.

METHODS: We perform CSF and plasma-targeted proteomics using Olink's highly sensitive proximity extension assay from 354 participants, of which 4.2% had preclinical AD, and 19.5% had prodromal AD. Using data-driven bioinformatic pipeline, we describe proteomic signatures based on various AD traits.

RESULTS: The 276 measured proteins cluster into five modules that are associated with AD biomarkers and disease traits. We identify an AD signature in the CSF characterized by elevated levels of Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecules 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2 (SCARB2), and Plasminogen Activator Urokinase (PLAU) that was detectable even in preclinical AD. This signature also predicts clinical disease progression. Independent validation (n = 75) suggests that CSF adhesion molecules showed significant positive correlation with CSF Aβ-42: (R[2] ranged: 0.05-0.44) and pTau (R[2] ranged: 0.15-0.70).

CONCLUSIONS: Our results identify a signature centered around CSF vascular adhesion proteins that associates with AD pathology and disease progression, with elevation detectable even in the preclinical stage, warranting further mechanistic investigation.},
}

@article {pmid41883102,
year = {2026},
author = {Cheng, B and Chen, Y and Cai, F and Wen, X},
title = {Therapeutic Potential of Salvia miltiorrhiza Active Components in Various Diseases Based on the PI3K/Akt Signaling Pathway.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {3},
pages = {e03444},
doi = {10.1002/cbdv.202503444},
pmid = {41883102},
issn = {1612-1880},
support = {No.GJJ2400803//Science and Technology Research Project of the Jiangxi Provincial Department of Education/ ; No.2024B0016//the Science and Technology Project of the Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; No.202410412151//the Student Innovation and Entrepreneurship Project of Jiangxi University of Chinese Medicine/ ; No.2025WBZR006//the Doctoral Research Startup Foundation Project of Jiangxi University of Chinese Medicine/ ; },
mesh = {Humans ; *Salvia miltiorrhiza/chemistry/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism/antagonists & inhibitors ; *Signal Transduction/drug effects ; Animals ; *Phosphatidylinositol 3-Kinases/metabolism ; Neoplasms/drug therapy/metabolism ; *Drugs, Chinese Herbal/chemistry/pharmacology ; *Phosphatidylinositol 3-Kinase/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Atherosclerosis/drug therapy/metabolism ; Diabetic Nephropathies/drug therapy/metabolism ; },
abstract = {Salvia miltiorrhiza Bunge, known as danshen in China, is a key medicinal herb in traditional Chinese medicine that has long been used for the treatment of cardiovascular and cerebrovascular disorders. Its principal bioactive constituents fall into two broad categories: water-soluble phenolic acids (primarily including danshensu, salvianic acid A, salvianolic acid B, and rosmarinic acid) and lipid-soluble diterpenoids (primarily including tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone). Accumulating evidence shows that these active components exert diverse pharmacological effects, including anti-tumor, anti-inflammatory, antioxidant, and anti-neurodegenerative activities, via modulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Consistently, these components hold promising therapeutic potential against various diseases, including cancer, atherosclerosis, Alzheimer's disease, and diabetic nephropathy. Nevertheless, there is still a lack of a comprehensive and systematic summary of the precise mechanisms by which the active ingredients of danshen exert their therapeutic actions against the aforementioned diseases via the PI3K/Akt signaling pathway. To address this gap, this review systematically summarizes the regulatory effects of danshen's active components on the PI3K/Akt signaling pathway, aiming to clarify their therapeutic potential in various pathological conditions and thereby provide novel insights for the basic research and clinical application of danshen.},
}

Humans
*Salvia miltiorrhiza/chemistry/metabolism
*Proto-Oncogene Proteins c-akt/metabolism/antagonists & inhibitors
*Signal Transduction/drug effects
Animals
*Phosphatidylinositol 3-Kinases/metabolism
Neoplasms/drug therapy/metabolism
*Drugs, Chinese Herbal/chemistry/pharmacology
*Phosphatidylinositol 3-Kinase/metabolism
Alzheimer Disease/drug therapy/metabolism
Atherosclerosis/drug therapy/metabolism
Diabetic Nephropathies/drug therapy/metabolism

@article {pmid41883280,
year = {2026},
author = {Bugnon, A and Temperli, P and Abbes, H and Doser, N},
title = {[Cerebral amyloid angiopathy-related inflammation and anti-amyloid immunotherapies].},
journal = {Revue medicale suisse},
volume = {22},
number = {955},
pages = {1-7},
doi = {10.53738/REVMED.2026.22.955.e47917},
pmid = {41883280},
issn = {1660-9379},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/therapy/complications/diagnosis/immunology ; Alzheimer Disease/therapy ; *Immunotherapy/methods ; *Inflammation/therapy/etiology ; Prognosis ; },
abstract = {Cerebral amyloid angiopathy can be complicated by an inflammatory form known as CAA-ri (cerebral amyloid angiopathy-related inflammation), a rare but sometimes severe condition whose prognosis is improved by early diagnosis and treatment. CAA-ri shares physiopathological, clinical and radiological features with amyloid-related imaging abnormalities (ARIA), a complication observed during the development of novel anti-amyloid immunotherapies for Alzheimer's disease (AD). These ARIA are more frequent and severe in patients with CAA, requiring particular attention given the significant overlap between AD and this pathology. This article aims to raise awareness and improve recognition of these entities associated with amyloid deposition.},
}

Humans
*Cerebral Amyloid Angiopathy/therapy/complications/diagnosis/immunology
Alzheimer Disease/therapy
*Immunotherapy/methods
*Inflammation/therapy/etiology
Prognosis

@article {pmid41883437,
year = {2026},
author = {García Menéndez, S and Inserra, F and de Cavanagh, EM and Ferder, L and Manucha, W},
title = {Renin-angiotensin system blockade attenuates brain mitochondrial dysfunction, oxidative stress, and neuroinflammation associated with hypertension, metabolic disorders, and aging.},
journal = {World journal of experimental medicine},
volume = {16},
number = {1},
pages = {113259},
pmid = {41883437},
issn = {2220-315X},
abstract = {Although aging is an inherent part of life, it represents a process of progressive dysfunction rather than a fixed biological outcome. Consequently, highly prevalent conditions such as cardiorenal-metabolic syndrome-which encompasses obesity, hypertension (HTN), and metabolic disorders-can accelerate age-related changes. The renin-angiotensin system (RAS) plays a critical role in pathophysiology and affects multiple organs, including the brain. The central nervous system contains both RAS branches: The ACE/Ang II/AT1 and AT2 receptor axis, as well as the ACE2/Ang-(1-7)/Mas receptor axis. Neuroinflammation is a chronic process characterized by glial cell activation triggered by increased production of reactive oxygen and nitrogen species, resulting in oxidative stress. Mitochondria are the primary cellular sites where these processes occur. Under conditions such as metabolic disorders, obesity, HTN, and aging, these reactions are markedly accelerated. Associated mechanisms include insulin resistance, elevated levels of advanced glycation end-products, and disruption of the blood-brain barrier. The consequences of these alterations may include brain dysfunction, cognitive decline, Parkinson's disease, and neurodegenerative conditions such as Alzheimer's disease. This review focuses on the primary effects of therapeutic interventions on mitochondrial function, with particular attention to the modulation of oxidative stress, chronic neuroinflammation, and glial dysregulation. We highlight the strategic use of angiotensin receptor blockers and ACE2 activators as promising tools that may redefine the prevention and treatment of vascular dementia and other neurodegenerative diseases of inflammatory origin.},
}

@article {pmid41884282,
year = {2026},
author = {Chu, H and Sun, Y and Huang, C and Wang, L and Guo, Q and Jiang, L},
title = {Polydopamine Modified with Brain Targeting Peptide Rabies Virus Glycoprotein for Treatment of Alzheimer's Disease by Inhibiting Oxidative Stress and Inflammatory Response.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {564013},
pmid = {41884282},
issn = {1178-2013},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology ; Oxidative Stress/drug effects ; *Indoles/chemistry/pharmacology/administration & dosage ; Mice ; *Polymers/chemistry/pharmacology/administration & dosage ; *Glycoproteins/chemistry/pharmacology/administration & dosage ; Nanoparticles/chemistry ; Brain/drug effects/metabolism ; *Viral Proteins/chemistry/pharmacology/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Reactive Oxygen Species/metabolism ; Mice, Transgenic ; Humans ; Inflammation/drug therapy ; Male ; Ferroptosis/drug effects ; Peptide Fragments ; },
abstract = {PURPOSE: Polydopamine (PDA) has been recognized as an antioxidant and anti-inflammatory agent. However, the difficulty to cross blood-brain barrier (BBB) limits PDA's neuroprotective effects in the brain. Here, we aimed to construct PDA-rabies virus glycoprotein (RVG) by modifying the RVG29 polypeptide on PDA nanoparticles (NPs) and investigate whether PDA-RVG improved the cognitive function and pathology of Alzheimer's Disease (AD) by inhibiting oxidative stress and inflammatory response.

METHODS: We prepared and characterized PDA NPs and tested whether PDA improved AD pathology in APP/PS1 mice. To facilitate PDA's penetration across BBB, we modified RVG29 on PDA and examined its brain-specific targeting ability and biocompatibility. We further tested the effects of PDA-RVG on oxidative stress, inflammatory response and ferroptosis in both in vitro and in vivo AD models.

RESULTS: PDA demonstrated robust reactive oxygen species (ROS)-scavenging activity and effectively reduced Aβ deposition and the expression of APP and PS1 in APP/PS1 mice. PDA-RVG successfully crossed BBB in an in vitro BBB model. Meanwhile, compared with PDA, PDA-RVG intravenous injection exhibited good brain-specific targeting ability. Moreover, the hematological analysis revealed no significant differences between the PDA-RVG and control groups. In the in vitro AD experiment, PDA-RVG reduced ROS, inducible nitric oxide synthase, and pro-inflammatory cytokines levels in BV2 cells. Besides, PDA-RVG decreased ROS and apoptosis, while increased glutathione peroxidase4 (GPX4) and the viability of PC12 cells. More importantly, intravenous delivery of PDA-RVG improved cognitive function assessed by Morris water maze, and upregulated the ferroptosis-protective proteins Ferritin Heavy Chain 1 and GPX4 expression, while PDA alone did not lead to cognitive improvement.

CONCLUSION: PDA reduces AD pathology, which is possibly attributed to its ability to scavenge ROS, ameliorate the inflammatory microenvironment and inhibit ferroptosis. Intravenous delivery of PDA-RVG has good brain-specific targeting ability and biocompatibility, and improves cognitive function in AD mice. This study provides a safe, effective, and promising therapeutic strategy for AD via oxidative stress-associated target.},
}

Animals
*Alzheimer Disease/drug therapy/pathology
Oxidative Stress/drug effects
*Indoles/chemistry/pharmacology/administration & dosage
Mice
*Polymers/chemistry/pharmacology/administration & dosage
*Glycoproteins/chemistry/pharmacology/administration & dosage
Nanoparticles/chemistry
Brain/drug effects/metabolism
*Viral Proteins/chemistry/pharmacology/administration & dosage
Blood-Brain Barrier/metabolism/drug effects
Disease Models, Animal
Neuroprotective Agents/pharmacology/administration & dosage/chemistry
Reactive Oxygen Species/metabolism
Mice, Transgenic
Humans
Inflammation/drug therapy
Male
Ferroptosis/drug effects
Peptide Fragments

@article {pmid41884668,
year = {2026},
author = {Xia, L and Liu, T and Li, Z and Ao, X and Chen, Q and Zhou, X and Jiang, Q and Huang, N and Luo, Y},
title = {Icaritin ameliorates mitochondrial dysfunction and autophagy impairment in cellular models of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1741339},
pmid = {41884668},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory decline, with neuropathological hallmarks including amyloid plaques and neurofibrillary tangles. Current treatments only alleviate symptoms and cannot halt disease progression. Icaritin (ICT), a natural compound, has shown neuroprotective potential. Transactive response DNA-binding protein 43 (TDP-43) is widely recognized as a key neuropathological hallmark of AD and related dementias. This study investigated the protective effects of ICT against TDP-43-induced damage in N2a/APP695swe (APP) cells and explored the underlying mechanisms.

METHODS: N2a/APP695swe/TARDBP cells overexpressing APP and TDP-43 were constructed via lentiviral transfection, and the optimal ICT dosage was determined using the CCK-8 assay. The effects of ICT on TDP-43 cell phenotypes were then assessed using CCK-8, ELISA, and Western blot. Finally, transmission electron microscopy, flow cytometry, assay kits, and Western blot were used to investigate the protective mechanisms of ICT.

RESULTS: ICT treatment significantly increased cell viability, reduced Aβ42 levels, and alleviated phospho-Tau and phospho-TDP-43 accumulation. Mechanistically, ICT improved mitochondrial morphology, decreased ROS levels, enhanced ATP production, and modulated the AMPK/mTOR and PINK1/Parkin autophagy signaling pathways to mitigate TDP-43-mediated cellular stress.

CONCLUSION: ICT protects cells from TDP-43-induced mitochondrial dysfunction and autophagy impairment, providing mechanistic insight into its potential as a therapeutic agent for AD.},
}

@article {pmid41885175,
year = {2026},
author = {Young, CB and Sheng, J and Winer, JR and Cody, K and Sai, I and Carlson, ML and Younes, K and Insel, PS and Schultz, AP and Mormino, EC},
title = {Longitudinal trajectories of divergent cortical tau patterns in preclinical Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag113},
pmid = {41885175},
issn = {1460-2156},
abstract = {Approximately 10% of clinically unimpaired individuals with abnormal amyloid (A+; preclinical Alzheimer's disease) have "divergent" cortical tau pathology (A+TCortical+), defined as greater than expected tau in cortical regions relative to medial temporal lobe and/or cortical asymmetry on tau PET in addition to or instead of traditional medial temporal lobe tau burden. Although these A+TCortical+ individuals have subtle cognitive deficits at baseline, the longitudinal imaging and clinical outcomes are unknown. We aimed to characterize longitudinal trajectories of A+TCortical+ individuals compared to other biomarker-defined clinically unimpaired groups given that identifying those at highest risk for decline is critical for informing prevention trials and understanding early disease mechanisms. In this longitudinal study, we examined tau PET, MRI, cognitive, and functional data from 395 clinically unimpaired participants, ages 65 to 85 years, enrolled in the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study. Participants had 2-5 flortaucipir scans over a mean (standard deviation) follow-up period of 4.7 (1.6) years. Change in regional and voxelwise tau patterns, atrophy, cognition, and functioning were examined. Longitudinal trajectories from A+TCortical+ (n=34) were compared to preclinical Alzheimer's disease with elevated tau PET signal in medial temporal lobe only (A+TMTL+, n=102), preclinical Alzheimer's disease without significant tau (A+TMTL-, n=210), and those without amyloid or tau (A-TMTL-, n=49). Cortical tau accumulation was fastest in A+TCortical+ (0.018-0.034 standardized uptake value ratios per year), whereas medial temporal lobe tau accumulation was comparable across A+TCortical+, A+TMTL+, and A+TMTL- groups (0.010-0.013 standardized uptake value ratios per year). Tau continued to accumulate in affected regions and contralateral homotopic regions in A+TCortical+ participants with asymmetrical tau at baseline such that asymmetrical patterns were maintained over time. Younger A+TCortical+ participants had an especially fast cortical accumulation rate. The A+TCortical+ group showed significantly greater neurodegeneration and faster clinical decline (Clinical Dementia Rating Scale Sum of Boxes = 0.610 points per year; Mini-Mental State Examination = -0.780 points per year) than all other biomarker-defined subgroups (Clinical Dementia Rating Scale Sum of Boxes = 0.048-0.182 points per year; Mini-Mental State Examination = -0.189-0.006 points per year). In summary, individuals with divergent cortical tau patterns continue to accumulate cortical tau at a faster rate, show greater neurodegeneration, and have faster cognitive and functional decline than other preclinical Alzheimer's disease subgroups. Clinical trials and research examining tau progression and clinical decline in preclinical Alzheimer's disease without subtyping may be disproportionately influenced by this small, high-risk subgroup.},
}

@article {pmid41885326,
year = {2026},
author = {Dangpiaei, S and Kamal, KM and Shoair, OA and Al-Mamun, MA},
title = {Incidence of amyloid-related imaging abnormalities and health resource utilization in patients with Alzheimer disease receiving monoclonal antibody treatments: A real-world evidence study.},
journal = {Journal of managed care & specialty pharmacy},
volume = {32},
number = {4},
pages = {470-484},
doi = {10.18553/jmcp.2026.32.4.470},
pmid = {41885326},
issn = {2376-1032},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Female ; Aged ; Male ; Retrospective Studies ; Aged, 80 and over ; Incidence ; *Antibodies, Monoclonal/adverse effects/therapeutic use ; Middle Aged ; *Health Resources/statistics & numerical data ; Patient Acceptance of Health Care/statistics & numerical data ; },
abstract = {BACKGROUND: All recently approved monoclonal antibodies (eg, aducanumab, lecanemab, and donanemab) for Alzheimer disease (AD) were shown to increase the risks of amyloid-related imaging abnormalities (ARIA) in randomized clinical trials, which can include brain swelling or hemorrhage. Real-world evidence (RWE) studies are critically warranted to evaluate the associated risks of ARIA and health care resource utilization (HRU) with monoclonal treatments compared with existing nonmonoclonal (eg, donepezil, memantine and rivastigmine) treatments.

OBJECTIVE: To evaluate the risk of ARIA in patients receiving monoclonal vs nonmonoclonal treatments. The secondary aim was to investigate the HRUs including emergency department (ED) and inpatient visits between the 2 groups.

METHODS: We conducted a retrospective study using a large electronic health record dataset. Individuals (aged ≥18 years) diagnosed with AD and receiving monoclonal treatment were matched with a nonmonoclonal treatment group using propensity score matching. An Andersen-Gill survival model was used to estimate the cumulative hazard of ARIA after adjusting for baseline comorbidities. Negative binomial regression was applied to assess the HRUs between the 2 groups.

RESULTS: The monoclonal group included 240 patients. Most patients in both groups were aged 70-80 years (47.08% vs 47.29%), female (55.42% vs 56.25%), and White (85.42% vs 85.83%) in the monoclonal and the nonmonoclonal groups, respectively. The monoclonal group had significantly higher cumulative hazard of ARIA (hazard ratio = 4.65, 95% CI = 3.77-5.73; P < 0.001) compared with the nonmonoclonal group. Concurrent antithrombotic use (1.87, 1.48-2.37; P < 0.001), a history of stroke (1.59, 1.21-2.10; P < 0.001), and hyperlipidemia (1.41, 1.09-1.84; P = 0.008) were also associated with increased hazard of ARIA. Among those patients who had at least 180 days of follow-up, the monoclonal group had significantly fewer inpatient visits (β = -2.71, -3.84 to -1.58; P < 0.001) compared with the nonmonoclonal group.

CONCLUSIONS: Monoclonal treatment was associated with higher cumulative hazard of ARIA but fewer inpatient visits. This study indicated the potential of RWE, despite its distinct observational design and differences from randomized clinical trials, to serve as a credible proof-of-concept in postapproval assessment and to inform personalized treatment guidelines based on patients' risk factors.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging
Female
Aged
Male
Retrospective Studies
Aged, 80 and over
Incidence
*Antibodies, Monoclonal/adverse effects/therapeutic use
Middle Aged
*Health Resources/statistics & numerical data
Patient Acceptance of Health Care/statistics & numerical data

@article {pmid41885876,
year = {2026},
author = {Wang, J and Zhang, B and Liu, L and Li, X and Xie, Z and Yang, X},
title = {Vanadyl Complexes (VOp-Dmada) Promote Healthy Aging by Regulating Electron Transport Mediated by Mitochondrial Complex II.},
journal = {ChemMedChem},
volume = {21},
number = {6},
pages = {e202600003},
doi = {10.1002/cmdc.202600003},
pmid = {41885876},
issn = {1860-7187},
support = {22177007//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Mice ; *Electron Transport Complex II/metabolism/antagonists & inhibitors ; Electron Transport/drug effects ; *Mitochondria/metabolism/drug effects ; *Healthy Aging/drug effects ; *Coordination Complexes/pharmacology/chemistry/chemical synthesis ; Caenorhabditis elegans/drug effects ; Reactive Oxygen Species/metabolism ; Molecular Structure ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; *Vanadium Compounds/pharmacology/chemistry ; },
abstract = {Vanadium compounds are promising metallodrug candidates, with well-documented antidiabetic, antitumor, and anti-Alzheimer's activities. In search for the long-term beneficial or adverse effects of antidiabetic vanadyl complexes, we serendipitously discovered that the vanadyl complexes VOp-dmada exerted pro-healthy aging effects across a diverse panel of model organisms, i.e., yeast, C. elegans, and SAMP8 mice. Furthermore, VOp-dmada attenuated replicative senescence in mouse embryonic fibroblasts and alleviated thymic epithelial cell aging while preserving thymic architecture and function in a mouse model of dexamethasone-induced acute thymic atrophy. Mechanistic investigations revealed that VOp-dmada improved the structural integrity and functional capacity of mitochondrial complex II. This effect was mediated by activation of the c-Myc/S-phase kinase-associated protein 2 (SKP2)/sirtuin 3 (SIRT3) signaling axis, which in turn upregulated succinate dehydrogenase subunit A (SDHA) expression. Thus, vanadyl complexes suppressed reactive oxygen species (ROS) generation at the source, disrupted the deleterious ROS-thioredoxin-interacting protein (TXNIP) vicious cycle, and ultimately decelerated the aging process. Our findings highlight the potential application of antidiabetic vanadium complexes in the treatment of other aging-related disorders and corroborate the chronic safety profile. Moreover, these results support the targeting of mitochondrial complex II function and integrity as a novel strategy for the discovery of pro-healthy aging agents.},
}

Animals
Mice
*Electron Transport Complex II/metabolism/antagonists & inhibitors
Electron Transport/drug effects
*Mitochondria/metabolism/drug effects
*Healthy Aging/drug effects
*Coordination Complexes/pharmacology/chemistry/chemical synthesis
Caenorhabditis elegans/drug effects
Reactive Oxygen Species/metabolism
Molecular Structure
Structure-Activity Relationship
Dose-Response Relationship, Drug
*Vanadium Compounds/pharmacology/chemistry

@article {pmid41886471,
year = {2026},
author = {Luo, N and Pandit, H and Kalra, S and Tran, E and Mandelblatt, J and Vicini, S and Rebeck, GW},
title = {APOE4 and doxorubicin impair inhibitory interneuron function and homeostatic regulation in the entorhinal cortex.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0343276},
doi = {10.1371/journal.pone.0343276},
pmid = {41886471},
issn = {1932-6203},
mesh = {Animals ; *Doxorubicin/pharmacology/adverse effects ; *Apolipoprotein E4/genetics/metabolism ; *Entorhinal Cortex/drug effects/metabolism/physiology ; *Interneurons/drug effects/metabolism/physiology ; Mice ; *Homeostasis/drug effects ; Pyramidal Cells/drug effects/metabolism/physiology ; Humans ; Parvalbumins/metabolism ; Male ; Female ; Genotype ; Mice, Transgenic ; },
abstract = {APOE4 is a risk factor for several disease states associated with cognitive impairment, including Alzheimer's disease and cancer-chemotherapy induced cognitive impairment. Using mouse knock-in models of human APOE alleles, we examined the effects of APOE genotype and chemotherapy on the ex vivo electrophysiological characteristics of excitatory and inhibitory neurons in the entorhinal cortex (EC). We found that APOE4 is associated with a significantly higher excitatory/inhibitory ratio (0.33 ± 0.04) in the layer 2/3 pyramidal cells of the entorhinal cortex compared to APOE3 (0.19 ± 0.04). We crossed APOE mice to mice with parvalbumin (PV) interneurons tagged with tdTomato, allowing us to measure effects specifically on this inhibitory cell type. For EC pyramidal neurons, the chemotherapeutic agent doxorubicin caused increases in the amplitudes of both spontaneous excitatory and inhibitory post-synaptic currents, with significant responses (***p < 0.001; **p < 0.01 respectively) in APOE3 brains. For EC PV neurons, APOE4 genotype was associated with significantly lower firing rates at injections of high currents (**p < 0.01), but rates were unaffected by doxorubicin. Doxorubicin doubled the percentage of PV cells that showed inactivation block in APOE3 brains (25% to 52%) but had no effect on APOE4 brains (50% to 54%). This ex vivo study suggests that APOE4 impairs homeostatic synaptic transmission in pyramidal cells under control conditions and causes a lack of responsiveness to a stressor (doxorubicin treatment) in PV cells.},
}

Animals
*Doxorubicin/pharmacology/adverse effects
*Apolipoprotein E4/genetics/metabolism
*Entorhinal Cortex/drug effects/metabolism/physiology
*Interneurons/drug effects/metabolism/physiology
Mice
*Homeostasis/drug effects
Pyramidal Cells/drug effects/metabolism/physiology
Humans
Parvalbumins/metabolism
Male
Female
Genotype
Mice, Transgenic

@article {pmid41699585,
year = {2026},
author = {Zhang, R and Chen, D and Qin, Y and Han, H and Yu, H},
title = {Longitudinal multi-modal data prediction model for mild cognitive impairment by deep survival analysis.},
journal = {BMC medical informatics and decision making},
volume = {26},
number = {1},
pages = {},
pmid = {41699585},
issn = {1472-6947},
abstract = {BACKGROUND: Timely prediction of cognitive decline in patients with Mild Cognitive Impairment (MCI) is crucial for guiding optimal therapeutic interventions. In this study, we aimed to develop a deep survival analysis model that leverages longitudinal, multi-modal data to estimate the probability of dementia conversion, thereby facilitating personalized treatment planning in clinical practice.

METHODS: We employed a deep neural network model specifically designed for survival analysis to predict the progression from MCI to Alzheimer’s Disease (AD). The model integrated longitudinal biomarkers, including neuropsychological assessments and neuroimaging measures, along with baseline demographic characteristics and genetic risk factors, using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

RESULTS: This study enrolled 922 baseline MCI patients for analysis. The predictive performance was evaluated using a test set at time intervals [Formula: see text] = 1, 2, 3, 4 years from the landmark time s = 1. The prognostic model exhibited outstanding predictive capability, attaining cdAUC values of 0.9089 ± 0.01 alongside BS of 0.1651 ± 0.01 with [Formula: see text] = 1 year on the test set, when all variable sets were incorporated into the time-dependent Cox survival neural network (tdCoxSNN) model. Through feature significance evaluation, the Functional Activities Questionnaire (FAQ) emerged as the most influential predictive element.

CONCLUSIONS: By systematically integrating diverse longitudinal biomarkers, we developed a dynamic prediction model for MCI using deep survival analysis. This approach enables accurate individual risk stratification, facilitates the early identification of high-risk individuals, and supports informed, personalized clinical decision-making.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12911-026-03387-3.},
}

@article {pmid41876052,
year = {2026},
author = {Harutyunyan, H and Minasyan, R and Kalueff, AV and Yenkoyan, KB},
title = {Neurobiological links between Alzheimer's disease and reward system dysfunction.},
journal = {Neuroscience},
volume = {603},
number = {},
pages = {57-68},
doi = {10.1016/j.neuroscience.2026.03.028},
pmid = {41876052},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a highly prevalent progressive neurodegenerative disorder with unclear etiology, complex symptoms, and limited treatment options. Early pathological processes in AD emerge long before the onset of overt cognitive and motor symptoms and involve the accumulation of amyloid-β oligomers and neurofibrillary tangles, accompanied by neuroinflammation and neuronal loss. Importantly, the brain reward system comprises cortical and subcortical structures that share neurochemical pathways and reciprocal connectivity with regions affected during AD progression. Consistent with this overlap, reward-related behavioral deficits, including apathy, anhedonia, and motivational impairments, are frequently observed in both patients with AD and experimental models of the disease. Here, we discuss the neuroanatomical, neurochemical, and molecular overlap between AD pathology and reward-related neural circuits and propose that dysfunction of the reward system may represent an important pathogenetic endophenotype of AD. A better understanding of these multilevel interactions may help refine the conceptual framework of AD and support the development of novel therapeutic strategies targeting reward-related circuits and their underlying molecular mechanisms.},
}

@article {pmid41877272,
year = {2026},
author = {Scenna, MS and Maceroni, E and Cimini, A and Castelli, V and d'Angelo, M},
title = {Hypertension and brain damage: evidence from rodent models.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {41877272},
issn = {1738-6055},
abstract = {Hypertension is a prevalent condition that significantly raises the incidence of cerebrovascular and cognitive disorders. This review focuses on the factors most closely linked to stroke, cognitive impairment, and Alzheimer's disease. Research into pathophysiology and treatment of hypertensive brain damage has greatly benefited from rodent models, which have been crucial in uncovering the underlying mechanisms and developing effective therapeutic strategies. Rodent models, particularly spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHR-SP), have been essential in elucidating the pathophysiological mechanisms connecting hypertension to brain damage. These models exhibit structural and functional cerebrovascular alterations, including blood-brain barrier disruption, microvascular rarefaction, and neuroinflammation. Interventions targeting the renin-angiotensin system have shown promise in mitigating these adverse effects. This review synthesizes current findings from rodent studies, underscoring the pivotal impact of hypertension in brain pathology and the potential therapeutic benefits of antihypertensive treatments.},
}

@article {pmid41877626,
year = {2026},
author = {Zhou, X and Wang, R and Yan, J and Wu, X and Yuan, D and Wang, Q and Li, H and Zhao, W},
title = {Atractylenolide I mitigates Alzheimer's disease pathology in ApoE [-/-] mice via ARG1/nNOS axis and lipid homeostasis regulation.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026055},
pmid = {41877626},
issn = {1745-7270},
abstract = {Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Atractylodes macrocephalaKoidz., exhibits multimodal bioactivities with demonstrated anti-inflammatory and neuroprotective properties. To explore its therapeutic potential against AD pathology, we use high-fat diet (HFD)-fed ApoE knockout (ApoE [-/-]) mice treated with or without AI for 12 weeks. Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis, particularly cerebral lipid deposition, suppresses neuroinflammation via downregulation of M1 macrophage polarization markers, and restores cognitive function through neuronal preservation in hippocampal regions. Mechanistically, AI orchestrates cholesterol efflux by upregulating ATP-binding cassette transporter A1 (ABCA1) and liver X receptor (LXR) expression, while concurrently modulating the abundance of arginine biosynthesis metabolites (urea, malic acid, and creatinine) to rebalance neurovascular homeostasis. Notably, western blot and RT-qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1 (ARG1) and simultaneously upregulates the expression of neuronal nitric oxide synthase (nNOS). Further molecular docking and surface plasmon resonance (SPR) analyses confirm the direct binding of AI to ARG1, indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism. These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.},
}

@article {pmid41877664,
year = {2026},
author = {Pennington, C and Apurva, P and Chen, A and Duncan, A and Mackay, G and Masters, H and Paramore, K and Russ, T and Skinner, H and Zeidler, M},
title = {Disease modifying treatments for Alzheimer's disease: Clinician perspectives.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261429859},
doi = {10.1177/13872877261429859},
pmid = {41877664},
issn = {1875-8908},
abstract = {In recent years there have been exciting developments in the diagnosis and treatment of mild cognitive impairment and dementia due to Alzheimer's disease. Robust biomarkers and potentially disease modifying therapies are now available, with multiple other agents in clinical trials alongside on-going validation studies of blood-based biomarkers. Recent and probable future developments in the diagnosis and care of people with Alzheimer's disease pathology warrants serious re-evaluation of the structure and function of cognitive clinical services. Here we report recommendations from the November 2024 Brain Health Scotland roundtable discussion of opportunities and challenges for modern memory services.},
}

@article {pmid41878314,
year = {2026},
author = {Tang, S and Liao, Y and Yang, M and Yue, R},
title = {Brain insulin resistance: a key pathological hub linking metabolic and neuropsychiatric comorbidities.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1716291},
pmid = {41878314},
issn = {1663-4365},
abstract = {The high rate of comorbidity between metabolic diseases and neuropsychiatric disorders suggests a shared underlying pathogenic mechanism. However, the biological basis of this relationship remains unclear. This study aims to clarify the role of brain insulin resistance (BIR) in linking metabolic dysfunction to neuropsychiatric symptoms based on existing evidence. The analysis shows that BIR disrupts limbic system function through two primary molecular pathways: (1) impairment of the PI3K/Akt/mTOR pathway, which decreases the expression of synaptic plasticity-related proteins and causes deficits in long-term potentiation (LTP); (2) activation of the TLR4/MyD88 inflammatory axis, promoting pro-inflammatory cytokine release from glial cells. These changes result in characteristic neuropsychiatric phenotypes, including amygdala hyperactivity (emotional disorders), hippocampal atrophy (memory impairment), and decreased prefrontal cortex (PFC) function (executive dysfunction). This review highlights that interventions targeting BIR might simultaneously improve metabolic outcomes and neuropsychiatric symptoms, providing a theoretical foundation for trans-diagnostic treatment models. The findings support the view of BIR as a modifiable interface for metabolic- neuropsychiatric comorbidities and advocate for the development of a multidisciplinary collaborative framework to facilitate mechanism-based precision therapy.},
}

@article {pmid41879387,
year = {2026},
author = {Cheng, J and Zhang, C and Yang, L and Li, G and Jiang, X and Chen, P and Duan, X},
title = {An integrated strategy including chemical profiling, network pharmacology and experimental evaluation was used to investigate the effects of Rubia yunnanensis water decoction on vascular dementia.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {5},
pages = {1262-1283},
doi = {10.36721/PJPS.2026.39.5.REG.14029.1},
pmid = {41879387},
issn = {1011-601X},
mesh = {Animals ; *Network Pharmacology/methods ; *Dementia, Vascular/drug therapy/metabolism/pathology/psychology ; *Drugs, Chinese Herbal/pharmacology/chemistry ; Rats ; *Neuroprotective Agents/pharmacology ; Male ; Rats, Sprague-Dawley ; Disease Models, Animal ; Signal Transduction/drug effects ; Apoptosis/drug effects ; },
abstract = {BACKGROUND: Vascular dementia (VaD) is the second most prevalent cause of dementia following Alzheimer's disease. Rubia yunnanensis, a medicinal plant recorded in the Chinese Materia Medica, has historically been utilized for managing cerebral ischaemia-related disorders. While recent attention has focused on its neuroprotective potential, the specific mechanisms underlying the effects of Rubia yunnanensis water decoction (RY-W) on VaD remain unelucidated.

OBJECTIVES: This study aimed to identify the active chemical components and elucidate the molecular mechanisms of RY-W in the treatment of VaD by integrating network pharmacology with experimental validation.

METHODS: The chemical constituents of RY-W and their potential therapeutic targets were analyzed using UPLC-MS/MS and network pharmacology techniques. To validate these findings, the cerebral protective effects of RY-W were assessed in a rat model of VaD. Cognitive function was evaluated using the Morris Water Maze (MWM) test. Pathological changes and molecular markers were analyzed via Hematoxylin and Eosin (HE) staining, Nissl staining, TUNEL fluorescence staining, Immunohistochemistry (IHC), and Western blotting.

RESULTS: Network pharmacology analysis identified IL-6, IL-1β, ALB, TNF, and AKT1 as potential core targets for RY-W. Experimental results demonstrated that RY-W significantly alleviated cognitive deficits in VaD rats. Furthermore, RY-W exhibited anti-inflammatory properties and reduced neuronal apoptosis. These neuroprotective effects appear to be mediated through the regulation of ALB and the PI3K-Akt signaling pathway.

CONCLUSION: RY-W effectively ameliorates VaD pathology by exerting anti-inflammatory and anti-apoptotic effects. These findings highlight the involvement of ALB and the PI3K-Akt signaling pathway in the therapeutic action of RY-W, supporting its potential as a treatment for vascular dementia.},
}

Animals
*Network Pharmacology/methods
*Dementia, Vascular/drug therapy/metabolism/pathology/psychology
*Drugs, Chinese Herbal/pharmacology/chemistry
Rats
*Neuroprotective Agents/pharmacology
Male
Rats, Sprague-Dawley
Disease Models, Animal
Signal Transduction/drug effects
Apoptosis/drug effects

@article {pmid41879434,
year = {2026},
author = {Hu, S and Chen, Z and Fu, Y},
title = {EEG Oscillations and the Modulation of tES and TMS in Patients with Mild Cognitive Impairment.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050430368260120052142},
pmid = {41879434},
issn = {1875-5828},
abstract = {Mild cognitive impairment (MCI) is characterized by objective cognitive decline that does not severely impact daily independence. This clinical stage may stem from various underlying causes, including Alzheimer's disease pathology. MCI provides a valuable opportunity to study interventions that could slow cognitive decline. Individuals with MCI show alterations in neural oscillations linked to cognitive impairment. Non-invasive brain stimulation (NIBS) techniques, including transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), along with their major forms, transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), can effectively modulate neural oscillations and improve cognition in MCI patients. Due to the potential of NIBS in the treatment of MCI, this review focuses on EEG abnormalities of neural oscillations in MCI patients and examines how repetitive TMS (rTMS), tDCS, and tACS improve cognitive function by targeting specific EEG frequency bands. A literature review was conducted for this study using the PubMed database, including studies published up to May 2025. Studies demonstrated that MCI patients have significant changes in EEG activity, with increases in the low-frequency band (δ-θ, 0.5-8 Hz) and decreases in the high-frequency band (β-γ, 12-100 Hz), and there are few reports on changes in mid-frequency α (8-12 Hz) EEG activity. Notably, tDCS improves cognition in MCI patients by decreasing low-frequency and increasing highfrequency EEG activity, whereas rTMS and tACS achieve similar effects mainly by increasing highfrequency EEG activity. Overall, this review provides an understanding of the role of NIBS in modulating neural oscillations and improving cognition in MCI, which may guide future therapeutic strategies. Future studies could explore the specific molecular pathways of neural oscillatory dysfunction in MCI and investigate the correlation between neural oscillations and other biomarkers, such as amyloid plaques and tau tangles, for a more comprehensive understanding of the disease.},
}

@article {pmid41879436,
year = {2026},
author = {Hu, G and Zhang, M},
title = {Efficacy and Safety of Donanemab in the Treatment of Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050425914260119063736},
pmid = {41879436},
issn = {1875-5828},
abstract = {INTRODUCTION: Donanemab is a monoclonal antibody targeting amyloid-β plaques. This study aims to quantify donanemab's consistent cognitive benefits, biomarker efficacy, and safety risks by pooling data from all available RCTs.

MATERIALS AND METHODS: Systematic searches were conducted in PubMed, the Cochrane Library, Web of Science, and Embase. Phase II/III randomized controlled trials comparing donanemab with placebo in amyloid-positive early Alzheimer's disease were included. After screening 133 records, two trials met the inclusion criteria.

RESULTS: Donanemab significantly reduced cognitive decline (iADRS +2.93; 95% CI: 1.52- 4.33; P < 0.0001) and functional progression (CDR-SB -0.66; 95% CI: -0.90 to -0.42; P < 0.00001), with amplified benefits in low/medium tau burden patients (iADRS +3.80; 95% CI: 2.10- 5.50). Amyloid clearance was dramatically higher with donanemab (risk ratio (RR) = 234.46; 95% CI: 68.17-806.38; P < 0.00001), with 76.4% achieving amyloid-negative status. There were significantly elevated risks of ARIA-E (RR = 12.90; 95% CI: 8.15-20.43; P < 0.00001), ARIA-H (RR = 2.86; 95% CI: 1.61-5.06; P = 0.0003), and treatment discontinuation (RR = 3.26; 95% CI: 2.38- 4.47; P < 0.00001), whereas all-cause mortality was not significantly different (RR = 1.44; 95% CI: 0.69-3.00).

DISCUSSION: Donanemab showed statistically significant cognitive benefits, but its clinical meaningfulness warrants careful interpretation. The iADRS improvement of 2.93 points and the CDRSB reduction in all patients of 0.66 points did not approach their minimal clinically important difference (MCID).

CONCLUSION: Donanemab provides statistically significant but modest benefits in early AD, particularly in low-tau subgroups. However, the magnitude of cognitive and functional improvement did not approach the threshold for a MCID in the overall population, which requires stringent safety monitoring for ARIA. Clinical implementation should prioritize PET stratification and APOEguided surveillance.},
}

@article {pmid41871009,
year = {2026},
author = {Hallam, RD and Foran, G and Fletcher, NK and MacPherson, REK and Necakov, A},
title = {BDNF alters β-cleavage of APP and subcellular distribution of BACE1.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.00642.2025},
pmid = {41871009},
issn = {1522-1563},
support = {PGS-D//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; PGS-D//NSERC | RES'EAU-WaterNET/ ; RGPIN-2017-03904//NSERC | RES'EAU-WaterNET/ ; RGPIN-2018-06781//NSERC | RES'EAU-WaterNET/ ; },
abstract = {The accumulation and deposition of amyloid-beta (Aß) peptides is detrimental to neuronal networks and is driven by the cleavage of amyloid precursor protein (APP) by beta-secretase 1 (BACE1). The proteolytic processing of APP is tightly regulated by the opposing activities of BACE1 and ADAM10, with the latter producing a truncated, non-amyloidogenic fragment. Maintaining this balance is critical for normal physiological function, as complete inhibition of BACE1 has proven detrimental owing to the important physiological roles of its many substrates. Brain-derived neurotrophic factor (BDNF), an important mediator of neuronal function and survival, has recently been shown to reduce BACE1 activity in neural tissue, but the mechanism for this remains unknown. Previous research suggests that BACE1 cleavage of APP is favoured at acidic intracellular compartments, whereas non-amyloidogenic processing preferentially occurs at the plasma membrane. Hence, we hypothesized that BDNF alters the subcellular distribution of BACE1, reducing ß-cleavage of APP. Here, we show that acute BDNF treatment of differentiated neural cells (SH-SY5Y) reduced levels of sAPPß, a product of BACE1 cleavage of APP. Using confocal microscopy and quantitative image analysis, we found that this reduction in sAPPß levels is coincident with increased BACE1 localization to the plasma membrane, and a concomitant reduction of BACE1 localization to early endosomes. This effect appears to be independent of clathrin-mediated endocytosis (CME), as inhibition of CME by PitStop2 treatment increased a-cleavage of APP but did not reduce ß-cleavage independent of BDNF treatment. Hence, BDNF may reduce production of Aß by altering BACE1 distribution and decreasing upstream ß-cleavage.},
}

@article {pmid41872339,
year = {2026},
author = {Vrillon, A and Götze, K and Dumurgier, J and Cognat, E and Hourrègue, C and Munoz-Musat, E and Decaix, T and Hugon, J and Estrada, J and Sebbagh, M and Bouaziz-Amar, É and Lilamand, M and Paquet, C},
title = {Eligibility for lecanemab treatment in a French memory clinic setting.},
journal = {Journal of neurology},
volume = {273},
number = {4},
pages = {},
pmid = {41872339},
issn = {1432-1459},
support = {1310194//Foundation Alzheimer Young Researcher Program/ ; },
mesh = {Humans ; Female ; Male ; Aged ; France ; Retrospective Studies ; *Alzheimer Disease/drug therapy/cerebrospinal fluid/diagnosis ; Aged, 80 and over ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Eligibility Determination ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Patient Selection ; },
abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies, including lecanemab and donanemab, are now available for the treatment of Alzheimer's disease (AD). Defining real-world patient eligibility and identifying barriers to access are critical for their effective implementation in routine clinical practice.

METHODS: Retrospective observational multicenter study of patients who underwent CSF AD biomarker testing at Lariboisière Hospital (Paris, France) from 2023 to 2024, assessing lecanemab eligibility using CLARITY AD trial criteria and the French Memory Clinic Federation appropriate use recommendations (AURs) following EMA authorization.

RESULTS: From a source population of 3075 patients, 676 underwent CSF testing, and 356 had biomarker-confirmed AD; 315 patients with MRI, APOE status, and MMSE data available (mean age 73.2 ± 8.1 years; 47.8% female; median MMSE 22 [IQR 19-26]) were screened. Using CLARITY AD trial criteria, 90 patients (28.6%) were eligible; low MMSE scores and MRI findings were the most frequent exclusion criteria. French AURs reduced eligibility to 75 patients (23.8%), excluding patients with a CSF A + T - profile and APOE ε4 homozygotes. Eligibility did not differ by age group. Eligibility rates from the entire source population equated to only 2.9% of patients using the CLARITY AD criteria and 2.4% using the French AURs. At follow-up, 34.5% of initially eligible patients no longer met the MMSE eligibility criteria.

DISCUSSION: In specialized settings, lecanemab eligibility remained limited, highlighting the need for early AD diagnosis and efficient screening pathways.},
}

Humans
Female
Male
Aged
France
Retrospective Studies
*Alzheimer Disease/drug therapy/cerebrospinal fluid/diagnosis
Aged, 80 and over
Middle Aged
*Antibodies, Monoclonal, Humanized/therapeutic use
*Eligibility Determination
Amyloid beta-Peptides/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
*Patient Selection

@article {pmid41872889,
year = {2026},
author = {Merikle, E and Presnall, C and Feaster, T and Moxon, R and Siemers, E and Kerwin, D and Cline, S},
title = {Elucidating the phase 1 trial experience among study participants following completion of the INTERCEPT-AD study of sabirnetug (ACU193) for early Alzheimer's disease: a qualitative interview study.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-026-09656-w},
pmid = {41872889},
issn = {1745-6215},
abstract = {BACKGROUND: Recruitment and retention remain persistent challenges in Alzheimer's disease (AD) clinical trials, particularly as studies increasingly focus on earlier disease stages and require longer participation and more invasive procedures. Understanding how trial enrollment and participation are experienced is critical to improving acceptability and sustaining engagement. Qualitative interviews conducted alongside clinical trials offer an opportunity to capture participant and study partner perspectives on the trial experience. In INTERCEPT-AD, a phase 1 trial evaluating safety and tolerability of the Aβ oligomer-selective monoclonal antibody sabirnetug (ACU193) among participants with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD), semi-structured qualitative interviews concerning trial experience were conducted with a subset of participants and their study partners.

METHODS: Participant/study partner dyads completed qualitative interviews following the final study visit. A semi-structured interview guide elicited descriptions regarding motivations for participating, enrollment decision-making, and positive and negative aspects of participation. Principles of applied qualitative thematic analysis guided the qualitative analyses. Exploratory analyses examined how factors differ by participant gender.

RESULTS: Twenty-eight participants (64.2% female) and their study partners were interviewed, representing 43% of the trial population (n = 65; 53.8% female). Participants and study partner dyads described varied pathways to trial awareness and enrollment decision-making, including both independent and family-involved decisions. Motivations for participation reflected anticipated personal benefit as well as altruistic goals. While interactions with study staff were viewed positively, dyads reported meaningful burdens related to travel, time commitment, and study procedures, with cognitive testing more frequently described as challenging than invasive procedures. A recurring theme was the desire for clearer communication and greater access to study-related information, including test results and treatment assignment. Exploratory analyses suggested that perceived burden and enrollment decision-making may differ by participant gender.

CONCLUSIONS: Study findings suggest opportunities to enhance the AD trial experience by addressing trial-related burdens and logistical aspects of participation. Exploratory gender analyses yielded additional insight into the patient trial experience but should be further examined along with race/ethnicity and study partner characteristics to enhance clinical study design and execution.},
}