@article {pmid41555076,
year = {2026},
author = {Sasmita, AO and Depp, C},
title = {A Question of Origins: Non-neuronal Sources of Amyloid-β.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41555076},
issn = {1995-8218},
abstract = {Amyloid-β (Aβ) plaques and neurofibrillary tau tangles are hallmarks of Alzheimer's disease (AD). While the intracellular localization of tau tangles within neurons nominates them as the primary producers of tau, the cellular origin of Aβ is less clear as plaques accumulate extracellularly. Neurons have been considered the sole source of Aβ, leading to the generation of many AD animal models expressing familial AD protein variants specifically in neurons. However, emerging evidence showed that non-neuronal cells abundantly express amyloid precursor protein (APP) and its processing machinery. Among these, oligodendrocytes (OLs) exhibit the highest expression of amyloidogenic components, produce Aβ, and contribute to plaque burden in vivo. Here, we highlight reports on non-neuronal Aβ production in the context of AD and the function of APP processing in these cells. Understanding Aβ processing in non-neuronal cells might enable the identification of novel therapeutic targets, especially in humans whose brain structures differ greatly from animal models.},
}

@article {pmid41554957,
year = {2026},
author = {Burns, AP and Duran, MI and Fortel, I and Lazarov, O and Zhan, L and Bendlin, B and Leow, A},
title = {Excitation-inhibition homeostasis in Alzheimer's disease: a selective multiscale review of mechanisms, sex differences, and therapeutic opportunities.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41554957},
issn = {1740-634X},
support = {R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Alzheimer's disease is increasingly viewed as a breakdown of balanced excitation-inhibition (E/I) homeostasis layered atop classical proteinopathy. Restoring circuit-level neural excitation and inhibition is rapidly becoming a tractable therapeutic strategy, guiding trials of circuit-modulating drugs such as levetiracetam. To date, however, findings across species and modalities remain fragmented, and it is unclear how to contextualize AD-focused E/I findings across scales and methodologies. Synthesizing over 150 studies of E/I homeostasis in AD, we organize the results into several prevailing themes: excitatory/inhibitory effects of amyloid and tau, whether hyperexcitation precedes amyloid plaque deposition, progressive oscillatory slowing (a shift of aggregate neural signal frequencies towards lower frequencies) as AD worsens, early preclinical hyperexcitation peaking in MCI and transitioning to hypoexcitation in AD, sex differences in E/I trajectories, APOE4 as a mediating factor, the contribution of neuroinflammation and metabolic dysfunction to E/I imbalance, and E/I-focused trials/experiments, particularly involving levetiracetam. These dominant themes are interpreted in a framework of multidimensional E/I homeostasis, rather than a single-axis imbalance. To support this integration, we first outline the microscale, mesoscale, and macroscale techniques used to assess E/I in AD, ranging from patch clamping and extracellular recordings to EEG/MEG and fMRI. By charting these multiscale E/I shifts, our synthesis offers a unifying framework to guide future experimental work and accelerate the design of biomarker-driven trials of E/I-targeted therapies in Alzheimer's disease.},
}

@article {pmid41554903,
year = {2026},
author = {Tuo, QZ and Bush, AI and Lei, P},
title = {Ferroptosis in neurological diseases: moving towards therapeutic intervention.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41554903},
issn = {1476-5578},
abstract = {Ferroptosis is a regulated cell death driven by iron-dependent lipid peroxidation and has been implicated in major neurological diseases. The brain is enriched in polyunsaturated fatty acids (PUFAs) and iron, which makes it particularly susceptible to lipid peroxidation, leading to ferroptosis. In neurological diseases such as Alzheimer's disease (AD) and stroke, such mechanisms are dysregulated and contribute to neuronal loss. Physiologically, the lipid peroxidation resistance systems in the brain, including defenses (such as SOD, CAT, Prxs, GPxs) and repair systems (such as GPx4, FSP1), prevent ferroptosis and repair damaged phospholipid membranes. However, the efficacy of endogenous resistance systems is often compromised in pathological states, positioning exogenous antioxidants as promising therapeutic candidates. Future research could optimize the delivery of these compounds and explore new candidates that specifically target the ferroptosis signaling pathway to prevent neurodegeneration occurring in neurological diseases.},
}

@article {pmid41554668,
year = {2026},
author = {Masood, F and Al-Hyari, A and Al-Wajidi, W and , },
title = {Comparison Study of Different Feature Selection Techniques for the Diagnosis of Alzheimer's Disease.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261418472},
doi = {10.1177/15333175261418472},
pmid = {41554668},
issn = {1938-2731},
mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; *Neuroimaging/methods ; Bayes Theorem ; Aged ; Male ; Female ; Biomarkers ; Machine Learning ; Magnetic Resonance Imaging ; },
abstract = {Objective: Alzheimer's disease (AD) continues to be a major challenge because handling high-dimensional data is time-consuming and expensive due to its complexity. A large feature space often increases computational costs and reduces model interpretability. This study addresses this problem by evaluating and comparing multiple feature selection techniques to identify the most informative biomarkers for AD diagnosis.Methods: Our study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to implement and test three feature selection approaches, visualization-based, filter-based, and wrapper-based, within a Naive Bayes (NB) classification framework.Results: Based on the results of the analysis, the wrapper method achieved 96.77% classification accuracy, outperforming both visualization and filter methods with 86.19 and 91.87%, respectively. Interestingly, even when over 92.5% of the original features were removed the classifier still performed well, indicating that only a small set of features is necessary to ensure reliable diagnosis.Discussion: This study illustrates that strategically selecting features improves diagnostic accuracy while reducing computational burden, providing a more efficient framework for machine learning applications in Alzheimer's disease research.},
}

*Alzheimer Disease/diagnosis/diagnostic imaging
Humans
*Neuroimaging/methods
Bayes Theorem
Aged
Male
Female
Biomarkers
Machine Learning
Magnetic Resonance Imaging

@article {pmid41554659,
year = {2026},
author = {Srimaharaj, W},
title = {Corrigendum to "Brain dysfunction assessment in Alzheimer's disease: A phase-space projection and interactive signal decomposition framework" [Comput. Biol. Med. (2026) 111440 201].},
journal = {Computers in biology and medicine},
volume = {},
number = {},
pages = {111483},
doi = {10.1016/j.compbiomed.2026.111483},
pmid = {41554659},
issn = {1879-0534},
}

@article {pmid41554532,
year = {2026},
author = {Kang, S and Lim, JI and Stenzel, L and Kim, KY and Kim, E and Jeon, HJ and Park, DH and Lim, HK and Shim, Y and Jang, JW and Kim, Y and Lee, S and Park, KH},
title = {Efficacy and Safety of Mobile App-Based Metamemory Cognitive Training for Mild Cognitive Impairment: Multicenter Randomized Clinical Trial.},
journal = {JMIR mHealth and uHealth},
volume = {14},
number = {},
pages = {e73464},
doi = {10.2196/73464},
pmid = {41554532},
issn = {2291-5222},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/psychology/therapy ; Aged ; *Mobile Applications/standards/statistics & numerical data ; Middle Aged ; *Cognitive Behavioral Therapy/methods/standards/instrumentation/statistics & numerical data ; Aged, 80 and over ; Treatment Outcome ; Neuropsychological Tests/statistics & numerical data ; Quality of Life/psychology ; Cognitive Training ; },
abstract = {BACKGROUND: Metamemory training (MMT) offers a potential nonpharmacological approach to enhance cognitive function in individuals with mild cognitive impairment (MCI). While digital cognitive training improves accessibility, the effectiveness of mobile app-based MMT has not been evaluated in a randomized clinical trial.

OBJECTIVE: We aimed to evaluate the efficacy and safety of a mobile app-based MMT program, ET-101 (Cogthera), compared to a sham device control group in individuals with MCI.

METHODS: This multicenter, randomized controlled trial enrolled participants with MCI, recruited from 7 medical centers, and randomly assigned them to the ET-101 or control group (1:1 ratio). The intervention lasted 12 weeks, with a 12-week follow-up. The ET-101 group received metamemory-based multimemory strategy training and real-time feedback. Assessments of cognition, the daily activities of living, and the quality of life were conducted at baseline, week 12, and week 24. The primary outcome was the proportion of participants who showed cognitive improvement as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)-14 at weeks 12 and 24. Secondary outcomes included changes in the scores of scales assessing cognition, daily activities, and quality of life. Safety analysis assessed adverse events and their relation to digital therapeutics.

RESULTS: In the full analysis set, 49 participants were included in the ET-101 group and 50 in the control group. At week 24, the proportion of responders who maintained or improved their ADAS-Cog-14 scores was significantly higher in the ET-101 group than in the control group (P=.002). Additionally, the ET-101 group showed a significant improvement in ADAS-Cog-14 scores at week 24 compared to baseline levels (estimates=-2.53; t265=-3.05; Bonferroni-adjusted P=.003). A subdomain analysis revealed significant improvements in the memory (estimates=-2.50; t264=-4.03; Bonferroni-adjusted P<.001) and language (estimates=-0.807; t290=-3.68; Bonferroni-adjusted P<.001) domains at week 24 in the ET-101 group compared to the control group. In the safety analysis, 6 adverse events occurred in the ET-101 group and 4 in the control group, but none were related to the interventions. The attrition rate in the ET-101 group was 22.4% (11/49).

CONCLUSIONS: ET-101 significantly improved cognitive function compared to the sham device, with effects observed not only in the memory domain but also in the language domain, indicating a transfer effect. Therefore, ET-101 has the potential to provide effective MMT to a broader population with MCI by overcoming location and personnel limitations through a mobile app-based platform.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05938426; https://clinicaltrials.gov/study/NCT05938426.},
}

Humans
Male
Female
*Cognitive Dysfunction/psychology/therapy
Aged
*Mobile Applications/standards/statistics & numerical data
Middle Aged
*Cognitive Behavioral Therapy/methods/standards/instrumentation/statistics & numerical data
Aged, 80 and over
Treatment Outcome
Neuropsychological Tests/statistics & numerical data
Quality of Life/psychology
Cognitive Training

@article {pmid41554530,
year = {2026},
author = {Okabe, K and Nagata, T and Nukariya, K and Kito, S and Shinagawa, S},
title = {Executive and General Cognitive Domain as a Relevant Factor of Specific Neuropsychiatric Symptoms in Alzheimer's Disease.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {1},
pages = {e70345},
doi = {10.1111/ggi.70345},
pmid = {41554530},
issn = {1447-0594},
support = {24K10690//JSPS KAKENHI (Japan Society for the Promotion of Science)/ ; JP24wm0625505//AMED (Japan Agency for Medical Research and Development) under Grant Numbers/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis/physiopathology ; Male ; Female ; Cross-Sectional Studies ; Aged ; *Executive Function/physiology ; Aged, 80 and over ; Neuropsychological Tests ; Severity of Illness Index ; *Cognition/physiology ; Mental Status and Dementia Tests ; },
abstract = {AIM: To elucidate the pathophysiological mechanisms between neurocognition and neuropsychiatric sub-symptoms in Alzheimer's disease (AD), the present cross-sectional study compared severity of each subitem in a neuropsychiatric symptom (NPS) scale among four neurocognitive groups classified based on the pattern of executive and general cognitive function.

METHODS: Of 546 consecutive outpatients who visited Memory Clinic at Jikei University Kashiwa Hospital, we selected 160 with AD and classified them into four neurocognitive groups based on score in the MMSE (Mini-Mental State Examination: ≥ 21 point was general cognitive preserved) or FAB (Frontal Assessment Battery: ≥ 13 was executive cognitive preserved): BPC (both cognitive preserved); GCP (general cognitive preserved); ECP (executive cognitive preserved); NCP (neither cognitive preserved). We compared the severity of each subitem of the Behavioral Pathology in Alzheimer's Disease (Behave-AD) scale among the four groups.

RESULTS: Among seven subitems of Behave-AD, the scores for diurnal rhythm disturbances and anxieties/phobias differed significantly among the four groups. The score for diurnal rhythm disturbances was significantly higher in GCP than BCP, and the score for anxiety/phobias was significantly higher in ECP than BCP. However, no significant difference was shown between each cognitive group and the NCP.

CONCLUSION: The general cognitive preservation without executive preservation may be relevant to the diurnal rhythm disturbances by self-correction for own behavior, and the executive preservation without general cognition preservation may contribute to the transient anxiety as emotional reaction. Such dissociative relations between executive and general neurocognition may be relevant to specific neuropsychiatric sub-symptoms emergence or severity in AD.},
}

Humans
*Alzheimer Disease/psychology/diagnosis/physiopathology
Male
Female
Cross-Sectional Studies
Aged
*Executive Function/physiology
Aged, 80 and over
Neuropsychological Tests
Severity of Illness Index
*Cognition/physiology
Mental Status and Dementia Tests

@article {pmid41554349,
year = {2026},
author = {Roddick, KM and Northrup, PA and Schellinck, HM and Brown, RE},
title = {Motor deficits in the McGill-R-Thy1-APP transgenic rat model of Alzheimer's Disease.},
journal = {Behavioural processes},
volume = {},
number = {},
pages = {105341},
doi = {10.1016/j.beproc.2026.105341},
pmid = {41554349},
issn = {1872-8308},
abstract = {The McGill-R-Thy1-APP rat is a transgenic model of Alzheimer's Disease (AD) which expresses APP with two mutations found in cases of familial AD, resulting in the development of amyloid pathology and cognitive deficits. Motor deficits are common symptoms of AD, emerging early in the disease, and are correlated with AD neuropathology and cognitive symptoms. This study evaluated hemizygous and homozygous McGill-R-Thy1-APP rats and their wildtype littermates for spontaneous alternation and locomotion in the T and Y mazes, and motor behaviour on an accelerating rotarod at 12 to 13 months of age. We found no genotype or sex effects in spontaneous alternation in either maze, nor a significant correlation of spontaneous alternation behaviour between the mazes. Female rats travelled greater distances than male rats in both mazes. While there was no genotype effect in the T maze on distance travelled, in the Y maze the hemizygous rats travelled shorter distances than the wildtype rats, while the homozygous rats travelled greater distances. There was a significant correlation between the distances travelled in each maze. Both hemizygous and homozygous rats performed worse than their wildtype littermates on the rotarod, while heavier rats performed worse than lighter rats, and female rats performed worse than male rats once their differences in weights were accounted for. These findings support the continued use of these rats as a model of AD and highlight the need to consider the possible confounding effect motor impairments have on other behavioural tests.},
}

@article {pmid41554303,
year = {2026},
author = {Çelik, H and Çelik, O and Aydın, Ş and Küçükler, S and Çomaklı, S and Topal, A and Akay, R and Gönüllü, S and Yıldız, MO and Alım, B and Özdemir, S},
title = {Small extracellular vesicles carrying miRNA34 in Alzheimer's disease: effects on oxidative stress, neuroinflammation, cognitive function, and mitochondrial/ferroptosis-related protein regulation.},
journal = {Gene},
volume = {},
number = {},
pages = {150014},
doi = {10.1016/j.gene.2026.150014},
pmid = {41554303},
issn = {1879-0038},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, and persistent neuroinflammation. Recent studies have increasingly focused on the regulatory role of microRNAs in AD pathogenesis. In this study, we investigated the therapeutic potential of small extracellular vesicles (sEV) enriched with microRNA34 (miRNA34) to target key pathogenic mechanisms of AD. We hypothesized that miRNA34-loaded sEV could alleviate oxidative damage, inhibit neuroinflammatory responses and ferroptosis, reduce mitochondrial impairment, and ultimately improve cognitive function. We evaluated the effects of miRNA34 administration on oxidative stress markers, pro-inflammatory cytokines, synaptic plasticity indicators, and behavioral outcomes in an in vivo Aβ-induced mouse model of AD. The experimental design included five groups, each consisting of seven mice. The findings demonstrated that miRNA34-loaded sEV treatment significantly reduced oxidative stress and neuroinflammation while enhancing memory and learning performance. Overall, our results indicate that miRNA34-enriched sEV represent a promising and minimally invasive therapeutic strategy capable of modulating AD pathogenesis. This research provides a novel perspective on the potential clinical application of miRNA34 and sEVin neurodegenerative disorders.},
}

@article {pmid41553948,
year = {2026},
author = {Fang, Y and Cao, K},
title = {Estimates of Global Needs for Neurorehabilitation: A Systematic Analysis Based on the GBD-WHO Rehabilitation Database 2021.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-32},
doi = {10.1159/000550340},
pmid = {41553948},
issn = {1423-0208},
abstract = {BACKGROUND: Neurological disorders affect approximately 3.4 billion people worldwide and are the leading cause of disability. We conducted this study to explore global neurorehabilitation requirements and project trends from 2022 to 2036.

METHODS: The data on health conditions that may benefit from neurorehabilitation were sourced from the World Health Organization Rehabilitation Need Estimator. Prevalence and years lived with disability (YLDs) of neurorehabilitation needs were analyzed overall and by sex, age, region, country, and health condition. Estimated annual percentage changes (EAPCs) were calculated to quantify trends in age-standardized rates. A decomposition analysis was conducted to identify drivers of changes in neurorehabilitation needs. Projections of neurorehabilitation needs were made until 2036 using Bayesian age-period-cohort analysis (BAPC).

RESULTS: Globally, in 2021, neurological disorders requiring rehabilitation affected 225.38 million (95% UI 215.84-235.21) individuals, contributing to 52.35 million (95% UI 37.57-67.46) YLDs. The age-standardized prevalence rate (ASPR) and YLD rate (ASYR) were 2,758.37 (95% UI 2,644.02-2,878.23) and 640.5 (95% UI 459.39-824.44) per 100,000 persons, respectively. From 1990 to 2021, neurorehabilitation needs increased significantly, with prevalent cases and YLDs rising by 97.5% and 96.4%, respectively. This trend was reflected in a significant annual increase in both ASPR and ASYR, with an EAPC of 0.17 (95% CI 0.15-0.19) and 0.13 (95% CI 0.11-0.15), respectively, and is expected to continue increasing by 2036. Furthermore, decomposition analysis identified population growth and aging as the primary drivers of this increase. Most neurorehabilitation needs occur in low- and middle-income countries (LMICs). From 2021 to 2036, the highest contributors to the global need for neurorehabilitation will remain stroke, cerebral palsy, and Alzheimer's disease and dementia.

CONCLUSIONS: Our findings reveal a large and escalating global burden of neurological disorders requiring rehabilitation, driven by demographic aging and population growth. It is essential to expand rehabilitation services and integrate them into primary healthcare systems, particularly in LMICs.},
}

@article {pmid41553900,
year = {2026},
author = {Wang, C and Wang, Y and Xue, Q and Zhou, Z and Yan, G and Qi, X},
title = {Classification of Alzheimer's Disease by Modeling Brain Networks as Signed Networks under Deep Learning Frameworks.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3655150},
pmid = {41553900},
issn = {2998-4165},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that remains a global challenge due to its complex pathology and the lack of definitive diagnostic tools. This paper introduces an innovative approach to predicting and analyzing Alzheimer's disease by constructing signed brain network models and leveraging signed graph neural network technologies. By modeling the brain network as a signed graph that incorporates both positive and negative correlations, we capture the nuanced interactions between brain regions more effectively than traditional methods. We utilize graph convolutional networks (GCNs) and their variants to process these signed brain networks, significantly improving the accuracy of Alzheimer's disease prediction. Comparative analysis reveals that the signed graph model outperforms its unsigned counterparts in diagnostic precision (with an improvement of at least $19\%$), emphasizing the importance of incorporating negative correlations in neural interactions. Furthermore, precisely because of the additional negative edge information that we can utilize both positive and negative attention matrices, derived from these prediction tasks, to determine important brain region biomarkers. This work is an attempt to systematically validate the role of negative information through comparisons of different signed graph variants, which holds particular promise for enhancing Alzheimer's disease diagnostic accuracy at early stages. We believe that this approach will have significant clinical applications in the future.},
}

@article {pmid41553746,
year = {2026},
author = {David, L and Maniewicz, S and Chebib, N and Gold, G and Srinivasan, M and Müller, F},
title = {Implant Therapy in Patients With Neurodegenerative Diseases-A Scoping Review.},
journal = {Clinical oral implants research},
volume = {},
number = {},
pages = {},
doi = {10.1111/clr.70080},
pmid = {41553746},
issn = {1600-0501},
abstract = {OBJECTIVES: The increasing longevity of populations has resulted in a growing number of older adults requiring prosthodontic care, including those with neurodegenerative diseases (NDs). Neurodegenerative diseases pose significant challenges to prosthodontic care, and it remains unclear whether implant therapy in this population achieves outcomes comparable to those observed in the general older population.

MATERIALS AND METHODS: A first systematic review was reframed to a scoping review using a PCC framework with Population (individuals with neurodegenerative diseases, who were partially or completely edentulous), Concept (implant therapy, planning, placement and maintenance, and any reported complications) and Context (dental and geriatric care settings).

RESULTS: The literature search identified 634 studies or case reports, of which none fulfilled the inclusion criteria. Seven papers (1 retrospective study, 2 prospective studies and 4 case reports) outside the inclusion criteria reported on patients with neurodegenerative diseases receiving implants, which suggest that dental implants seem to offer initial benefits in improving chewing efficiency, the quality of life and weight gain, especially in Parkinson's disease (PD) patients. However, their suitability for patients with advanced ND is uncertain.

CONCLUSION: Although high-level evidence on implant survival and success in patients with neurodegenerative diseases is lacking, the limited available evidence offers promising indications of reasonably successful implant treatments in early-stage cases. However, continuous monitoring of disease progression, oral health and denture management is crucial to retrofit the restoration when necessary.},
}

@article {pmid41553693,
year = {2026},
author = {Brandt, PJ and Pototska, O and Stys, PK},
title = {Fluorescence from dual molecular rotors allows sensitive detection of widespread brain pathology in a mouse model of Alzheimer's disease.},
journal = {Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology},
volume = {},
number = {},
pages = {},
pmid = {41553693},
issn = {1474-9092},
abstract = {Amyloid fibrils formed by the misfolding and aggregation of proteins are a pathological hallmark of many neurodegenerative conditions including Alzheimer's disease (AD). Although recent studies have shown that pre-fibrillar species including low molecular-weight oligomers are more toxic in vitro than mature fibrils, and correlate better with cognitive decline in AD patients, techniques to study this subtle pathology remain limited. Here, we describe the use of the dye pair 9-(dicyanovinyl)julolidine (DCVJ) and crystal violet (CV), two fluorescent molecular rotors, to detect widespread pathology in the 5xFAD mouse model of AD via fluorescence spectroscopy. DCVJ and CV individually displayed a limited ability to detect spectral differences between WT and non-plaque areas of 5xFAD brain samples. However, when used in combination, the two probes discerned subtle but significant differences in a much higher proportion of tissue compared to either dye alone. These spectral differences were eliminated after treatment to disaggregate macromolecular protein assemblies, providing evidence that the dye pair was able to detect subtle pathology present in the parenchyma of the 5xFAD mouse brain. These findings demonstrate that the combined use of DCVJ and CV could be a valuable addition to the tools currently available to study the early stages of protein misfolding, which is essential for advancing therapeutics and diagnostic technologies in many neurodegenerative diseases.},
}

@article {pmid41553625,
year = {2026},
author = {Kaur, S and Mannan, A and Singh, TG},
title = {The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {372},
pmid = {41553625},
issn = {1559-1182},
mesh = {Humans ; *Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism ; Animals ; *Organelle Biogenesis ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *Mitochondria/metabolism ; Oxidative Stress ; Dopaminergic Neurons/metabolism ; },
abstract = {The transcription factor Nurr1 (NR4A2) serves as an essential element in dopaminergic neuron development since it functions predominantly in the substantia nigra, which becomes severely affected during Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 regulates dopamine synthesis, survival-promoting, and oxidative stress genes that affect mitochondrial formation. Nurr1 binds to PGC-1α, allowing for mitochondrial activity regulation. This relationship supports mitochondrial biogenesis. Post-translational changes, including phosphorylation and acetylation, modify Nurr1 transcriptional regulation in order to enhance its ability to regulate mitochondrial genes. The assessment examines Nurr1's involvement in dopaminergic neuron development and mitochondrial formation while showing its role in reducing oxidative damage for an extensive understanding of its neurological disease functionality. Nurr1 serves as a therapeutic candidate for analysis, while the review explores obstacles and potential paths for using Nurr1-based treatments against Parkinson's disease alongside Alzheimer's disease and other neurodegenerative disorders. The extensive research utilized multiple databases, PubMed, Scopus, Medline, and EMBASE, with keywords "Nurr1," "NR4A2," "Neurodegenerative disorders," "Mitochondrial biogenesis," "Oxidative stress," "Parkinson's disease," "Alzheimer's disease," and "Therapeutic target." The analysis examined published research regarding Nurr1-mediated control of dopaminergic function and survival and mitigation of neurological and mitochondrial deficits within the past decade. Nurr1's interactions with important co-regulators like PGCα, its post-translational changes, and its effects on neuroinflammation have also received particular focus. In neurodegenerative illnesses, mitochondrial dysfunction adds to neuronal damage. Nurr1's regulation of mitochondrial biogenesis helps recover mitochondrial function, alleviate oxidative stress, and sustain neuronal survival. Dysregulation of Nurr1 expression is connected to decreased mitochondrial activity and accelerated neurodegeneration.},
}

Humans
*Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
Animals
*Organelle Biogenesis
*Neurodegenerative Diseases/metabolism/therapy/pathology
*Mitochondria/metabolism
Oxidative Stress
Dopaminergic Neurons/metabolism

@article {pmid41553588,
year = {2026},
author = {Bjørklund, G and Butnariu, M and Caunii, A and Peana, M},
title = {Metallothioneins in Neurodegenerative Diseases: Metal Homeostasis, Autoimmunity, and Therapeutic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {373},
pmid = {41553588},
issn = {1559-1182},
mesh = {Humans ; *Homeostasis/physiology ; *Metallothionein/metabolism ; *Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy ; *Autoimmunity/physiology ; Animals ; *Metals/metabolism ; },
abstract = {Neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and are frequently linked to metal dysregulation, oxidative stress, and immune dysfunction. Metallothioneins (MTs), a family of cysteine-rich, metal-binding proteins, are critical in maintaining metal homeostasis, mitigating oxidative damage, and modulating immune responses, functions highly relevant in these pathologies. MTs regulate essential metals like copper and iron by preventing their participation in harmful redox reactions and control zinc availability for enzymatic and signaling processes. They also detoxify neurotoxic metal(oid)s such as cadmium, mercury, lead, and arsenic, thereby reducing their adverse neurological and immunological effects. In autoimmune neurodegeneration, MTs modulate pro- and anti-inflammatory cytokines (e.g., IL-6, TNF-α, IL-10) and influence immune cell activity, particularly microglia and T cells, which are central to neuroinflammation and autoimmunity. Through these mechanisms, MTs play a dual role in sustaining immune homeostasis and counteracting oxidative stress. Their capacity to integrate metal regulation with immune modulation positions them as promising therapeutic targets, with preclinical and some clinical evidence supporting strategies to enhance MT expression or develop MT-mimetic agents to address both metal dysregulation and immune imbalance. Additionally, MTs show emerging utility as biomarkers, as alterations in MT isoform expression and metal-bound complexes in biofluids have been associated with disease onset, progression, and therapeutic response in specific neurodegenerative conditions. This article reviews the multifaceted roles of MTs in neurodegenerative diseases, emphasizing their function in metal and immune regulation and their emerging potential as therapeutic targets and clinical biomarkers.},
}

Humans
*Homeostasis/physiology
*Metallothionein/metabolism
*Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy
*Autoimmunity/physiology
Animals
*Metals/metabolism

@article {pmid41553152,
year = {2026},
author = {Bačić Toplek, F and Maiorana, NV and Guidetti, M and Marceglia, S and Capelli, R and Priori, A and Camilloni, C},
title = {Electric field-induced destabilization and surface modulation of Aβ42 fibrils in molecular simulations: theoretical implications for direct current stimulation in Alzheimer's disease.},
journal = {Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/13506129.2026.2616753},
pmid = {41553152},
issn = {1744-2818},
abstract = {BACKGROUND: The amyloid-β peptide 42 (Aβ42) forms fibrillar aggregates that are a hallmark of Alzheimer's disease. While recent therapeutic strategies targeting Aβ42 fibrils and oligomers have shown promise, safer and more effective interventions are still needed. Noninvasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have emerged as potential complementary approaches, yet the molecular mechanisms by which electric fields influence amyloid aggregation remain poorly understood.

METHODS: We performed atomistic molecular dynamics simulations to investigate the response of Aβ42 fibrils to static electric fields of increasing strength. Simulations were based on an ex vivo fibril structure with reconstructed N-terminal regions, and different structural restraint conditions were used to disentangle surface and core effects.

RESULTS: Electric fields perturb the disordered N-terminal 'fuzzy coat', altering its conformational dynamics and weakening its interactions with the fibril core, thereby modifying the fibril surface properties. Simulations with unrestrained fibril ends further reveal increased fluctuations in core residues, indicating field-induced destabilization that may hinder elongation.

CONCLUSIONS: These findings provide molecular-level insight into how static electric fields can modulate amyloid fibril formation and propagation, offering a possible mechanistic basis for the effects of tDCS and related brain stimulation techniques.},
}

@article {pmid41553038,
year = {2026},
author = {Han, X and Zhu, S and Zhang, H and Xia, T and Gu, X},
title = {Multiplex Cerebrospinal Fluid Proteomics Identifies Biomarkers Predicting Neuropsychiatric Symptom Progression in Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {2},
pages = {e71447},
doi = {10.1096/fj.202504014R},
pmid = {41553038},
issn = {1530-6860},
support = {82171193//the National Natural Science Foundation of China/ ; ZDXK202232//Jiangsu Provincial Medical Key Discipline/ ; },
mesh = {*Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Biomarkers/cerebrospinal fluid ; Male ; Female ; *Proteomics/methods ; Aged ; Disease Progression ; Mice ; Animals ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {Neuropsychiatric symptoms (NPS), commonly concomitant with Alzheimer's disease (AD), substantially impair the quality of life and accelerate disease progression, yet reliable biomarkers for early identification of individuals at high NPS risk remain elusive. In this study, we leveraged the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), incorporating longitudinal data from 509 participants diagnosed with mild cognitive impairment (MCI) or mild AD at baseline and followed up for 1 and 2 years. The dataset included cerebrospinal fluid (CSF) proteomic profiles comprising 6361 proteins, along with comprehensive data on NPS diagnosis, cognitive function, and AD pathology. LASSO regression and recursive feature elimination were applied to identify NPS-related CSF proteins, followed by random forest modeling to predict NPS risk at baseline, 1 year, and 2 years. Incorporating selected CSF proteins significantly improved NPS prediction compared to the reference model, with AUCs increasing from 0.64 to 0.76 at baseline, 0.63 to 0.80 at 1 year, and 0.63 to 0.81 at 2 years. Notably, Cyclin-Dependent Kinase-Like 2 (CDKL2), Nidogen 2 (NID2), and Lin-7 Homolog B (LIN7B) were consistently associated with NPS across all time points. Among them, CDKL2 and NID2 were significantly associated with AD biomarkers and cognitive scores, and their expression changes were independently validated in cerebrospinal fluid from a mouse model, highlighting their potential as stable predictive biomarkers. Our findings highlight CSF proteomic signatures that robustly predict NPS progression in individuals with MCI and mild AD, offering a framework for early risk stratification and precision intervention in NPS.},
}

*Cognitive Dysfunction/cerebrospinal fluid/diagnosis
Humans
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Biomarkers/cerebrospinal fluid
Male
Female
*Proteomics/methods
Aged
Disease Progression
Mice
Animals
Aged, 80 and over
Longitudinal Studies

@article {pmid41553037,
year = {2026},
author = {Shahid, N and Azhar, L and Hussain, I and Khan, MS},
title = {Emerging Alzheimer's therapies: clinical efficacy versus economic feasibility.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/17582024.2026.2617857},
pmid = {41553037},
issn = {1758-2032},
}

@article {pmid41552837,
year = {2026},
author = {Hirmiz, R},
title = {Dementia, Advance Directives, and Second-Order Volitions.},
journal = {Bioethics},
volume = {},
number = {},
pages = {},
doi = {10.1111/bioe.70085},
pmid = {41552837},
issn = {1467-8519},
abstract = {This paper contributes to the ongoing debate over the authority of advance directives in cases where patients with dementia express desires that conflict with their earlier wishes. Drawing on Harry Frankfurt's concept of second-order volitions, I argue that the preferences of the pre-dementia self (the "then-self") should, in most cases, take precedence over those of the post-dementia self (the "now-self")-particularly in instances where the now-self has lost the capacity to form second-order volitions and is no longer able to meaningfully repudiate prior values and commitments.},
}

@article {pmid41552820,
year = {2025},
author = {Fakhri, S and Gravandi, MM and Majnooni, MB and Farzaei, MH and Abbaszadeh, F and Rashidi, K and Echeverría, J},
title = {Ferula ammoniacum gum aqueous extract exerts anti-inflammatory and antioxidant mechanisms to combat aluminum chloride-induced Alzheimer's disease in rats: possible involvement of opioid pathways.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1708643},
pmid = {41552820},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, significantly affects memory and behavior due to dysregulated pathways involving oxidative stress, inflammation, and opioidergic systems. Currently, no effective treatments are available, underscoring the need for novel alternatives. Ferula ammoniacum (D.Don) Spalik, M. Panahi, Piwczyński, and Puchałka [Apiaceae] (FA), an Iranian medicinal plant, is known for its anti-seizure, anti-inflammatory, and analgesic properties, with its gum utilized as a nerve tonic.

PURPOSE: This study investigates the anti-AD effects of F. ammoniacum gum aqueous extract (FAGAE) using an aluminum chloride (AlCl3)-induced Wistar rat model of AD.

MATERIALS AND METHODS: The aqueous extract, prepared by macerating powdered gum in distilled water for 48 h at ambient temperature, was subjected to phytochemical analysis using ultraviolet, infrared, and nuclear magnetic resonance spectroscopy. Thirty rats were assigned to five different groups: one receiving saline, one receiving AlCl3 (100 mg/kg, i.p.), two receiving AlCl3 followed by oral treatment with FAGAE at doses of 50 or 100 mg/kg, and one receiving naloxone (an opioid receptor antagonist) along with AlCl3 and the effective dose of FAGAE. Behavioral changes were evaluated using the open-field, passive avoidance, and elevated plus maze tests. Furthermore, biochemical analyses were conducted to measure the serum nitrite levels, changes in weight, matrix metalloproteinase (MMP) activity, and histopathological changes in brain tissue.

RESULTS AND DISCUSSION: The phytochemical analysis of FAGAE revealed the presence of polysaccharide compounds with tentative arabinogalactan structures. FAGAE decreased step-through latency in the passive avoidance test and modified AlCl3-induced weight changes. FAGAE also significantly increased mobility, grooming, and crossing in the open-field test. Naloxone reversed the anti-AD effects of FAGAE, suggesting a possible role for opioidergic pathways in its therapeutic effects. Zymography results showed that FAGAE reduced MMP-9 activity while increasing MMP-2 activity. Histopathological analysis revealed a preserved number of intact neurons in the hippocampus, whereas reduced serum nitrite levels were observed after FAGAE administration in rats with AD.

CONCLUSION: Behavioral, biochemical, and histopathological impairments induced by AlCl3 were significantly attenuated by FAGAE, possibly through the opioidergic pathway, which combats inflammation and oxidative stress and supports neuronal survival.},
}

@article {pmid41552817,
year = {2025},
author = {Chen, Y and Xiao, W and Qian, C and Huang, L and Lv, J and Wang, Z and Luo, Y},
title = {System Xc-pathway as a potential regulatory target in neurological disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1701320},
pmid = {41552817},
issn = {1663-9812},
abstract = {The System Xc-pathway is composed of the 12-transmembrane transporter protein SLC7A11 (xCT) and the single-channel transmembrane protein SLC3A2 (CD98hc). We detail the pathway's characteristics and distribution within the central nervous system, as well as its canonical role in maintaining glutathione synthesis and inhibiting ferroptosis, and its emerging non-canonical functions in metabolic coupling and neuroimmunity. A core theme is the pathway's context-dependent and often paradoxical role across major neurological disorders, including ischemic stroke, Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Critically, we analyze how pathological activation of N-methyl-D-aspartate receptors (NMDARs) can dysregulate System Xc-through mechanisms involving calcium overload, reactive oxygen species, and specific signaling axes (e.g., Nrf2, PP2A/AMPK/HMGB1), thereby exacerbating excitotoxicity and oxidative damage. Conversely, System Xc-dysfunction can further fuel NMDAR-mediated injury, creating vicious pathogenic cycles. This analysis reveals that System Xc-is not a unitary target but a dynamic node within a complex network. Consequently, effective therapeutic strategies must move beyond broad inhibition and instead aim for nuanced, cell-type-specific, and disease-stage-precise modulation. This approach will selectively correct the dysfunction of System Xc-while preserving its essential physiological roles. It presents both a significant challenge and a promising frontier for future neuroprotective drug development.},
}

@article {pmid41552642,
year = {2026},
author = {Badeji, AA and Olalekan, SO and Adeleke, AA and Edim, MM and Olaniyi, TO and Alli, OO and Quadri, ON and Oladipo, SD},
title = {Targeting Alzheimer's diseases via nitro-substituted Schiff base derivatives: synthesis, DFT, and molecular dynamics studies.},
journal = {In silico pharmacology},
volume = {14},
number = {1},
pages = {28},
pmid = {41552642},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease, a major neurodegenerative disorder, is strongly linked to cholinergic dysfunction, making cholinesterase inhibition a key therapeutic strategy. Herein, the synthesis and in-silico studies of nitro-substituted Schiff base derivatives were studied as potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) targeting Alzheimer's disease. The three synthesized compounds (B1-B3) were obtained in good yields (68-73%). DFT results showed that the vibrational frequencies agreed with the experimental data, and B3 had the smallest HOMO-LUMO gap (6.026 eV) from frontier molecular orbital analysis, indicating higher chemical reactivity. NBO analysis showed it exhibits a strong donor-acceptor interaction with a stabilization energy of 34.80 kcal/mol. Molecular docking results (kcal/mol) showed that B1 (-7.09/-6.59), B2 (-5.30/-6.78), and B3 (-7.42/-6.35) exhibited stronger interactions with AChE and BChE respectively, than the reference drug rivastigmine (-6.66/-5.21). Molecular dynamics simulations showed that rivastigmine had the most favourable binding affinity for AChE, while the Schiff bases, B1-B3 outperformed Rivastigmine against BChE with B3 showing the strongest binding affinity (ΔGbind = - 28.10 kcal/mol for AChE and - 26.31 kcal/mol for BChE) further confirming the result from DFT studies. Structural stability analyses revealed that AChE-B2 (RMSD = 1.384 Å, RoG = 22.817 Å) and BChE-B2 (RMSD = 1.619 Å, RoG = 23.211 Å) complexes were particularly stable, indicating that Schiff bases can form stable and energetically favorable interactions comparable to rivastigmine. Therefore, the study identifies B1 - B3 as promising dual cholinesterase inhibitors with favorable physicochemical properties, suggesting their potential as lead candidates for Alzheimer's disease therapy; however, further in-vitro and in-vivo investigations are essential to validate and confirm their efficacy and safety profiles.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00544-w.},
}

@article {pmid41552530,
year = {2026},
author = {Kurşun-Aktar, BS and Oruç-Emre, EE and Bulut, Z and Ekinci, E and Eyüpoğlu, V and Adem, Ş and Karaküçük-İyidoğan, A},
title = {New Sulfonate-Semicarbazone Hybrid Molecules: Synthesis, Theoretical Evaluations, Molecular Simulations, and Butyrylcholinesterase Inhibition Activity.},
journal = {ACS omega},
volume = {11},
number = {1},
pages = {1727-1744},
pmid = {41552530},
issn = {2470-1343},
abstract = {In the present work, 18 novel semicarbazone-sulfonate hybrids were synthesized to evaluate their potential as butyrylcholinesterase (BChE) inhibitors. Among all compounds, 4-[(E)-(2-carbamoylhydrazinylidene)-methyl]-phenyl 2-(trifluoromethoxy)-benzene-1-sulfonate (12), 4-[(E)-(2-carbamoylhydrazinylidene)-methyl]-phenyl naphthalene-1-sulfonate (17), and 4-[(E)-(2-carbamoylhydrazinylidene)-methyl]-phenyl naphthalene-2-sulfonate (18) exhibited the most potent BChE inhibition, with IC50 values of 61.88, 77.02, and 93.67 μM, respectively, outperforming the reference drug pyridostigmine bromide (IC50: 130.04 μM). As shown by molecular docking studies, numerous interactions, including hydrogen bonds, π-π stacking, π-sulfur contacts, and halogen bonds, supported the high binding of compounds' affinities to the BChE active site. Also, this study employed molecular dynamics (MD) simulations to assess the inhibitory potential of compounds 12, 17, and 18 against BChE. All ligands retained structural integrity during simulations. Compound 17 exhibited the highest conformational stability (minimal RMSD values) and formed robust interactions with critical binding site residues. Additionally, compound 18 demonstrated superior hydrogen bonding capacity, while compound 17 achieved the strongest binding affinity. Furthermore, in silico ADME predictions for the most active molecules showed good pharmacokinetic profiles and drug-likeness. Consequently, the results suggested that semicarbazone-sulfonate hybrid compounds 12, 17, and 18 were promising potential multifunctional agents targeting cholinergic dysfunction in Alzheimer's disease (AD).},
}

@article {pmid41551992,
year = {2025},
author = {Dias da Costa, M and Verdelho, A},
title = {Antipsychotic Use during the COVID-19 Pandemic in a Portuguese Dementia Outpatient Clinic.},
journal = {Portuguese journal of public health},
volume = {},
number = {},
pages = {},
pmid = {41551992},
issn = {2504-3145},
abstract = {BACKGROUND: The COVID-19 pandemic and its consequent confinement have caused a major impact on people living with dementia (PLD). We aimed to ascertain the use of antipsychotic medication in this population due to behavioural symptoms during confinement.

METHODS: We conducted a retrospective study evaluating clinical registrations, namely the use of psychoactive medication, of PLD followed regularly in a Portuguese dementia outpatient clinic during two different confinement periods.

RESULTS: A total of 101 patients were included. Alzheimer's disease was the most frequent diagnosis, most of them in moderate/severe stage. Antipsychotics were used in 21.7% of patients. During confinement, a residual number of patients needed antipsychotic dose increase.

CONCLUSION: Confinement due to COVID-19 in this population was not associated with a significant increase of antipsychotics use. We hope our work may help clarify issues related to the need for antipsychotic medication in behavioural symptoms during confinement in PLD.},
}

@article {pmid41551851,
year = {2026},
author = {Guevara, JE and Matusz, EF and Wang, WE and DeSimone, JC and Yawer, B and Fiala, J and Levy, SA and Arias, F and Rayaprolu, S and Barker, WW and Marsiske, MM and Cid, REC and DeKosky, ST and McFarland, NR and Armstrong, MJ and Adjouadi, M and Vaillancourt, DE and Smith, GE and Loewenstein, DA and Duara, R and Asken, BM},
title = {Factors associated with discordant visual and quantitative amyloid PET results.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70241},
pmid = {41551851},
issn = {2352-8729},
abstract = {INTRODUCTION: Factors underlying discordant visual and quantitative amyloid beta-positron emission tomography (Aβ-PET) results and their clinical implications are not well understood.

METHODS: Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ-PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E (APOE) status, biomarkers, and cognition among older adults with concordant and discordant visual-quantitative Aβ-PET. Discordance was defined as positive visual read (V) of Aβ-PET with below-threshold Centiloid quantification (Q; CL <25; V+/Q-) or negative visual read with CL ≥25 (V-/Q+).

RESULTS: We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q-, V-/Q+ had a higher frequency of APOE ε4 carriers (40%). Black/African American participants were overrepresented in V-/Q+ (40.9%). Both discordant groups had higher plasma phosphorylated tau 217 (p-tau217) and glial fibrillary acidic protein (GFAP) than V-/Q- but lower than V+/Q+. Discordant groups had greater gray matter volume and better cognitive performance than V+/Q+.

DISCUSSION: Discordant Aβ-PET findings likely hold clinical significance and may reflect early stages of neuropathological progression.

HIGHLIGHTS: Groups with concordant/discordant visual-quantitative amyloid beta-positron emission tomography (Aβ-PET) results were compared.Visual-/quant+ were more likely than visual+/quant- to be apolipoprotein E (APOE) ε4 carriers and Black/African American.Discordant groups had higher plasma phosphorylated tau 217 (p-tau217) and glial fibrillary acidic protein (GFAP) than concordant negative.Discordant groups had less atrophy and better cognition than concordant positive.Centiloid quantification should supplement visual reads in clinical settings.},
}

@article {pmid41551731,
year = {2025},
author = {Lim, S and Lee, HW and Yoon, S and Han, JW and Chung, JY and Yoon, S},
title = {Sex differences in efficacy/safety of anti-amyloid-beta monoclonal antibodies for the treatment of Alzheimer's disease.},
journal = {Translational and clinical pharmacology},
volume = {33},
number = {4},
pages = {212-223},
pmid = {41551731},
issn = {2289-0882},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. AD exhibits notable sex-related disparities in prevalence, progression, and treatment response. With the recent approval of anti-amyloid-beta monoclonal antibodies-aducanumab, lecanemab, and donanemab-understanding sex differences in their clinical effects has become increasingly relevant. This review article investigates sex differences in the pharmacokinetics, efficacy, and safety of aducanumab, lecanemab, and donanemab and discusses the possible mechanism underlying the observed differences. Although sex-specific analyses were largely underreported in clinical trials, population pharmacokinetic models identified sex as a covariate affecting clearance and volume of distribution for aducanumab and lecanemab and higher exposure to lecanemab was predicted for females. Subgroup analyses of phase 3 trials revealed that males tended to experience greater benefit from aducanumab and lecanemab, whereas females showed better response to donanemab. The overall incidence of adverse events, including amyloid-related imaging abnormalities, did not show significant differences between sexes. Potential mechanisms underlying these differences include sex-related variations in blood-brain barrier permeability, apolipoprotein E4-associated neuroinflammatory responses, and baseline disease characteristics. These findings underscore the need for future AD clinical trials to incorporate sex-based analyses and to consider sex as a key factor in optimizing treatment strategies.},
}

@article {pmid41551727,
year = {2026},
author = {Singh, S and Singh, P and Varada, MP and Vijaivasudev, MJ and Kumar, R and Malik, I},
title = {eVGeMdb: a manually curated database for experimentally validated genetic modifiers of neurodegenerative disorders.},
journal = {NAR molecular medicine},
volume = {3},
number = {1},
pages = {ugaf044},
pmid = {41551727},
issn = {2976-856X},
abstract = {Genetic modifiers are genes that, while not directly causing disease, can alter the onset, progression, severity, or specific phenotypes of a disease by interacting with the primary disease-causing genes. Despite their importance, knowledge of these modifiers remains fragmented across different experimental models of neurodegenerative disorders (NDs). To address this lacuna, we developed eVGeMdb (https://project.iith.ac.in/cgntlab/eVGeMdb/), a manually curated, comprehensive database of experimentally validated genetic modifiers of major NDs, including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinocerebellar ataxias, Fragile X-associated Tremor/Ataxia Syndrome, and other general PolyQ disorders. eVGeMdb integrates modifiers from commonly used diverse experimental model systems, including Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, cellular models (human, mice, Drosophila cells), and mouse. The database currently incorporates over 17000 entries, each annotated with experimental context, gene-specific functional information, relevant human orthologs, and links to protein-protein interaction networks and enriched pathways. The resource enables cross-disease and model-specific comparisons, allowing the identification of both universal and disease-specific modifiers. By consolidating dispersed genetic modifier information into a single, accessible platform, eVGeMdb provides a comprehensive tool for researchers in the field to explore modifier effects, prioritize experimental validations, formulate novel hypotheses, and investigate pathophysiological mechanisms underlying neurodegenerative disorders.},
}

@article {pmid41551313,
year = {2025},
author = {Zhu, T and Yang, D and Quan, F and Chen, Y and Cui, J},
title = {Neural mechanisms of acupuncture in amnestic mild cognitive impairment: a protocol for an fMRI-based systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1641297},
pmid = {41551313},
issn = {1664-2295},
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), characterized by progressive memory decline, represents a prevalent transitional state in global aging populations and exhibits high conversion rates to Alzheimer's disease (AD), constituting a critical window for preventive interventions. While accumulating evidence supports acupuncture's efficacy in enhancing cognitive performance, the precise neural mechanisms underlying its therapeutic effects remain poorly characterized. This neuroimaging investigation aims to elucidate the cerebral reorganization patterns mediating acupuncture-induced cognitive improvement in aMCI pathophysiology.

METHODS AND ANALYSIS: A systematic search strategy was implemented across eight electronic databases supplemented by manual searches, covering publications from each database's inception to May 1, 2025. Eligible study designs included randomized controlled trials (RCTs), prospective case-control studies, and observational investigations. Two independent investigators performed literature screening and data extraction, with discrepancies resolved through consensus or third-party adjudication. Methodological quality appraisal was conducted using the validated Agency for Healthcare Research and Quality (AHRQ) checklist. Primary outcomes focused on resting-state functional MRI (rs-fMRI) whole-brain functional imaging parameters. Meta-analytic synthesis of neuroimaging data will utilize seed-based d mapping with permutation of subject images (SDM-PSI, version 6.21), while clinical outcome analyses will be performed using RevMan 5.3 software (Cochrane Collaboration). Reporting will strictly adhere to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

CONCLUSION: This study synthesizes findings from independent neuroimaging investigations to establish comprehensive evidence supporting the neurotherapeutic effects of acupuncture in aMCI.

https://www.crd.york.ac.uk/prospero/, Identifier CRD420251033511.},
}

@article {pmid41551223,
year = {2026},
author = {Alam, MT and Rauf, MA and Khan, A and Hussain, R},
title = {Mechanistic Insights Into Protein Aggregation Inhibition by Green-Synthesized Silver Nanoparticles: A Study on Human Lysozyme.},
journal = {IET nanobiotechnology},
volume = {2026},
number = {},
pages = {2694374},
pmid = {41551223},
issn = {1751-875X},
mesh = {*Silver/chemistry/pharmacology ; *Metal Nanoparticles/chemistry ; Humans ; *Muramidase/chemistry/metabolism ; *Protein Aggregates/drug effects ; Green Chemistry Technology/methods ; },
abstract = {A characteristic of many neurodegenerative disorders, such as Parkinson's and Alzheimer's, is amyloidogenic protein aggregation, for which there are currently no proven cures. Aging, mutation, and physiological stress can cause proteins to deviate from their natural folding patterns, potentially leading to the formation of hazardous protein aggregates. Noble metal nanoparticles (NPs), due to their unique physicochemical properties, have emerged as promising tools in biomedicine, with applications ranging from tissue engineering to drug delivery and diagnostics. Although concerns regarding cytotoxicity exist, small-sized silver (Ag) NPs (AgNPs) have demonstrated potential in antiviral, anticancer, and antibacterial therapies. This study investigated the development of biocompatible AgNPs using a green synthesis approach and examined their chaperone-like activity against protein aggregation, emphasizing the role of meticulous in vitro design. Human lysozyme (HLZ) served as a model protein for aggregation inhibition assays. Biogenic AgNPs exhibited a concentration-dependent effect on HLZ aggregation, demonstrating an optimal inhibitory concentration, followed by a decrease in efficacy at higher concentrations. Furthermore, astrocytes treated with AgNPs displayed reduced protein aggregation, suggesting a chaperone-like behavior. The initial phase focused on the detailed characterization of AgNPs synthesized using orange juice extract. Subsequently, this study explored the mechanistic understanding of AgNP-mediated inhibition of protein aggregation under controlled conditions. A battery of biophysical techniques, including circular dichroism (CD), 8-anilino-1-naphthalene-sulfonic acid (ANS) fluorescence, thioflavin T (ThT) fluorescence, Congo red (CR) assay, and turbidity measurements, was employed to meticulously assess the inhibitory effect on HLZ aggregation in vitro.},
}

*Silver/chemistry/pharmacology
*Metal Nanoparticles/chemistry
Humans
*Muramidase/chemistry/metabolism
*Protein Aggregates/drug effects
Green Chemistry Technology/methods

@article {pmid41551043,
year = {2025},
author = {Sykora, M and Harmackova, M and Parobkova, E and Rusina, R and Matěj, R},
title = {An unexpected discovery of a novel potentially pathogenic APP gene variant: a case report of slowly progressive Alzheimer's disease with prominent cerebral amyloid angiopathy.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1703718},
pmid = {41551043},
issn = {1662-4548},
abstract = {Amyloid precursor protein (APP) plays an essential role in brain function and development. Variants in the APP gene are associated with both familial Alzheimer's disease and cerebral amyloid angiopathy. We report a case of early onset, slowly progressive mixed dementia with a newly identified APP variant. The patient developed mild cognitive impairment at age 51, followed by neuropsychiatric symptoms, seizures, and progressive white matter changes. Despite a fluctuating clinical course, significant deterioration occurred later, culminating in death at age 77. Genetic testing revealed an APP c.2086G > A (p.Gly696Ser) variant, currently classified as a variant of uncertain significance (VUS). Postmortem examination showed definite AD neuropathologic changes, with fully blown amyloid pathology including amyloid deposits in plaques as well as in severe generalized cerebral angiopathy with concomitant advanced FTLD-tau pathology. In silico analysis of the variant's impact was performed, and the inconclusive results are discussed later.},
}

@article {pmid41551000,
year = {2026},
author = {He, Y and Leng, Y and Vranceanu, AM and Ritchie, CS and Blacker, D and Das, S},
title = {A predictive model for cognitive decline using social determinants of health.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100056},
pmid = {41551000},
issn = {2534-773X},
abstract = {BACKGROUND: Early diagnosis of Alzheimer's disease and related dementias (AD/ADRD) is critical but often constrained by limited access to fluid and imaging biomarkers, particularly in low-resource settings.

OBJECTIVE: To develop and evaluate a predictive model for cognitive decline using survey-based data, with attention to model interpretability and fairness.

METHODS: Using data from the Mexican Health and Aging Study (MHAS), a nationally representative longitudinal survey of adults aged 50 and older (N = 4095), we developed a machine learning model to predict future cognitive scores. The model was trained on survey data from 2003 to 2012, encompassing demographic, lifestyle, and social determinants of health (SDoH) variables. A stacked ensemble approach combined five base models-Random Forest, LightGBM, XGBoost, Lasso, and K-Nearest Neighbors-with a Ridge regression meta-model.

RESULTS: The model achieved a root-mean-square error (RMSE) of 39.25 (95 % CI: 38.12-40.52), representing 10.2 % of the cognitive score range, on a 20 % held-out test set. Features influencing predictions, included education level, age, reading behavior, floor material, mother's education level, social activity frequency, the interaction between the number of living children and age, and overall engagement in activities. Fairness analyses revealed model biases in underrepresented subgroups within the dataset, such as individuals with 7-9 years of education.

DISCUSSION: These findings highlight the potential of using accessible, low-cost SDoH survey data for predicting risk of cognitive decline in aging populations. They also underscore the importance of incorporating fairness metrics into predictive modeling pipelines to ensure equitable performance across diverse groups.},
}

@article {pmid41550978,
year = {2026},
author = {Moien, MAS and Saghravanian, SJ and Fereidoni, M},
title = {Evaluating the impact of intracerebroventricular norepinephrine on spatial memory in rats: Insights into sporadic Alzheimer's pathogenesis.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {84-93},
pmid = {41550978},
issn = {2667-2421},
abstract = {One consequence of stress is the increased release of norepinephrine (NE) in the central nervous system, primarily driven by activation of the sympathetic nervous system. Given the importance of chronic stress in the development and progression of Alzheimer's disease (AD), clarifying the specific contributions of stress-related pathways, including the sympathetic axis and the hypothalamic-pituitary-adrenal (HPA) axis, is critical. In this study, we examined the effects of repeated central NE administration, as a potential contributor to stress-related cognitive impairment, on spatial memory in rats, alone or in combination with a low-dose streptozotocin (STZ) model of sporadic AD. Forty-nine rats were assigned to seven groups: control (no treatment), sham (saline; i.c.v.), low-dose streptozotocin (0.5 mg/kg, i.c.v.), norepinephrine administration at either 1 (adolescent) or 3 (adult) months of age (30 or 50 μg, respectively; i.c.v.), and co-administration of norepinephrine with streptozotocin at 1 or 3 months of age. Spatial memory was assessed using the Morris Water Maze test. Norepinephrine administration during adolescence and adulthood impaired spatial memory similar to streptozotocin in different parameters of the MWM, with adult rats showing the most significant vulnerability (p < 0.001). However, co-administration of both substances did not exacerbate the impairment caused by each alone. The results suggest that norepinephrine may impair cognition through mechanisms distinct from those of STZ-induced deficits. Additionally, they raise questions about the contribution of the sympathetic axis of chronic stress to the progression of sporadic AD.},
}

@article {pmid41550956,
year = {2025},
author = {Piccolino, I and Iannuzzi, F and Lionetti, L and Mazzonello, B and Barreca, V and Banaj, N and Arezzini, V and Piras, F and Bossù, P},
title = {The immunomodulating effect of palmitoylethanolamide on human myeloid dendritic cells and its possible impact on Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1664164},
pmid = {41550956},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/drug therapy/metabolism ; *Palmitic Acids/pharmacology ; *Dendritic Cells/immunology/drug effects/metabolism ; *Ethanolamines/pharmacology ; *Amides/pharmacology ; *Myeloid Cells/immunology/drug effects/metabolism ; Cells, Cultured ; *Immunomodulation/drug effects ; *Immunologic Factors/pharmacology ; },
abstract = {Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that has emerged as a promising therapeutic candidate for neurodegenerative disorders, particularly Alzheimer's disease (AD). Recognized for its inherent anti-inflammatory, analgesic, immunomodulatory, and neuroprotective properties, PEA possesses a good potential as a novel treatment addressing neuroinflammation associated with neurodegeneration, even though its precise mechanisms of action remain to be fully understood. Dendritic cells (DCs) are specialized migratory innate immune cells that play a crucial role in initiating and regulating immune responses and inflammation in both the body and the brain. In AD, DCs display a dysfunctional, pro-inflammatory profile, suggesting their involvement in disease pathology and progression. To explore the therapeutic potential of PEA, this study investigated its effects in vitro on human monocyte-derived DCs under both normal and AD-like conditions. The results show that PEA exerts significant immunomodulatory effects, promoting the maturation of DCs in both healthy and disease states. Notably, PEA treatment appears to correct the dysregulated state of DCs observed in AD conditions. This study reveals a novel mechanism by which PEA modulates immune activity through its action on DCs. By restoring normal DC function in neurodegenerative settings, PEA may help reduce inflammation, highlighting its potential as a therapeutic agent for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/immunology/drug therapy/metabolism
*Palmitic Acids/pharmacology
*Dendritic Cells/immunology/drug effects/metabolism
*Ethanolamines/pharmacology
*Amides/pharmacology
*Myeloid Cells/immunology/drug effects/metabolism
Cells, Cultured
*Immunomodulation/drug effects
*Immunologic Factors/pharmacology

@article {pmid41550754,
year = {2026},
author = {Casanova-Pagola, J and Varriano, F and López-Gil, X and Campoy-Campos, G and Abellí-Deulofeu, E and García-González, C and López-Bravo, E and Tudela, R and Muñoz-Moreno, E and Aguado, F and Prats-Galino, A and Molina-Porcel, L and Malagelada, C and Soria, G},
title = {Early-life cognitive intervention preserves brain function in aged TgF344-AD rats with sex-specific effects.},
journal = {iScience},
volume = {29},
number = {1},
pages = {114381},
pmid = {41550754},
issn = {2589-0042},
abstract = {Alzheimer's disease is characterized by progressive cognitive decline, and its effects are mitigated by cognitive reserve. We investigated whether long-term cognitive stimulation, initiated before amyloid deposition, preserves brain function in male and female TgF344-AD rats. Transgenic and wild-type (WT) rats underwent cognitive training or remained untrained. Resting-state fMRI assessed functional connectivity, the novel object recognition test evaluated memory, and molecular analyses examined synaptic plasticity, inhibitory signaling, and microglial reactivity. At baseline, females showed greater task engagement and higher synaptic protein levels (PSD95, TrkB, and VGLUT) than males. Cognitive training improved connectivity and memory in males, with limited benefits in females. At 19 months, trained transgenic rats maintained entorhinal-hippocampal connectivity resembling WT rats, with males showing sustained plasticity markers and reduced parvalbumin-positive interneurons. Trained 11-month-old rats showed enhanced microglial recruitment to plaques and a less reactive phenotype. Overall, early and sustained cognitive stimulation enhances brain resilience, with sex-specific mechanisms shaping outcomes.},
}

@article {pmid41550689,
year = {2025},
author = {Pinky, and Wali, Z and Neha, and Tiwari, P and El-Tanani, M and Rabbani, SA and Parvez, S},
title = {Aging and Alzheimer's: the critical role of mitochondrial dysfunction and synaptic alterations.},
journal = {Frontiers in synaptic neuroscience},
volume = {17},
number = {},
pages = {1676317},
pmid = {41550689},
issn = {1663-3563},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic dysfunction, and mitochondrial impairment. Despite multiple therapeutic strategies, currently available treatments only provide symptomatic relief without halting disease progression. Emerging evidence implicates mitochondrial dysfunction-including oxidative stress, impaired calcium signaling, mitophagy deficits, disrupted proteostasis, and electron transport chain abnormalities, as central to AD pathogenesis. These dysfunctions contribute to synaptic degeneration, increased reactive oxygen species, and neuronal death. This review consolidates current knowledge on the mechanistic pathways of mitochondrial impairment in AD and their downstream effects on neuronal health. We also explore the therapeutic potential of multitarget approaches, including agents targeting Aβ and tau pathology, oxidative stress mitigation, mitochondrial quality control, and synaptic restoration. By integrating evidence from recent preclinical and clinical studies, this work highlights mitochondrial homeostasis as a promising frontier for disease-modifying therapies in AD.},
}

@article {pmid41550591,
year = {2026},
author = {Madhi, I and Kim, JH and Shin, HS and So, YH and Jung, EM and Kim, Y},
title = {Ginsenoside Re mitigates Aβ1-42-induced neurotoxicity by promoting autophagy and suppressing NLRP3 inflammasome.},
journal = {Journal of ginseng research},
volume = {50},
number = {1},
pages = {100911},
pmid = {41550591},
issn = {1226-8453},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and neuroinflammation. Activation of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in microglia significantly contributes to AD-associated neuroinflammation and neuronal damage. Ginsenoside Re (G-Re), a major bioactive constituent of Panax ginseng, exhibits anti-inflammatory properties, but its role in modulating inflammasome activation in AD remains unclear.

METHODS: This study evaluated the therapeutic potential of G-Re in mice intracerebroventricularly injected with Aβ1-42 and delineated its molecular mechanisms in complementary cell-based models. We employed behavioral testing, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assays, Annexin V apoptosis assays, and mitochondrial functional assays.

RESULTS: Intraperitoneal administration of G-Re significantly improved cognitive performance, as evidenced by enhanced outcomes in the T-maze and novel object recognition tests. G-Re treatment reduced microglial activation and interleukin-1β (IL-1β) levels in the cortex and hippocampus. In vitro, G-Re protected neurons from conditioned medium derived from Aβ1-42-stimulated microglia, showing neuroprotection comparable to anti-IL-1β treatment. G-Re also inhibited Aβ1-42-induced activation of the NLRP3 inflammasome, as indicated by diminished levels of NLRP3, cleaved caspase-1, cleaved gasdermin D (GSDMD), IL-1β, and IL-18 in brain tissues and cultured microglia. Mechanistically, G-Re reduced mitochondrial reactive oxygen species (mtROS), preserved mitochondrial membrane potential, and activated autophagy via SIRT1/AMPK/mTOR signaling, thereby suppressing inflammasome activation.

CONCLUSION: G-Re ameliorates Aβ1-42-induced neuroinflammation and cognitive impairment by restoring mitochondrial homeostasis, enhancing autophagy, and suppressing NLRP3 inflammasome activation. These findings suggest G-Re as a potential therapeutic intervention for neurodegenerative disorders including AD.},
}

@article {pmid41550584,
year = {2025},
author = {Britt, KC and Obeng Boateng, AC and Nwadiogbu, C and Ashida, S and Tranel, D and Thorpe, RJ and Dahodwala, N},
title = {Facets of Religion/Spirituality and Cognitive Health: Association Variations Across Gender and Race Among Older Adults.},
journal = {Religions},
volume = {16},
number = {9},
pages = {},
pmid = {41550584},
issn = {2077-1444},
abstract = {Religion and spirituality (R/S) may be associated with better cognitive health, yet most published studies have been conducted in primarily White populations without investigating association variations by gender and race. A cross-sectional analysis of 1,041 community-dwelling diverse older adults from the Philadelphia Healthy Brain Aging (PHBA) cohort study was conducted using multiple regression analysis. We examined associations between facets of R/S and total cognitive scores and performed stratification analysis separately by gender and race to explore potential gender- and race-specific variations. Higher non-organizational R/S was associated with lower cognitive scores, while greater religious and spiritual coping was associated with higher cognitive scores, controlling for age, education, chronic conditions, race, and financial constraints. Across gender and race variations, non-organizational R/S was associated with lower cognitive scores in women alone, with no variations across race. Higher religious and spiritual coping was associated with higher cognitive scores in both Black and White women, but not men, while higher religious and spiritual healing was associated with lower cognitive scores in Black women only. Associations between religious and spiritual facets and cognitive health differ across gender and race; longitudinal studies are needed.},
}

@article {pmid41550486,
year = {2026},
author = {Gao, H and Yang, S and Zhaorong, O and Wang, Y and Tang, J and Hou, Q and Fang, Z and Shao, N and Cai, B},
title = {Aloe-emodin attenuates Aβ25-35-induced HT22 cell pyroptosis via inhibiting NLRP3 inflammasome pathway.},
journal = {3 Biotech},
volume = {16},
number = {2},
pages = {71},
pmid = {41550486},
issn = {2190-572X},
abstract = {Neuronal death in Alzheimer's disease (AD) is closely associated with NLRP3 inflammasome-mediated pyroptosis. This study aimed to investigate the protective effects of Aloe-emodin (AE) in an AD cellular model and to explore the underlying mechanisms involving the NLRP3 inflammasome pathway. Molecular docking simulations predicted strong binding affinities between AE and key pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD), with the highest affinity observed for NLRP3. In an Aβ25-35-induced AD cellular model, AE (6 µM) significantly enhanced cell viability and alleviated pyroptotic morphological changes, including cellular swelling and rupture. EdU staining and immunofluorescence analysis further revealed that AE promoted HT22 cell proliferation and reduced Aβ deposition. Moreover, assessments of plasma and mitochondrial membrane integrity, via Hoechst 33,342/PI staining and mitochondrial permeability transition pore (MPTP) assay, respectively, revealed that AE treatment reduced the population of PI-positive cells and suppressed MPTP opening. Western blot, immunofluorescence, and ELISA analyses consistently demonstrated that AE downregulated the expression of pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD, GSDMD-N) and suppressed the release of inflammatory cytokines (IL-1β, IL-18, IL-6, TNF-α). The inhibitory effect of AE on the pyroptosis pathway was comparable to that of the specific NLRP3 inhibitor MCC950. These results suggest that AE exerts neuroprotective effects in the AD cellular model by inhibiting NLRP3 inflammasome activation, thereby blocking Caspase-1 and GSDMD-N activation, attenuating neuronal pyroptosis, reducing inflammatory responses, and mitigating Aβ-induced pathological damage. Collectively, these findings identify AE as a promising therapeutic candidate for AD.},
}

@article {pmid41550444,
year = {2026},
author = {Fabi, A and Alves, AS and Neutzner, A and Frank, S and Lariu, A and Muller, L and Ismail, T and Gkotsoulias, DG and Guzman, R and Schaefer, DJ and Grossman, N and Busche, MA and Kappos, EA},
title = {Neurolymphatic clearance in neurodegenerative disease: Emerging mechanisms and potential translational strategies.},
journal = {JPRAS open},
volume = {48},
number = {},
pages = {438-449},
pmid = {41550444},
issn = {2352-5878},
abstract = {INTRODUCTION: Neurolymphatic dysfunction has been linked to cognitive decline and implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Despite its growing recognition, the potential role of pharmacological or surgical neurolymphatic modulation remains poorly understood.

OBJECTIVES: This review summarizes current evidence on the neurolymphatic system's anatomy, physiology and its involvement in neurodegenerative diseases. It also examines emerging pharmacological and lymphatic reconstructive techniques.

METHODS: A comprehensive literature search was conducted in PubMed, yielding 187 studies related to the neurolymphatic system. Studies were screened for the following topics: (1) Anatomy and physiology of the neurolymphatic system, (2) The association between neurolymphatic dysfunction and neurodegenerative diseases, (3) Pharmacological and (4) Microsurgical neurolymphatic modulation.

RESULTS: Current evidence suggests that the neurolymphatic system facilitates drainage of interstitial and cerebrospinal fluid to the deep cervical lymph nodes. Preclinical models suggest that enhancing their clearance may promote the clearance of neurotoxic proteins and potentially improve cognitive function.

CONCLUSIONS: Scientific evidence on neurolymphatic modulation in neurodegenerative diseases is scarce. Both pharmacological and microsurgical modulatory techniques remain experimental approaches for neurodegenerative diseases, with a significant potential to improve patients' quality of life. However, further research is warranted to establish their safety, feasibility, and efficacy. The current knowledge gaps underscore the need for a detailed mapping of the neurolymphatic pathways, preclinical evaluation, and translational interdisciplinary trials.},
}

@article {pmid41550364,
year = {2025},
author = {Schedlowski, J and Maes, JHR and van Asselt, RJ and Bertens, D and Egger, JIM and Kessels, RPC},
title = {Identity Matching and Stimulus Equivalence Learning Paradigms for Memory Rehabilitation of Explicit Memory Deficits: A Scoping Review.},
journal = {Perspectives on behavior science},
volume = {48},
number = {4},
pages = {759-802},
pmid = {41550364},
issn = {2520-8977},
abstract = {Explicit memory dysfunction, such as in Alzheimer's dementia, impairs learning and daily functioning, requiring effective rehabilitation strategies to promote functional independence. Relational learning paradigms such as stimulus equivalence learning (SEL) imply the formation of networks of relations in which trained relations give rise to emergent relations, potentially providing a novel approach to addressing deficits in remembering and stimulus control. We evaluated the scope and nature of research on the application of relational learning paradigms for memory rehabilitation. In particular, we outline the evidence for the efficacy of identity matching and SEL in specific disorders, the associated effective strategies, and challenges to guide future research. A systematic search following the PRISMA-ScR guidelines identified 23 reports categorized into identity matching, arbitrary matching, and differential outcome procedure (DOP) paradigms. Findings were mixed regarding the success of training procedures. Studies indicate particularly positive outcomes under the DOP and overall efficacy seemed to depend on impairment severity. However, current evidence on the efficacy of relational learning paradigms in individuals with explicit memory dysfunction remains inconclusive due to uncontrolled designs and methodological weaknesses in statistical analysis and patient reporting. Nevertheless, insights from the reviewed studies can inform more rigorous future research. The focus should be on identifying the necessary and sufficient conditions for training stimulus equivalence relations in this population, within meaningful and well-controlled experimental designs to validate the preliminary findings and assess SEL's potential as a cognitive intervention.},
}

@article {pmid41550299,
year = {2025},
author = {Dhaka, P and Pinky, and Neha, and Khan, MA and Rabbani, SA and El-Tanani, M and Parvez, S},
title = {Trazodone modulates behavioral alterations in scopolamine-induced cognitive deficit by targeting brain-derived neurotropic factor and cAMP response element-binding protein signaling.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1681080},
pmid = {41550299},
issn = {1662-5102},
abstract = {BACKGROUND: Trazodone, an antidepressant, may play a potential role in enhancing long-term memory by combining anxious behavior deficits induced by scopolamine. The current study proposes the potential novel mechanistic insights between oxidative stress and memory biomarkers, including BNDF and CREB pathways, to modulate the pathogenesis of AD-like symptoms.

METHODS: Behavioral deficits were studied in terms of biochemical determination of lipid peroxidation and acetylcholinesterase activities. In addition, the study looked at the immunohistochemistry of BDNF and CREB against scopolamine-induced AD-like symptoms. Moreover, histopathological alterations were also performed against an AD-like model. Aβ42 proteins immunofluorescence was performed due to its known mechanism under AD. Finally, scopolamine-induced intraperitoneal mechanisms were studied in rats to establish an AD-like model.

RESULTS: The present study findings showed that administration of TRAZ considerably improved cognitive impairments as validated by NOR and display of anti-anxiety behavior, as verified by EPM. In addition, biochemical findings confirmed that TRAZ lowered oxidative stress through LPO, reduced Aβ deposition, and decreased the AChE. Furthermore, there was a notable upregulation of BDNF and CREB signaling expression, as confirmed by the IHC.

CONCLUSION: Overall, the study findings confirmed that TRAZ could be useful in mitigating the negative effects of scopolamine-induced cognitive impairment and lowering oxidative stress by enhancing memory indicators.},
}

@article {pmid41550298,
year = {2025},
author = {Saminathan, P and McArdle, S and Corey, M and Nadig, N and Fang, C and Gibbons, A and Rayadurgam, M and Sharma, S},
title = {Unmasking early microglial remodeling in an Alzheimer's disease mouse model.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1720382},
pmid = {41550298},
issn = {1662-5102},
abstract = {Early neuroimmune remodeling is a critical yet understudied component of Alzheimer's disease (AD) pathogenesis. To investigate microglial contributions to AD development prior to overt plaque deposition, we developed an open-source morphometric pipeline to systematically quantify hippocampal microglial structure and activation states in pre-plaque 5xFAD mice. Across ∼11,000 cells, we extracted multidimensional parameters including area, circularity, convex hull, branch points, nearest-neighbor distance, and nuclear features, alongside Iba1 and CD68 intensity measurements. While no significant overt gliosis was observed at this early stage, microglia from 5xFAD mice exhibited subtle trends toward increased structural complexity compared to wild-type controls. Importantly, significant sex-specific differences were detected within the CA1 subregion: male 5xFAD microglia displayed hyper-ramified morphologies consistent with enhanced surveillance states, whereas female microglia demonstrated greater density and a more reactive phenotype. Correlation analyses revealed a conserved association between microglial complexity and Iba1/CD68 expression, independent of sex or genotype, underscoring a fundamental link between cytoskeletal remodeling and phagolysosomal activity. These findings highlight the capacity of morphometric profiling to sensitively detect early, region-specific, and sex-dependent shifts in microglial phenotype before amyloid deposition. By integrating quantitative morphology with canonical molecular markers, this framework provides a robust and unbiased approach for characterizing microglial activation trajectories. Such early readouts may inform biomarker discovery and therapeutic strategies aimed at modulating microglial responses to delay or prevent AD progression.},
}

@article {pmid41550140,
year = {2026},
author = {Bota, PM and Picón-Pagès, P and Fanlo-Ucar, H and Almabhouh, S and Bagudanch, O and Zeylan, ME and Senyuz, S and Gohl, P and Molina-Fernández, R and Fernandez-Fuentes, N and Barbu, E and Vicente, R and Nattel, S and Ois, A and Puig-Pijoan, A and Garcia-Ojalvo, J and Keskin, O and Gursoy, A and Muñoz, FJ and Oliva, B},
title = {Oxidative stress-driven transcriptomic remodeling in human astrocytes reveals network signatures associated with neurodegenerative and cardiovascular processes.},
journal = {Computational and structural biotechnology journal},
volume = {31},
number = {},
pages = {263-275},
pmid = {41550140},
issn = {2001-0370},
abstract = {Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms by which astrocytes respond to aging-related stressors remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 µM H2O2) as a proxy for age-related cellular stress, we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defenses, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signaling. We then performed network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte oxidative stress responsive genes and six with phenotype-associated gene sets (Alzheimer's disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5 % scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, α-actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between amyloid precursor protein (APP) and valosin-containing protein (VCP), and between p53 and 14-3-3ζ, potentially linking proteostasis and stress signaling. Together, these analyses identify a conserved astrocyte-centered network signature that may relate neurodegenerative and cardiovascular processes, and prioritize structurally testable candidates for biomarker and intervention hypothesis testing.},
}

@article {pmid41549952,
year = {2026},
author = {Alanazi, M and Al-Kuraishy, HM and Hussain, NR and Waheed, HJ and Al-Gareeb, AI and Albuhadily, AK and Waheeb, TS and Batiha, GE},
title = {Targeting of PCSK9 in the Management of Alzheimer's Disease: Expanding the New Potential Key Player.},
journal = {Drug development research},
volume = {87},
number = {2},
pages = {e70231},
doi = {10.1002/ddr.70231},
pmid = {41549952},
issn = {1098-2299},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Proprotein Convertase 9/metabolism ; Animals ; *PCSK9 Inhibitors ; Brain/metabolism/pathology ; Oxidative Stress/drug effects ; Receptors, LDL/metabolism ; },
abstract = {Alzheimer's disease (AD) represents the most common cause of dementia in the elderly population worldwide. However, most of the anti-AD medications did not resolve the underlying neuropathology. Consequently, targeting other signaling pathways may be helpful in the management of AD. Particularly, preprotein convertase subtilisin/kexin type 9 (PCSK9), which is a regulator protein of low-density lipoprotein (LDL), is intricate in the pathogenesis of AD. Normally expressed PCSK9 in the brain plays a critical role in the regulation of neuronal differentiation and apoptosis, and degradation of LDL receptors (LDLRs). However, exaggerated brain PCSK9 via induction of inflammation and oxidative stress and related neurodegeneration may induce AD development. Therefore, neuronal PCSK9 has dual role in the CNS. Nevertheless, the exact role of PCSK9 in AD neuropathology is still elusive. Therefore, in the review, we try to revise and discuss the potential role of PCSK9 in the pathogenesis of AD, and how targeting of this protein may be helpful in the management of AD.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Proprotein Convertase 9/metabolism
Animals
*PCSK9 Inhibitors
Brain/metabolism/pathology
Oxidative Stress/drug effects
Receptors, LDL/metabolism

@article {pmid41549803,
year = {2026},
author = {Cheng, S and Zhang, M and Zhang, J and Xie, X and Li, Y and Dou, X and Jiao, X and Tang, Y and Wang, X and Tang, B},
title = {Bioorthogonally Activatable Chemiluminescence for the N-Methyl-d-aspartate Receptors Intravital Imaging.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e23648},
doi = {10.1002/anie.202523648},
pmid = {41549803},
issn = {1521-3773},
support = {22174089//National Natural Science Foundation of China/ ; 22134004//National Natural Science Foundation of China/ ; 92253304//National Natural Science Foundation of China/ ; 22377069//National Natural Science Foundation of China/ ; 22374093//National Natural Science Foundation of China/ ; YDZX2022012//Local Science and Technology Development Fund Guided by the Central Government of Shandong Province/ ; },
abstract = {The signal attenuation caused by skull/vertebrae remains a challenge in central nervous system (CNS) receptor imaging. Chemiluminescence (CL), free from external excitation, offers unparalleled tissue penetration in optical imaging. However, existing 1,2-dioxetane CL systems are shackled by two limitations: (i) short half-lives (<2 h) from rapid dioxetane decomposition and (ii) dependence on reactive biomolecules such as reactive oxygen species and enzymes to trigger dioxetane decomposition, rendering them incompatible with imaging nonreactive biomolecules like receptor proteins. Here we report a bioorthogonally activatable chemiluminescence (BACL) strategy that integrates click-to-release reactions with 1,2-dioxetane luminophores to enable tetrazine-triggered OFF-ON CL signals and bioorthogonally tunable half-lives (5.2-18 h). The tissue penetration depth was up to 6 cm. Through a tetrazine-conjugated specific ligand, BACL imaged N-methyl-d-aspartate receptors (NMDARs) in vivo with a signal background ratio of ∼182, allowing clear differentiation of NMDAR expression levels between Alzheimer's disease model mice and normal controls. Beyond imaging, the bioorthogonally spatiotemporally controlled CL emission positions BACL as a potential internal light source for deep-tissue precision phototherapeutics, bypassing external irradiation.},
}

@article {pmid41549419,
year = {2026},
author = {Singh, V and Rochakim, N and Ferraresso, F and Garg, K and Rizvi, AB and Choudhury, A and Kastrup, CJ and Ahn, HJ},
title = {Aquaporin-4 and caveolin-1 as mediators of fibrinogen-driven cerebrovascular pathology in cerebral amyloid angiopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71030},
doi = {10.1002/alz.71030},
pmid = {41549419},
issn = {1552-5279},
support = {NS104386/GF/NIH HHS/United States ; AG078245/GF/NIH HHS/United States ; HL168009/GF/NIH HHS/United States ; },
mesh = {*Caveolin 1/metabolism ; Animals ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Aquaporin 4/metabolism ; *Fibrinogen/metabolism ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Alzheimer Disease ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA), marked by amyloid beta (Aβ) accumulation in perivascular spaces (PVSs), contributes to vascular injury and inflammation in Alzheimer's disease. The mechanisms underlying CAA-related vascular pathology remain unclear. Increasing evidence indicates fibrinogen, the main component in blood clots, interacts with Aβ and exacerbates inflammation and co-deposits in PVS of CAA-positive vessels, yet its role in cerebrovascular dysfunction remains poorly defined.

METHODS: Using TgSwDI transgenic mice, which develop robust CAA, we examined fibrin(ogen) deposition, aquaporin-4 (AQP4) polarization, and caveolin-1 (Cav-1) expression. We further assessed the effects of fibrinogen depletion via small interfering RNA.

RESULTS: TgSwDI mice showed increased fibrin(ogen) extravasation, colocalization with Aβ in PVS, AQP4 depolarization, and elevated Cav-1 expression. Fibrinogen depletion reduced CAA, restored AQP4 polarization, decreased Cav-1 levels, attenuated microglial activation, and improved spatial memory.

DISCUSSION: These findings suggest that modulating fibrinogen-related pathways could be a promising strategy for mitigating CAA pathology and its associated cerebrovascular pathology.

HIGHLIGHTS: Fibrin(ogen)-Aβ colocalization aggravates CAA. AQP4 depolarization links fibrinogen-Aβ deposits to impaired clearance in CAA. Cav-1 increase drives fibrinogen leakage and neuroinflammation. Fibrinogen depletion reduces CAA, restores AQP4 polarity, and improves memory.},
}

*Caveolin 1/metabolism
Animals
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Aquaporin 4/metabolism
*Fibrinogen/metabolism
Mice
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Disease Models, Animal
Alzheimer Disease

@article {pmid41549415,
year = {2026},
author = {Kang, S and Ye, BS and Yun, M and Lee, YG and , },
title = {Effect of tau burden and Lewy pathology on neuropsychiatric symptoms in Aβ-positive individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71116},
doi = {10.1002/alz.71116},
pmid = {41549415},
issn = {1552-5279},
support = {U01AG024904/GF/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; /CAPMC/CIHR/Canada ; //Northern California Institute for Research and Education/ ; //Alzheimer's Therapeutic Research Institute/ ; //University of Southern California/ ; //Inje University/ ; HR22C141101//Korea Health Industry Development Institute/Republic of Korea ; RS-2025-25467534//Korea Health Industry Development Institute/Republic of Korea ; },
mesh = {Humans ; Male ; *Amyloid beta-Peptides/metabolism ; Female ; *tau Proteins/metabolism ; Aged ; Positron-Emission Tomography ; *Alzheimer Disease/pathology/metabolism/psychology/diagnostic imaging ; *Lewy Bodies/pathology/metabolism ; Aged, 80 and over ; Cohort Studies ; Brain/pathology/metabolism/diagnostic imaging ; Lewy Body Disease ; },
abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are common across the Alzheimer's disease (AD) spectrum. We aimed to evaluate the effects of amyloid beta (Aβ), tau, and Lewy body (LB) pathologies on NPS in Aβ-positive individuals.

METHODS: In 336 Aβ-positive participants from the Alzheimer's Disease Neuroimaging Initiative cohort, spanning from cognitively unimpaired to those with early dementia, NPS were assessed. Aβ and tau positron emission tomography were conducted. In a subgroup of 238 participants, dichotomized LB pathology was assessed by detecting α-synuclein seeding activity. The effects of Aβ, tau, and LB pathologies on NPS were evaluated using logistic regression analyses.

RESULTS: Greater tau burden was associated with delusion, agitation/aggression, irritability/lability, aberrant motor behavior, and appetite/eating disorder. In subgroup analyses, LB pathology was associated with delusion, anxiety, apathy, and sleep disturbance, independent of Aβ and tau burden.

DISCUSSION: Tau and LB pathologies are major determinants of NPS in Aβ-positive individuals, each contributing distinct symptom profiles.

HIGHLIGHTS: Tau burden was associated with delusion, agitation/aggression, irritability/lability, aberrant motor behavior, and appetite/eating disorder. Tau in frontal, temporal, and limbic cortices was associated with delusion. In amyloid beta (Aβ)-positive individuals, co-occurring Lewy body (LB) pathology is associated delusion, anxiety, apathy, and sleep disturbance, independent of tau. Tau and LB pathologies are associated with the distinct profiles of neuropsychiatric symptoms in Aβ-positive individuals.},
}

Humans
Male
*Amyloid beta-Peptides/metabolism
Female
*tau Proteins/metabolism
Aged
Positron-Emission Tomography
*Alzheimer Disease/pathology/metabolism/psychology/diagnostic imaging
*Lewy Bodies/pathology/metabolism
Aged, 80 and over
Cohort Studies
Brain/pathology/metabolism/diagnostic imaging
Lewy Body Disease

@article {pmid41549413,
year = {2026},
author = {Burns, JM and Alford, S and Coppinger, J and Jiménez-Mausbach, M and Ray, S and Pandey, H and Laird, R},
title = {Early Alzheimer's diagnosis: U.S. primary care physicians and use of blood biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e70986},
doi = {10.1002/alz.70986},
pmid = {41549413},
issn = {1552-5279},
support = {//Novo Nordisk Inc./ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; *Physicians, Primary Care/psychology ; United States ; Male ; Female ; *Attitude of Health Personnel ; Early Diagnosis ; Middle Aged ; },
abstract = {INTRODUCTION: We aimed to explore primary care physicians' (PCP) attitudes, perceptions, and barriers toward Alzheimer's disease (AD) diagnosis and incorporating blood biomarker (BBM) tests into the diagnostic workflow.

METHODS: Remote 60-min interviews with 20 PCPs were conducted (May 2023). Participants included generalists and geriatricians representing urban, suburban, and rural U.S. practices. Interviews encompassed early AD diagnosis, PCP role, and BBM test implementation.

RESULTS: Most PCPs view investigating cognitive decline as an important part of their role and are somewhat confident in diagnosing AD. Barriers include the complexity and inefficiency of current diagnostic workflows, lack of effective treatments, and stigma. PCPs consider BBM tests accurate and cost-effective but have concerns about reimbursement and diagnostic pathway placement.

DISCUSSION: PCPs are interested in AD diagnosis and receptive toward BBM testing. Education on BBM test use and AD diagnosis may benefit PCPs in the care of individuals with cognitive decline.

HIGHLIGHTS: Early Alzheimer's disease (AD) diagnosis is crucial for initiating treatment Primary care physicians (PCPs) find investigation of cognitive decline important PCPs consider blood biomarker (BBM) tests accurate and cost-effective PCPs seek clarity on reimbursement of BBM tests and their context of use Education on BBM test interpretation and AD diagnosis may benefit primary care.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Biomarkers/blood
*Physicians, Primary Care/psychology
United States
Male
Female
*Attitude of Health Personnel
Early Diagnosis
Middle Aged

@article {pmid41549411,
year = {2026},
author = {Crane, PK and Li, C and Cohen, T and Seitz, A and Rhodes, E and Choi, SE and Lee, M and Mukherjee, S and Nakano, C and Albertson, S and Asadollahi, A and Velderrain-Lopez, K and Gallée, J and Rabin, LA and Gaynor, L and Dumitrescu, L and Turner, S and Hohman, TJ and Gibbons, LE and Trittschuh, EH and Saykin, AJ and Mez, J},
title = {Cognitive data harmonization in the ADRC Network and beyond-Past, present, and future.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71086},
doi = {10.1002/alz.71086},
pmid = {41549411},
issn = {1552-5279},
support = {U24 AG074855/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; *Neuropsychological Tests ; *Psychometrics ; *Cognitive Dysfunction/diagnosis ; *Cognition ; United States ; },
abstract = {The National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) includes extensive cognitive data contributed by Alzheimer's Disease Research Centers (ADRCs) since 2005. The UDS has evolved over time and is on its fourth iteration. In addition to this core dataset, individual ADRCs have administered augmented neuropsychological batteries to research participants that go beyond the UDS. Here we describe ongoing efforts and future plans to optimize use of these data with modern psychometric methods. Modern psychometric methods address challenges from an evolving battery of cognitive tests. To date, most efforts using modern psychometric methods have focused on harmonization and co-calibration of ADRCs' UDS and non-UDS cognitive data, while recent efforts address additional areas such as subjective cognitive impairment. Modern psychometric methods provide a workable framework for anticipated future developments, including digital cognitive testing and analyses of spoken responses. These methods facilitate optimal use of NACC's data riches to further its mission to facilitate collaborative research. HIGHLIGHTS: National Alzheimer's Coordinating Center (NACC) data collection includes an extensive cognitive battery that has changed over time. An ambitious project has harmonized and co-calibrated cognitive domain scores for memory, executive functioning, and language. Scores and their standard errors are available from the NACC. Those scores are co-calibrated with domain scores from many additional studies, facilitating cross-study scientific investigation. Future opportunities include digital data collection, consideration of neuropsychiatric symptoms and subjective cognitive impairment, and other uses of the granular cognitive data.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
*Neuropsychological Tests
*Psychometrics
*Cognitive Dysfunction/diagnosis
*Cognition
United States

@article {pmid41549404,
year = {2026},
author = {Kennedy, JT and Wisch, JK and Boerwinkle, AH and Millar, PR and McKay, NS and Brickman, AM and Chhatwal, JP and Mendez, PC and Christian, BT and Cohen, A and Cruchaga, C and Daniels, A and Flores, S and Handen, BL and Hartley, SL and Head, E and Ibanez, L and Krisnsky-McHale, SJ and la Fougere, C and Lai, F and Laymon, CM and Lee, JH and Lee, JH and Levin, J and Llibre-Guerra, J and Aguillon, DF and Lott, IT and Mapstone, M and McDade, E and Morris, J and O'Bryant, SE and Price, JC and Rafii, MS and Roh, JH and Rosas, HD and Schupf, N and Supnet-Bell, C and Xiong, C and Zaman, S and Benzinger, TLS and Gordon, BA and Ances, BM and , },
title = {Brain volume trajectories in Down syndrome and autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71103},
doi = {10.1002/alz.71103},
pmid = {41549404},
issn = {1552-5279},
support = {U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054)//National Institute for Child Health and Human Development/ ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG16537//National Institutes of Health Programs: The Alzheimer's Disease Research Centers Program/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; U54 HD090256/HD/NICHD NIH HHS/United States ; U54 HD087011/HD/NICHD NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; },
mesh = {Humans ; *Down Syndrome/pathology/diagnostic imaging ; *Alzheimer Disease/pathology/diagnostic imaging/genetics ; Male ; Female ; *Brain/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Middle Aged ; Longitudinal Studies ; Organ Size ; Adult ; Disease Progression ; Aged ; },
abstract = {INTRODUCTION: It is unknown if neurodegeneration trajectories differ between Down syndrome (DS) and autosomal dominant Alzheimer's disease (ADAD), both of which are genetic forms of Alzheimer's disease (AD).

METHODS: We compared brain volumes in DS, ADAD, and unaffected family members serving as controls. Participants underwent magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET), deriving volumetric and amyloid burden, respectively. Nonlinear associations between regional volumes and estimated years to clinical symptom onset (EYO) were evaluated using generalized additive mixed-models.

RESULTS: Longitudinal data from 267 controls, 341 participants with DS, and 358 participants with ADAD were included, totaling 1908 scans. DS volumes were lower than ADAD and controls initially and dropped linearly. ADAD had similar volumes to controls until diverging, beginning at EYO -7. Amyloid was negatively associated with volume, with similar slopes in DS and ADAD.

DISCUSSION: ADAD and DS demonstrate distinct patterns of brain volume decline prior to symptom onset despite being similarly affected by amyloid.},
}

Humans
*Down Syndrome/pathology/diagnostic imaging
*Alzheimer Disease/pathology/diagnostic imaging/genetics
Male
Female
*Brain/pathology/diagnostic imaging
Magnetic Resonance Imaging
Positron-Emission Tomography
Middle Aged
Longitudinal Studies
Organ Size
Adult
Disease Progression
Aged

@article {pmid41549403,
year = {2026},
author = {Martinez, JE and Lopez, KA and Properzi, MJ and Kirn, D and Vila-Castelar, C and Ramirez-Gomez, L and Gonzalez Catalan, M and Buckley, R and Amariglio, RE and Rentz, DM and Johnson, K and Sperling, RA and Quiroz, YT},
title = {Neuroimaging markers and cognition in cognitively unimpaired older Latinos from the Harvard Aging Brain Study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71126},
doi = {10.1002/alz.71126},
pmid = {41549403},
issn = {1552-5279},
support = {P01AG036694//U.S. National Institute on Aging (NIA)/ ; R01AG066823//U.S. National Institute on Aging (NIA)/ ; R01AG077627//U.S. National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *Hispanic or Latino ; Male ; Female ; Aged ; *Neuroimaging ; *Cognition/physiology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Brain/diagnostic imaging/pathology/metabolism ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Hippocampus/pathology/diagnostic imaging ; *Aging ; Aged, 80 and over ; Biomarkers ; Middle Aged ; White ; },
abstract = {INTRODUCTION: Research examining Alzheimer's disease (AD) neuroimaging markers of brain pathology and cognition in older Latino adults remains limited. We compared neuroimaging and cognitive profiles between cognitively unimpaired older Latino and non-Latino adults from the greater Boston area.

METHODS: Twenty Latino and 230 non-Latino cognitively unimpaired older adults from the Harvard Aging Brain Study were included. Participants underwent neuroimaging to assess amyloid beta (Aβ), inferior temporal tau and hippocampal volume, as well as cognitive testing with the Preclinical Alzheimer Cognitive Composite-5. Associations between ethnicity and these outcomes were examined using linear regressions adjusted for age, education attainment, and sex.

RESULTS: Latino participants had higher levels of inferior temporal tau (p = 0.02) and lower cognitive performance (p < 0.001) compared to non-Latinos, but comparable Aβ deposition and hippocampal volume (all ps > 0.05).

DISCUSSION: These results highlight potential differences in vulnerability to cognitive decline between Latinos and non-Latinos, underscoring the need for further investigation.},
}

Humans
*Hispanic or Latino
Male
Female
Aged
*Neuroimaging
*Cognition/physiology
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
*Brain/diagnostic imaging/pathology/metabolism
Magnetic Resonance Imaging
Neuropsychological Tests
Hippocampus/pathology/diagnostic imaging
*Aging
Aged, 80 and over
Biomarkers
Middle Aged
White

@article {pmid41549381,
year = {2026},
author = {Lee, S and Lee, J and Jeon, J and Lee, H and Choi, B and Hong, J and Lee, SJ},
title = {PLGA Nanoparticle-based Anti-TLR2 scFv Gene Delivery for the Treatment of Alzheimer's Disease.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en25047},
pmid = {41549381},
issn = {1226-2560},
abstract = {In Alzheimer's disease (AD), persistent microglial neuroinflammation and the poor brain exposure and durability of current therapies underscore the need for new, long-acting treatments. We developed a non-viral gene therapy that suppresses microglial Toll-like receptor 2 (TLR2) signaling using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with a plasmid encoding the anti-TLR2 single-chain variable fragment (scFv33). Following intra-cisterna magna delivery, PLGA NPs exhibited microglia-biased uptake and enabled brain-wide transgene expression in mice. In 5xFAD mice, a single administration of scFv33 NPs improved recognition memory in the novel object recognition (NOR) assay, outperforming 8 weeks of weekly recombinant scFv33-Fc dosing. Histology showed selective reduction of small hippocampal Aβ plaques and a shift toward a ramified microglial morphology, indicative of reduced activation. In primary neuron-microglia co-culture, scFv33 reduced microglial hypertrophy, restored process complexity, and enhanced Aβ phagocytosis. Together, these data indicate that sustained, local expression of an anti-TLR2 scFv via a clinically translatable PLGA platform recalibrates microglial state and preferentially limits early-stage plaque accumulation, yielding cognitive benefit after a single dose.},
}

@article {pmid41550177,
year = {2024},
author = {Bu, S and Ji, J and Yang, M and Sun, J and Zhang, J and Qian, S and Lou, H and Fan, P},
title = {Chemical composition and neuroprotective activity of hemp seed aqueous extract and their chemotaxonomic significance.},
journal = {Pharmaceutical science advances},
volume = {2},
number = {},
pages = {100051},
pmid = {41550177},
issn = {2773-2169},
abstract = {Fructus Cannabis (hemp seed) is important in food and traditional Chinese medicinal applications. Several studies have shown it has antioxidant, antiaging, anti-inflammatory, and neuroprotective properties. Studies have reported its anti-Alzheimer's disease effects. However, its active substances have not been defined, and little is known about the chemical constituents of the aqueous extract. The chemical profile of the aqueous extract of Fructus Cannabis (EFC) was obtained via isolation, structural identification, and qualitative and quantitative analyses. Twenty-seven compounds were identified, including seven nucleosides (1-7), five phenylpropanamides (8-11, and 24), three alkaloids (15, 16, and 26), two cyclic dipeptides (17 and 25), and one pyrimidine (19). Compounds 1, 3-7, 12, 14-19, and 21-27 were not reported previously in the Cannabis genus. Therefore, their chemotaxonomic significance is discussed. Neuroprotective activity screening revealed that EFC and the isolated compounds, particularly 9, 11, and 17, showed significant neuroprotective effects in PC12 cells (rat pheochromocytoma cells). The novel object recognition experiment and Nissl staining showed that EFC improved cognitive impairment in APP/PS1 mice and that EFC intervention reduced the number of senile plaques. These findings will contribute to the utility of Fructus Cannabis.},
}

@article {pmid41550171,
year = {2024},
author = {Kamaljeet, and Singh, S and Gupta, GD and Aran, KR},
title = {Emerging role of antioxidants in Alzheimer's disease: Insight into physiological, pathological mechanisms and management.},
journal = {Pharmaceutical science advances},
volume = {2},
number = {},
pages = {100021},
pmid = {41550171},
issn = {2773-2169},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, cognitive decline, impairment in activities of daily living, and loss of independent function. Cognitive decline and brain shrinkage, particularly hippocampal atrophy, are associated with the accumulation of tau proteins. They cause inflammation, amyloid plaque deposition, neuronal loss, temporofrontal cortex atrophy, aberrant protein fragment clusters, and twisted fiber bundles. Given the significant role of oxidative processes in neurodegeneration, it is logical to consider the potential of antioxidants in the treatment of AD. Several antioxidants, including glutathione, astaxanthin, ascorbyl palmitate, catalase, and molecular hydrogen, play important roles in AD. Antioxidants interact with free radicals to neutralize them. Several studies have suggested that oxidative stress or damage is involved in the development of AD via different mechanisms and pathways. Thus, new approaches are needed to reduce the extent of oxidative damage that may be therapeutically effective against AD. Although certain antioxidants have exhibited notable benefits in animal models, their efficacy in human clinical trials has been limited, casting doubt regarding the efficacy of antioxidant treatments for AD. Therefore, a more focused and precise strategy that incorporates antioxidants is essential for slowing or stopping AD progression. The integrated role of antioxidants in reducing inflammation must be considered, because the link between inflammation and AD is undeniable. Therefore, the present study aimed to elucidate the role of antioxidants in AD, with the goal of aiding researchers in developing effective and potentially enhanced antioxidant-based therapeutic strategies.},
}

@article {pmid41549257,
year = {2026},
author = {Wang, C and Chen, H and Liu, M and Lu, W and Hao, Z and Wang, B},
title = {Efficacy of non-invasive neuromodulation technologies in improving cognitive function and activities of daily living in patients with Alzheimer's disease, Parkinson's disease, and stroke: a systematic review and network meta-analysis.},
journal = {Journal of neuroengineering and rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12984-025-01842-2},
pmid = {41549257},
issn = {1743-0003},
}

@article {pmid41549054,
year = {2026},
author = {Collingridge, GL},
title = {Glutamate Receptors and Synaptic Plasticity in Health and Disease: A Personal Journey.},
journal = {Hippocampus},
volume = {36},
number = {1},
pages = {e70062},
doi = {10.1002/hipo.70062},
pmid = {41549054},
issn = {1098-1063},
mesh = {Animals ; *Neuronal Plasticity/physiology ; Humans ; *Receptors, Glutamate/physiology/metabolism ; *Hippocampus/physiology/metabolism ; *Synapses/physiology ; },
abstract = {I describe my progress in understanding synaptic plasticity in the hippocampus. Over the decades my lab has focused on the roles of glutamate receptors (AMPARs, NMDARs, mGluRs and KARs) and associated signaling molecules in LTP and LTD. Most of our studies have been conducted in area CA1 (Schaffer collateral-commissural pathway) with some conducted in CA3 (mossy fiber pathway). We have made extensive use of electrophysiology and pharmacological tools, complemented with knock-out (KO) and transgenic mice, biochemistry and dynamic imaging. From a starting point in 1980, with essentially no molecular insights available, we have developed a detailed, but still incomplete, mechanism for LTP at CA1 and CA3 synapses as well as providing insights into LTD at CA1 synapses. We have also explored how dysregulated synaptic plasticity contributes to brain disorders, with an emphasis on Alzheimer's disease. Indeed, through a molecular understanding of synaptic plasticity, now we can explain how plaques and tangles are related mechanistically and, in essence, how the early stages of dementia are triggered. Therapeutic strategies, both pharmacological and lifestyle, for tackling dementia are touched upon. Our work, together with that of many other groups, has resulted in massive progress in the understanding of synaptic plasticity in the mammalian CNS in health and disease.},
}

Animals
*Neuronal Plasticity/physiology
Humans
*Receptors, Glutamate/physiology/metabolism
*Hippocampus/physiology/metabolism
*Synapses/physiology

@article {pmid41548934,
year = {2026},
author = {Neghabi, M and Nategh, P and Stauffer, AM and Hahn, MK and Blakely, RD and Ranji, M},
title = {Elesclomol Diminishes Redox Imbalance in Peripheral Tissues of Mblac1 Knockout Mice.},
journal = {Journal of biophotonics},
volume = {19},
number = {1},
pages = {e70224},
doi = {10.1002/jbio.70224},
pmid = {41548934},
issn = {1864-0648},
support = {EY031533/NH/NIH HHS/United States ; 2154267//National Science Foundation/ ; //Florida Atlantic University I-SENSE Seed Funding to MR/ ; //Florida Department of Health award to RDB/ ; },
mesh = {Animals ; Oxidation-Reduction/drug effects ; Mice ; Mice, Knockout ; Male ; Female ; Liver/metabolism/drug effects ; Kidney/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; Copper/metabolism ; *Hydrazines/pharmacology ; Organ Specificity/drug effects ; },
abstract = {OBJECTIVE: To determine whether loss of Mblac1, a gene implicated in copper metabolism and Alzheimer's disease, causes systemic mitochondrial redox imbalance and whether treatment with the copper chaperone elesclomol (ES) can restore this balance.

METHODS: We employed 3D cryoimaging to quantify redox ratio (RR) in kidneys and livers of Mblac1 knockout (KO) mice and their wildtype (WT) littermates. Mice of both sexes were administered either vehicle control (C) or ES (10 mg/kg, i.p.).

RESULTS: KO tissues exhibited reduced RR, indicating an oxidized metabolic state. ES treatment recovered 77% of the RR deficit in kidneys and 48% in livers, restoring RR to WT levels.

CONCLUSION: Mblac1 deletion disrupts mitochondrial redox homeostasis in peripheral tissues, while ES partially reverses this imbalance by restoring Cu(I)-dependent metabolism.

SIGNIFICANCE: Optical metabolic imaging reveals Mblac1 as a key regulator of systemic redox balance and supports ES as a potential therapy for Cu-linked metabolic dysfunctions.},
}

Animals
Oxidation-Reduction/drug effects
Mice
Mice, Knockout
Male
Female
Liver/metabolism/drug effects
Kidney/metabolism/drug effects
Mitochondria/metabolism/drug effects
Copper/metabolism
*Hydrazines/pharmacology
Organ Specificity/drug effects

@article {pmid41548855,
year = {2026},
author = {Jiang, A and Ma, Y and Bao, S and Shahbazi, MA and Reis, RL and Kundu, SC and Xiao, B and Shi, X},
title = {Metal-directed nanomedicines for imaging-guided disease treatment.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.01.032},
pmid = {41548855},
issn = {1878-7568},
abstract = {Metal-directed self-assembly, driven by metal-ligand coordination, represents a highly versatile and efficient strategy for constructing drug delivery systems with precisely tunable properties, inherent imaging capabilities, and broad biomedical applications. Stimuli-responsive metal-directed drug delivery systems (MDDSs), guided by advanced imaging techniques, enable precise control over their size and spatial architecture while facilitating site-specific drug release. Moreover, certain metal ions play a dual role, not only orchestrating the self-assembly process but also serving as therapeutic agents and regulatory components for the treatment of various diseases, including cancer, microbial infections, and Alzheimer's disease. This review provides a comprehensive overview of the self-assembly mechanisms underlying diverse MDDSs and their applications in image-guided therapy. Furthermore, we critically examine existing challenges in the field and propose strategic directions to propel the advancement of metal-directed self-assembly in drug delivery. Given the profound implications of this research, further exploration of the critical roles of metal coordination in self-assembly is imperative for the development of next-generation drug delivery platforms. STATEMENT OF SIGNIFICANCE: This review systematically summarize the self-assembly mechanisms of metal-directed drug delivery systems, outlines their applications in image-guided therapy and discusses the current challenges that remain. Furthermore, it elucidates the unique regulatory roles of metal ions in precise drug release and multimodal therapy, providing valuable insights and broad appeal for the development and clinical translation of next-generation smart nanomedicine platforms.},
}

@article {pmid41548752,
year = {2026},
author = {Li, B and Xu, J and Zhu, H and Ren, D and Xiao, L and Zhang, T and Li, R},
title = {The interaction between FLOT1 and FOSL2 promotes EphA2 transcription, regulating microglial polarization and affecting neuroinflammation in Alzheimer's disease.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110844},
doi = {10.1016/j.neuropharm.2026.110844},
pmid = {41548752},
issn = {1873-7064},
abstract = {BACKGROUND: Microglial activation plays a crucial role in Alzheimer's disease (AD), responding to amyloid-beta (Aβ) plaques and tau tangles. Initially protective, microglia clear Aβ deposits and support neuronal health, but later adopt a pro-inflammatory, neurotoxic state, releasing cytokines that exacerbate neuroinflammation and neuronal damage. Understanding the mechanisms driving this shift is essential for developing therapies to modulate microglial activation and slow AD progression.

METHODS: Quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF) assays were performed to confirm gene and protein expression levels. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (CoIP), and dual-luciferase assays were conducted to assess the interactions among FLOT1, FOSL2, and EphA2. The Morris water maze test was used to evaluate spatial learning and memory, with experiments conducted using the APP/PS1 mouse model.

RESULTS: In this study, we found that silencing of FLOT1 in APP/PS1 mice significantly reduced neuroinflammatory markers, prevented pro-inflammatory polarization, and improved spatial memory. Mechanistically, we observed that FLOT1 interacted with the transcription factor FOSL2, which upregulated EphA2 expression, leading to activation of the p38/MAPK signaling pathway. Disrupting EphA2 expression deactivated this pathway, reducing pro-inflammatory polarization in microglia. Our findings further confirmed that the FLOT1-FOSL2 axis regulated microglial polarization in vivo and that targeting this pathway improved cognitive outcomes in AD models.

CONCLUSION: Overall, these results highlight the FLOT1-FOSL2-EphA2 pathway as a potential therapeutic target for AD, as modulating this axis may reduce neurotoxic inflammation and help preserve cognitive function.},
}

@article {pmid41548720,
year = {2026},
author = {Wu, Y and Zhang, H and Qu, J and Zhu, R and Xu, G and Xu, W and Yan, G and Yang, J and Xin, J and Li, Y and Wang, D and , },
title = {Mapping structural disconnection and transcriptomic signatures in Alzheimer's disease with MIND networks.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111737},
doi = {10.1016/j.brainresbull.2026.111737},
pmid = {41548720},
issn = {1873-2747},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly conceptualized as a disconnection syndrome involving widespread alterations in large-scale brain networks. Previous studies using morphometric similarity networks (MSNs) have revealed broad structural and transcriptomic changes, yet vertex-level structural disconnection and its molecular basis remain poorly understood. We applied morphometric inverse divergence (MIND), an innovative approach for fine-grained mapping of structural disconnection and its transcriptomic correlates in AD.

METHODS: Utilizing two independent datasets: [ADNI (219 AD, 219 cognitively normal, CN) and the Qilu dataset (100 AD, 137 CN)], we mapped robust MIND network alterations in AD patients and examined their associations with cognitive performance and biomarker quantifications. Additionally, we linked MIND connectome to spatial gene expression using partial least squares regression, followed by gene enrichment analysis to identify relevant biological pathways. Finally, to validate the clinical utility of MIND, a residual deep neural network (ResDNN) was developed to compare its diagnostic performance against MSNs in distinguishing AD from CN.

RESULTS: Significantly decreased MIND degree was identified in the bilateral frontal, lateral occipital, and posterior temporal lobes (P FDR < 0.05), positively correlating with MMSE score and FDG-PET SUVR (all P < 0.001). Conversely, increased MIND degree was observed in the bilateral cuneus, entorhinal, lingual, and parahippocampal regions (P FDR < 0.05), negatively correlating with cognition assessment, CSF Aβ-42 levels and FDG-PET SUVR (all P < 0.001). These AD-related MIND alterations were spatially correlated with gene expression profiles crucial for synaptic function, neurotransmission, and metabolic regulation. Importantly, MIND achieved superior diagnostic efficacy (AUC=0.90/0.88 in ADNI/Qilu) over MSNs.

CONCLUSIONS: We mapped a robust pattern of structural disconnection in Alzheimer's disease with MIND approach and associate it with particular transcriptomic signatures. These findings not only improve our mechanistic understanding of AD as a disconnection syndrome but also demonstrate MIND as a sensitive tool for identifying disease-specific alterations, holding promise for future mechanistic and clinical investigations into AD pathology.},
}

@article {pmid41548719,
year = {2026},
author = {Li, X and Wan, R and Zhao, Y and Wu, Y and Chen, X and Li, Q and Luo, C},
title = {Decoding synaptic imbalance in neurodegenerative diseases: From pathological analysis to targeted intervention.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103028},
doi = {10.1016/j.arr.2026.103028},
pmid = {41548719},
issn = {1872-9649},
abstract = {Synapses serve as the central functional components mediating information transmission, integration, and storage within the central nervous system (CNS). Their functionality depends on the synergistic interplay of the presynaptic membrane, synaptic cleft, and postsynaptic membrane-three structures that collectively sustain neurotransmitter secretion, postsynaptic signaling, and synaptic plasticity. Of note, synaptic impairment represents an early, shared pathological hallmark across aging and age-related neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). This damage emerges prior to the demise of neuronal cell bodies and the manifestation of clinical symptoms, with its location and severity directly shaping disease phenotypes. Importantly, such synaptic dysfunction is closely linked to the pathological proteins specific to each disorder. This review comprehensively synthesizes current research advances regarding synaptic impairment in age-related neurodegenerative diseases. It elaborates on the location-specific pathological features of synaptic damage in AD, PD, HD, and ALS, with particular emphasis on their associations with disease-related pathological markers. Additionally, the work unpacks five core mechanisms driving synaptic dysfunction: the toxic effects of pathological proteins, dysregulated synaptic protein homeostasis, excitotoxicity coupled with disrupted calcium balance, oxidative stress and inflammatory responses, and deficiencies in neurotrophic factors. Ultimately, it summarizes potential biomarkers and targeted intervention strategies, aiming to provide a systematic reference for mechanistic investigations, early diagnosis, and clinical management of neurodegenerative diseases.},
}

@article {pmid41548697,
year = {2026},
author = {Takeda, A and Takeuchi, T and Minakawa, EN and Tanaka, N and Mochizuki, H and Nagai, Y},
title = {Blood extracellular vesicles contribute to the exercise-mediated suppression of brain Aβ pathology in the App[NL-G-F] knockin mouse model of Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106120},
doi = {10.1016/j.neuint.2026.106120},
pmid = {41548697},
issn = {1872-9754},
abstract = {Epidemiological, clinical, and experimental evidence suggest that physical exercise suppresses the deposition of amyloid β (Aβ) plaques in the brain and reduces the risk of Alzheimer's disease (AD). However, how exercise provides such beneficial effects on AD remains largely unclear. In this study, we show that the exercise-mediated suppression of Aβ deposition requires blood extracellular vesicles (EVs) that are upregulated by exercise. We demonstrated that treadmill exercise induces a transient increase in the secretion of blood EVs in both wild-type mice and the App[NL-G-F] knockin mouse model of AD. Comprehensive analysis of protein contents of the exercise-induced blood EVs demonstrated that molecular chaperones, such as heat shock proteins and cochaperones, are substantially increased, together with substantial changes in proteomic profiles after exercise. Importantly, long-term exercise led to the suppression of Aβ plaque deposition in App[NL-G-F] knockin mice, but this suppressive effect was almost completely diminished by the pharmacological inhibition of EV secretion. These results indicate that the secretion of blood EVs is increased by exercise, which contributes to the suppression of Aβ pathology in the brain. Our study identifies blood EVs as a key mediator of the benefits of exercise throughout the body including the brain, highlighting the therapeutic potential of exercise-induced EVs for the treatment of AD pathology.},
}

@article {pmid41548619,
year = {2026},
author = {Shao, S and Zu, R and Lu, H and Yuan, Y and Chen, Y and Wu, C and Yang, Y and Shao, S and Ma, H and Zhang, Z and Sun, Y},
title = {Kai-Xin-San alleviates Alzheimer's disease by targeting the DHFR-mediated folate-mitochondrial axis.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121230},
doi = {10.1016/j.jep.2026.121230},
pmid = {41548619},
issn = {1872-7573},
abstract = {Kai-Xin-San (KXS) is a classical herbal formula first recorded in the Tang Dynasty and has been used for more than 1,000 years for cognitive impairment and dementia.

AIM OF THE STUDY: To investigate whether KXS granules (KXSG) alleviate mitochondrial dysfunction in AD by engaging dihydrofolate reductase (DHFR) -linked folate metabolism.

MATERIALS AND METHODS: The pharmacodynamic effects of KXSG were evaluated in APP/PS1 transgenic mice using behavioral testing, neuropathological assessment, and ultrastructural examination of mitochondria. Pathways and candidate targets were first prioritized by brain-tissue DIA proteomics, and were further supported by a network pharmacology analysis based on putative brain-penetrant constituents. Mechanistic validation was performed both in vivo using APP/PS1 transgenic mice and in vitro using an APP-overexpressing HT22 cell model. Mitochondrial function, folate-cycle-related indices, and target protein expression were assessed in both systems, and pharmacological inhibition of DHFR with methotrexate was employed to probe causality.

RESULTS: KXSG treatment improved learning and memory performance, preserved hippocampal neuronal integrity, and reduced Aβ burden in APP/PS1 mice. Proteomic profiling showed that proteins reversed by KXSG were enriched for mitochondrial localization and were closely linked to folate metabolism. DHFR emerged as a key candidate within this network. In cellular assays, KXSG mitigated AD-related mitochondrial impairment while partially normalizing folate-cycle-associated markers and DHFR expression. Notably, methotrexate, a DHFR inhibitor, attenuated the mitochondrial benefits conferred by KXSG.

CONCLUSION: These data support DHFR-associated folate metabolism as an important mechanistic axis through which KXSG promotes mitochondrial function in AD, providing experimental evidence for a folate-mitochondria link underlying its neuroprotective effects.},
}

@article {pmid41548526,
year = {2026},
author = {Moon, SY and Chen, TF and Lee, BC and Moon, WJ and Kandiah, N and Kumar, S and Park, YH and Inaba, K and Dash, A},
title = {A regional framework for the detection and management of ARIA with anti-amyloid therapies in early Alzheimer's disease in Asia.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100477},
doi = {10.1016/j.tjpad.2026.100477},
pmid = {41548526},
issn = {2426-0266},
abstract = {Alzheimer's disease (AD) is a growing public health concern in Asia, with an increasing prevalence driven by demographic shifts and rising life expectancy. The introduction of anti-amyloid monoclonal antibodies such as lecanemab and donanemab marks a pivotal transition from symptomatic management of AD to disease-modifying approaches, but their clinical use requires careful monitoring for amyloid-related imaging abnormalities (ARIA), a key safety consideration that presents either as vasogenic edema or as microhemorrhages and superficial siderosis. ARIA has been observed in varying frequencies across global and Asian clinical trial populations, underscoring the need for region-specific guidance. With our early clinical experiences in South Korea, Taiwan and Singapore serving as archetypes in Asia, we outline a framework for the detection and management of ARIA in Asian healthcare settings, accounting for disparities in imaging infrastructure, genetic factors, and clinician experience. Pre-treatment risk stratification, standardized imaging protocols, and severity-based treatment modifications are central to the framework, highlighting the critical role of multidisciplinary collaboration involving neurologists, geriatricians, psychiatrists, and radiologists in ensuring accurate detection and management of ARIA. Additionally, the paper highlights the role of pharmacovigilance, real-world evidence generation, physician education, and healthcare system preparedness in optimizing the safety and efficacy of anti-amyloid therapies in Asia. The proposed framework aims to ensure safe and effective use of anti-amyloid therapies while mitigating ARIA-related risks, thereby optimizing therapeutic outcomes for early AD in diverse healthcare settings across Asia.},
}

@article {pmid41548335,
year = {2026},
author = {Dong, W and Yuan, Q and Wu, B and Gao, S and Zhang, Y and Pan, Y and Zhou, K and Jiang, H},
title = {Age at type 2 diabetes onset and risk of dementia: The modifying role of genetic susceptibility and mitochondrial function.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {3},
pages = {100780},
doi = {10.1016/j.jnha.2026.100780},
pmid = {41548335},
issn = {1760-4788},
abstract = {OBJECTIVES: To assess dementia risk after incident type 2 diabetes (T2D) by age at diagnosis and evaluate modification by treatment, genetic susceptibility, and mitochondrial function.

DESIGN: Prospective 1:1 age- and sex-matched cohort study using inverse-probability-weighted Cox models.

SETTING: Kunshan Aging Research with E-health (KARE) cohort in China (2018-2024).

PARTICIPANTS: 42,514 adults without diabetes or dementia at baseline, including 21,257 incident T2D cases and 21,257 non-diabetic controls.

MEASUREMENTS: Outcomes were all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) from linked medical records and annual examinations. T2D onset age was grouped as 45-54 years, 55-64 years, and persons 65 years and older. In genotyped participants (n = 14,455), a T2D polygenic risk score (PRS) and blood mitochondrial DNA copy number (mtDNA-CN) were examined.

RESULTS: Over a median 3.67 years, incident T2D was associated with higher risks of all-cause dementia (adjusted hazard ratio [AHR] 1.95, 95% CI 1.71-2.21), AD (2.21, 1.88-2.59), and VaD (1.57, 1.20-2.07). Glucose-lowering treatment was associated with lower dementia risk versus no treatment. Among patients aged 55-64 years, the low-PRS/low-mtDNA-CN subgroup had the highest AD risk (AHR 2.41, 95% CI 1.12-5.19).

CONCLUSION: Age at T2D onset was associated with variation in dementia risk. Earlier diagnosis and treatment were associated with lower observed cognitive risk, while genetic susceptibility and mitochondrial function may inform individualised risk stratification.},
}

@article {pmid41502044,
year = {2026},
author = {Rovito, D and Zanet, S and Trunfio, MGC and Calcagno, A and Ferroglio, E},
title = {Neurocognitive effects of latent Toxoplasma gondii infection in immunocompromised people with HIV.},
journal = {Parasitology},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/S0031182025101509},
pmid = {41502044},
issn = {1469-8161},
abstract = {Toxoplasma gondii (T. gondii) is a neurotropic parasite that establishes latent infection in the central nervous system (CNS), and may alter behaviour and contribute to neuronal dysfunction. However, its impact on cognitive performance and CNS pathophysiological alterations in people with HIV (PWH) remains unclear. A cross-sectional study of adult PWH was conducted, assessing latent T. gondii infection through serum IgG levels in the absence of neurotoxoplasmosis. Neurocognitive impairments were assessed through neurocognitive testing across 6 domains, along with depressive and anxiety symptoms evaluation, and educational attainment. CNS pathophysiological alterations were assessed through amyloid-β1-42, total tau, phosphorylated tau, neopterin, and S-100β quantification in cerebrospinal fluid (CSF). Fifty-eight PWH were included, and T. gondii seropositivity was detected in 46.5% of participants (27/58). Overall, cognitive performance was largely comparable between groups, although subtle, non-significant declines were observed across several domains. T. gondii-seropositive individuals demonstrated a faster completion of Trail Making Test Part B (β = -35.79 sec; 95% CI: -67.78 to -3.86), lower educational attainment (β = -1.92 years; 95% CI: -3.76 to -0.09), without different levels of CSF biomarkers for neuronal-synaptic degeneration, Alzheimer's pathology, beta-amyloid deposition, macrophage-derived inflammation and glial activation-degeneration. In PWH with low CD4 counts, latent T. gondii infection was not associated with overt cognitive impairment or detectable CNS pathophysiological alterations. Instead, an atypical profile emerged, combining faster task-switching with lower educational attainment and subtle, non-significant declines in other domains. These findings highlight the complex nature of T. gondii-host interactions and need for longitudinal studies to clarify long-term neurocognitive outcomes.},
}

@article {pmid41548010,
year = {2026},
author = {Nagaraj, S and Quintanilla-Sánchez, C and Ando, K and Lopez-Gutierrez, L and Gansemans, Y and Doeraene, E and Kosa, AC and Aydin, E and Van Nieuwerburgh, F and Brion, JP and Leroy, K},
title = {Differentially expressed miRNAs in the temporal cortex of Alzheimer's disease patients and their association to tau pathology.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-09530-0},
pmid = {41548010},
issn = {2399-3642},
abstract = {Alzheimer's disease (AD) is a major contributor to dementia in the elderly, characterized by progressive impairments in memory and behaviour. AD is marked by pathological hallmarks: amyloid plaques and neurofibrillary tangles (NFTs). Despite extensive efforts to understand these hallmarks, there is still a lack of efficient therapeutic approaches due to limited knowledge of the fundamental cellular mechanisms underlying the disease. One potential avenue of research involves the investigation of the roles of non-coding RNAs, particularly microRNAs (miRNAs), which bind to the 3' UTRs of target mRNAs to suppress expression. In our study, we analyse the temporal superior T1 isocortex of control and AD patients, identifying differentially expressed miRNAs using next-generation sequencing (NGS). To validate these findings, we utilize an additional technique, RT-qPCR. Our study confirms the previous findings on the dysregulation of miR-129-5p, miR-132-3p, and miR-146b-5p, while also provides insights into the dysregulation of miR-151a-5p and miR-1-3p. Importantly, the expression levels of miR-129-5p, miR-146b-5p, miR-132-3p, and miR-151a-5p are significantly correlated with the neuropathological Braak stages and with biochemically quantified tau phosphorylation levels in brain homogenates. Additionally, we find that miR-146b-5p and miR-151a-5p significantly modulate tau seeding in tau biosensor cell model, highlighting their potential roles in tau pathology.},
}

@article {pmid41547856,
year = {2026},
author = {Zhang, X and Yu, Z and Hao, G and Yao, Q and Hu, Y and Wang, F and Chen, X and Liu, L and Wong, KC and Li, X},
title = {Robust characterization and interpretation of rare pathogenic cell populations from spatial omics using GARDEN.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-68500-6},
pmid = {41547856},
issn = {2041-1723},
support = {62472195//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Spatial omics links molecular measurements to their positions in tissue, revealing cellular organization and interactions. Yet most computational tools highlight common cell types and overlook rare populations that can drive disease. Here we show GARDEN, a computational framework that identifies and characterizes these pathogenic cells or regions in spatial omics by embedding graph-based dynamic attention into a spatially-aware graph fusion contrastive model. GARDEN works consistently across tissues, species and resolution scales, and aligns consecutive sections to reconstruct 3D anatomy. In an Alzheimer's disease model, GARDEN localizes C1qa/C1qb-marked microglia in amyloid-β regions and reveals key immune pathways. In nasopharyngeal carcinoma it identifies tiny tertiary lymphoid structures, and in breast cancer it uncovers inflammatory M1-like macrophages near ductal carcinoma in situ and links them to pro-metastatic signaling. An interpretation module pinpoints key immune signatures, and GARDEN extends to spatial chromatin accessibility, providing insight into epigenetic regulation and informing diagnostics and therapeutic targeting.},
}

@article {pmid41547853,
year = {2026},
author = {Yanes, KJO and Bui, CT and Tomasello, J and Morsy, H and Kim, E and Lam, T and Tsourmas, K and Ayala, LA and Green, KN and Inlay, MA and Lodoen, MB},
title = {Toxoplasma gondii drives myeloid immune cell recruitment to amyloid plaques in Alzheimer's model mice.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03666-2},
pmid = {41547853},
issn = {1742-2094},
abstract = {Infections in the central nervous system result in immune cell trafficking into the brain and microglial activation, which may influence Alzheimer's Disease neuropathology. Toxoplasma gondii infection induces a robust neuroimmune response and a reduction in amyloid plaques in the brains of Alzheimer's model mice. We investigated the myeloid cell response in the immediate vicinity of amyloid plaques in the brain by injecting 3-month-old 5xFAD mice with T. gondii or PBS as a control. T. gondii chronic infection (6 weeks) resulted in reduced amyloid plaque area, volume, and intensity in the cortex, and plaques with decreased circularity based on 6E10 and Thio-S staining. The brains of T. gondii-infected mice also had increased AIF1, AXL, and CLEC7A transcripts for disease-associated microglia (DAM), and elevated IBA1, MAC2, and CD68 phagolysosomal colocalization with amyloid, indicating myeloid cell activation around plaques. CD4 and CD8 T cells were also increased near amyloid and IBA1[+] cells in T. gondii-infected mice. To determine the extent of peripheral myeloid cell recruitment to amyloid, bone marrow from CAG-CFP mice was transplanted into irradiated, head-shielded 5xFAD mice prior to infection. Cyan[+] cells were found surrounding plaques in the brains of T. gondii-infected mice and were comprised predominantly of Ly6C[lo] patrolling monocytes, followed by Ly6C[hi] inflammatory monocytes and T cells. In addition, the majority of myeloid cells and T cells recruited to the brain were derived from skull bone marrow. These data demonstrate that T. gondii infection increases the infiltration of monocytes and T cells from the skull bone marrow niche and the recruitment of highly activated myeloid cells surrounding amyloid plaques in the brains of 5xFAD mice.},
}

@article {pmid41547736,
year = {2026},
author = {Lobo, JD and Serrano, VB and Campbell, LM and Bell, T and Gouaux, B and Galasko, D and Letendre, S and Bondi, MW and Moore, DJ and Sundermann, EE},
title = {Cerebrospinal fluid markers of alzheimer's pathology relate to aMCI among people with HIV.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-025-04585-8},
pmid = {41547736},
issn = {1471-2377},
support = {K01DA060092/DA/NIDA NIH HHS/United States ; R01MH125720/MH/NIMH NIH HHS/United States ; H22D4432//California HIV/AIDs Research Program/ ; RF1[AG061070]//NIH NNTC/ ; RF1[AG061070]//NIH NNTC/ ; },
}

@article {pmid41547581,
year = {2026},
author = {Fan, SP and Liu, PC and Wang, JZ and Lin, CH and Lin, HH},
title = {Disease burden of neurodegenerative disorders in Taiwan.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.01.020},
pmid = {41547581},
issn = {0929-6646},
abstract = {BACKGROUND: With global aging, neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), have become major public health concerns. However, the evaluation of their burden trends in Taiwan is lacking. We assessed temporal and geographic trends in the burden of AD with other dementias and PD in Taiwan from 2000 to 2021, stratified by age, sex, and region.

METHODS: Data from Taiwan's National Health Insurance (NHI) and National Death Registry were analyzed for 2000-2021. Case definitions for Alzheimer's disease with other dementias (ADODs) and Parkinson's disease (PD) followed Global Burden of Disease 2021 criteria and were identified using ICD codes. Fatal burden was assessed using the National Death Registry. Disease burden was quantified by years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs), with additional geographic mapping to visualize regional variations.

RESULTS: Between 2000 and 2021, age-standardized prevalence rose sharply for ADODs (+885 %) and PD (+394 %), while mortality increased by 116 % and 31 %, respectively; incidence remained stable. DALY rates grew by 258 % for ADODs and 86 % for PD, mainly driven by rising YLDs. The greatest burden was among those aged ≥80 years, with ADODs and PD DALYs increasing by 357 % and 147 %, respectively. Geographically, the highest age-standardized DALYs for ADODs and PD were found in the Southern Taiwan.

CONCLUSION: The prevalence and health burden of ADODs and PD have increased substantially in Taiwan despite declining incidence, posing growing challenges to the aging population.},
}

@article {pmid41547342,
year = {2026},
author = {Huo, M and Kim, K and Brown, CK and Gilligan, M and Wang, W},
title = {Receiving caregiver support and its association with hair hormones in people living with Alzheimer's disease: The role of caregivers' perspective taking.},
journal = {Psychoneuroendocrinology},
volume = {186},
number = {},
pages = {107746},
doi = {10.1016/j.psyneuen.2026.107746},
pmid = {41547342},
issn = {1873-3360},
abstract = {Receiving support in later life is often experienced as stressful, but for people living with dementia (PLWD) support is an unavoidable necessity for daily functioning. The current study examined the association between receiving support in this unique context and PLWD's hair cortisol, dehydroepiandrosterone (DHEA), and DHEA-to-cortisol ratio, which serve as non-invasive, objective physiological measures that may reflect longer-term HPA-axis activity related to stress. Further, we explored whether caregivers' perspective taking-their ability to understand PLWD's thoughts and feelings-moderated associations between support receipt and hair hormones. Participants included 58 couples managing mild-to-moderate Alzheimer's disease (Mage = 77.60 for PLWD; Mage = 75.48 for caregivers). PLWD self-reported the frequency of emotional and practical support received from their spousal caregivers. Hair samples were collected from the posterior vertex to assess cortisol and DHEA concentrations and were assayed using enzyme immunoassay (EIA) method. Caregivers reported their own perspective taking and both spouses' demographic characteristics. Multiple regressions showed that receiving more frequent emotional support and less frequent practical support from spousal caregivers were associated with higher hair cortisol concentrations in PLWD. Yet, these associations were only evident if caregivers had greater perspective taking. In addition, caregiver perspective taking exacerbated the negative association between receiving emotional support and the DHEA-to-cortisol ratio. By using hair hormones, this study offers preliminary insights into PLWD's stress-related physiological processes in the context of intensive caregiving. Findings refine our understanding of the benefits and costs of caregivers' perspective taking and inform caregiver interventions.},
}

@article {pmid41547327,
year = {2026},
author = {Zothantluanga, JH and Chagaleti, BK and Roy, D and Abdalla, M and El-Arabey, AA and Alahmady, NF and Jha, NK},
title = {Dual inhibition of AChE and GSK-3β by flavonoids of Bergenia ciliata: Molecular dynamics insights into anti-Alzheimer's activity.},
journal = {Computational biology and chemistry},
volume = {122},
number = {},
pages = {108908},
doi = {10.1016/j.compbiolchem.2026.108908},
pmid = {41547327},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and is also responsible for more than half of all dementia cases. In our ongoing efforts to identify promising phytocompounds as potential modulators of AD-related molecular targets, we studied 53 phytocompounds from Bergenia ciliata, a medicinal plant known for its in vivo anti-Alzheimer activity. Acetylcholinesterase (AChE), GSK-3β, and β-site amyloid precursor protein cleaving enzyme (BACE1) were the target proteins. Molecular docking and 100 ns molecular dynamics (MD) simulations revealed that 3-O-galloylcatechin and 3-O-galloylepicatechin showed favorable interactions with AChE and GSK-3β, as they were able to outperform the positive controls in all of the studied parameters. However, the MM-GBSA binding free energy calculations revealed that only 3-O-galloylepicatechin, but not 3-O-galloylcatechin, outperformed the positive control of GSK-3β. Density functional theory (DFT) studies revealed that 3-O-galloylcatechin and 3-O-galloylepicatechin were stable and chemically reactive at the active sites of AChE and GSK-3β. The in-silico findings suggest that the observed in-vivo anti-Alzheimer activity of B. ciliata may be partly associated with the favorable molecular interactions of 3-O-galloylcatechin and 3-O-galloylepicatechin with AChE and GSK-3β. The current findings highlight the structural and mechanistic relevance of B. ciliata phytocompounds in modulating AD-associated targets. Based on the current findings, medicinal plants that contain 3-O-galloylcatechin and 3-O-galloylepicatechin may also be screened for their interactions with AD-related molecular targets.},
}

@article {pmid41547315,
year = {2026},
author = {Wang, J and Zhang, N and Tu, Z and Wu, Z and Yang, J and Chen, X and Lu, Y and Le, W and Luo, R},
title = {Chlorpyrifos induced dysregulation of arginine biosynthesis pathway aggravates Alzheimer's disease progression in 5XFAD mice via microbiota-gut-brain axis crosstalk.},
journal = {Environment international},
volume = {208},
number = {},
pages = {110064},
doi = {10.1016/j.envint.2026.110064},
pmid = {41547315},
issn = {1873-6750},
abstract = {Epidemiological evidence suggests that occupational or environmental exposure to Chlorpyrifos (CPF) is associated with Alzheimer's disease (AD)-like behaviors. However, the exact mechanisms remain elucidate. This study investigates the impact of environmentally relevant concentrations of CPF on AD progression in 5XFAD mice and explores potential intervention strategies. Our results demonstrate that CPF exposure exacerbates AD symptoms in 5XFAD mice, characterized by cognitive deficits, increased amyloid-β accumulation, neuroinflammation, and neuron loss. Mechanistically, CPF induces gut microbiota dysbiosis in 5XFAD mice, with significant decreases in beneficial taxa such as Muribaculaceae and Faecalibaculum, and a marked increase in pathogenic genus Tyzzerella. This dysbiosis leads to intestinal structural damage, compromised barrier function, and disruption of arginine biosynthesis pathway. Therefore, disruption of this pathway in gut microbiota metabolites results in a significant decrease in L-Citrulline (L-Cit) concentration, thereby causing a marked reduction in serum L-Arginine (L-Arg) levels. Importantly, these altered metabolites upregulate the transcription of hippocampal neuroinflammation-related pathway spectrum, particularly through significant upregulation of Casp1 and Ccl3, indicating the occurrence of neuroinflammation. L-Cit supplementation significantly increase serum L-Arg levels in CPF-exposed 5XFAD mice, thereby alleviating AD pathology and improving cognitive function. Collectively, these findings reveal a novel arginine metabolism-mediated mechanism along the microbiota-gut-brain axis in CPF-mediated AD pathogenesis and underscore the therapeutic potential of L-Cit for CPF-related neurodegenerative disorders.},
}

@article {pmid41547241,
year = {2025},
author = {Reichau, K and Crouzier, L and Gehrig, T and Flake, A and Schaller, E and Meunier, J and Bertrand-Gaday, C and Chatonnet, A and Zvejniece, L and Sotriffer, C and Maurice, T and Decker, M},
title = {Targeting neuroinflammation by activation of the sigma-1 receptor (S1R) and inhibition of butyrylcholinesterase (hBChE) leads to highly potent anti-amnesic compounds in an Alzheimer's disease mouse model.},
journal = {European journal of medicinal chemistry},
volume = {305},
number = {},
pages = {118486},
doi = {10.1016/j.ejmech.2025.118486},
pmid = {41547241},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective preventative or curative treatment has yet been identified. Due to the multifactorial nature and complex pathophysiology of the disease, we developed a multi-target ligand that both inhibits human butyrylcholinesterase (hBChE), a key enzyme linked to β-amyloid plaque formation, and activates the sigma-1 receptor (S1R), which modulates neuroinflammatory and protective pathways. To this end, a series of isoindolines were designed and synthesized, and their biological activities were evaluated. The most promising compound, 7c, exhibited significant dual activity, achieving nanomolar IC50 values against hBChE and potent S1R activation. Subsequent in vivo studies in an Aβ25-35 mouse model revealed a remarkable improvement in cognitive deficits in both short- and long-term memory at an effective dose of 0.01 mg/kg in WT Swiss-OF1 mice. This dose is 10-fold lower compared to single-target compounds 7a and 7b of this isoindoline series. The lack of neuroprotective effects in BChE knock-out (KO) mice confirmed the involvement of BChE inhibition in the pharmacological effects of compound 7c in WT mice. Further combinatorial studies employing a two-drug combination demonstrated synergy in the neuroprotective effect of addressing the two targets.},
}

@article {pmid41547191,
year = {2026},
author = {Ji, Q and Liu, Q and Xu, Y and Xu, M and Zhan, Y},
title = {Long-term exposure to residential greenspace, bluespace, traffic, and air pollutants with dementia: A prospective cohort study with exploratory mediation by plasma metabolites and telomere length.},
journal = {Ecotoxicology and environmental safety},
volume = {310},
number = {},
pages = {119750},
doi = {10.1016/j.ecoenv.2026.119750},
pmid = {41547191},
issn = {1090-2414},
abstract = {BACKGROUND: Residential environmental factors-including air pollution, traffic, greenspace, and bluespace-have been increasingly linked to dementia risk, yet the joint impacts and biological pathways remain underexplored. This study aimed to examine the associations between these diverse residential exposures and all-cause and cause-specific dementia, while exploring the mediating roles of plasma metabolites and telomere length.

METHODS: Using the UK Biobank (UKB) cohort, we analyzed 317,498 participants free of dementia at baseline. Exposures were assessed via geographic and model-based data, and outcomes included all-cause dementia (ACD), Alzheimer's disease (AD), vascular dementia (VaD), and other dementia subtypes (O). Cox proportional hazards models were applied to estimate the associations between exposures and dementia outcomes. Separate mediation analyses were conducted to examine the potential mediating roles of plasma metabolites and telomere length.

RESULTS: Pollutant exposures, especially NO₂ and PM10, were consistently associated with higher dementia risk, with age-specific patterns. Greenspace showed inverse associations, notably for ACD and VaD, while traffic proximity elevated VaD risk. Exploratory mediation suggested 49 metabolites for the PM2.5-10-ACD association in participants under 65, with the largest proportions for Omega-3 % (33.29 %) and S-VLDL-TG% (32.99 %).

CONCLUSION: Air pollution, especially particulate matter, was significantly associated with dementia risk, partially mediated by metabolic pathways. These findings underscore the importance of environmental interventions in dementia prevention.},
}

@article {pmid41547121,
year = {2026},
author = {Liu, H and Gui, Y and Zhao, B and Lu, H and Liu, M},
title = {A causal bidirectional selective state space model for imaging genetics in neurodegenerative diseases.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {198},
number = {},
pages = {108587},
doi = {10.1016/j.neunet.2026.108587},
pmid = {41547121},
issn = {1879-2782},
abstract = {Brain imaging genetics aims to uncover the pathological mechanisms and improve the diagnosis of brain diseases, particularly neurodegenerative disorders. While deep learning has advanced feature extraction and association modeling in this field, there are still two major challenges: extracting meaningful information from long genetic sequences and establishing causal relationships among genetics, imaging, and disease. To address these challenges, this paper proposes a deep causal bidirectional selective state space model (CausalMamba) that integrates multi-level feature extraction and causal inference into a unified representation learning framework. First, the long-sequence genetic data and whole-brain imaging data are divided into localized parts, extracting the fine-grained features. Then, a causal inference strategy based on counterfactual reasoning and contrastive learning is proposed to identify the most relevant genetic and imaging features and to construct a causal chain from genetics to disease via imaging. Finally, a bidirectional selective state space model (BiMamba) efficiently integrates the selected features into modality-specific global features, enabling accurate disease diagnosis. Our model is trained jointly on genetic and imaging data, but requires only genetic data at test time. We validate the proposed method on the simulated dataset, Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and Parkinson's Progression Markers Initiative (PPMI) dataset. Experimental results show that our method achieves accuracies of 80.5% and 77.3% using only genetic data in classifying Alzheimer's and Parkinson's diseases from normal controls, respectively, with the relative improvements of 4.2% and 2.7% over the state-of-the-art methods while also being more computationally efficient. The results demonstrate that CausalMamba can effectively identify causally relevant biomarkers across the entire genome and brain.},
}

@article {pmid41547056,
year = {2026},
author = {Finlay, J and Savard, G and Alvarez-McNelis, D and Sagehorn, M and Bowman, G and Sun, Y and Esposito, M},
title = {Cognability across adulthood: A qualitative investigation of neighborhoods and cognitive health behaviors.},
journal = {Social science & medicine (1982)},
volume = {392},
number = {},
pages = {118971},
doi = {10.1016/j.socscimed.2026.118971},
pmid = {41547056},
issn = {1873-5347},
abstract = {While geographic variation in Alzheimer's Disease and Related Dementias (ADRD) rates suggests that environmental factors are important in the development of dementia, understanding of specific neighborhood sites that impact dementia risk is limited, especially in early and mid adulthood. This paper extends Cognability to a life course perspective to conceptualize how neighborhoods may support cognitive health behaviors including physical activity, diet, cognitive stimulation, and socialization across adulthood. The Neighborhoods and Health at All Ages Study employed stationary and mobile interviews (August 2023-March 2024) across the Minneapolis-St. Paul (MN) metropolitan area. Participants were on average 42 years old (range: 23-75). About half (53 %) identified as female, 40 % male, and 7 % nonbinary. Participants reflected diverse racial and ethnic backgrounds, including Asian (22 %), Hispanic (22 %), non-Hispanic White (18 %), Multiracial (17 %), Black/African American (15 %), American Indian/Alaska Native (3 %), and Other/Missing (3 %). Reflexive thematic analysis identified ten neighborhood services and amenities that support cognitive health behaviors: parks and paths, recreation centers, eateries, grocers and food markets, retail stores, civic and social organizations, religious organizations, arts and cultural sites, libraries, and educational sites. The study captured nuanced, intersectional perspectives from adults with varied socioeconomic, racial/ethnic, and gender identities to illuminate how use and salience of neighborhood services and amenities vary across adulthood. As the global dementia burden grows and disparities widen, our results help inform upstream community-level interventions to create more equitable neighborhoods that reduce ADRD risk and support lifelong cognitive health and wellbeing.},
}

@article {pmid41546974,
year = {2026},
author = {Zhang, Y and Zhao, L and Yu, X and Liu, H and Zhao, M},
title = {Single-vesicle profiling of multiple biomarkers on serum EVs via EV-CATCH and nano-flow cytometry for clinical stratification of Alzheimer's disease.},
journal = {Biosensors & bioelectronics},
volume = {298},
number = {},
pages = {118399},
doi = {10.1016/j.bios.2026.118399},
pmid = {41546974},
issn = {1873-4235},
abstract = {Alzheimer's disease (AD) is a kind of progressive neurodegenerative disorder caused by neuron damage, which imposed significant economic and social burdens. Early and precise AD diagnosis remains an obstacle in the clinic, primarily attributable to the absence of simple, noninvasive, and reliable detection methods. Extracellular vesicles (EVs) carry molecular cargos reflecting cellular origin and can cross the blood-brain barrier, serving as promising biomarkers for neurological diseases. Herein, we propose a novel EV-CATCH-based nano-flow cytometry strategy for rapid, noninvasive, and single-vesicle profiling of multiple AD-related protein biomarkers on EVs. The EV-CATCH enables controlled capture and on-demand release of serum EVs, ensuring high specificity and structural integrity of the isolated vesicles. Four core AD biomarkers on serum EVs were profiled at the individual vesicle level for stratification, and their clinical utility was assessed in two cohorts. The first cohort included 29 Aβ-PET-negative and 42 Aβ-PET-positive participants. In this group, the biomarker panel demonstrated an AUC of 0.873 in differentiating Aβ-PET status, further supporting its value in reflecting cerebral amyloid pathology. The second cohort consisted of 110 serum samples, comprising those from healthy controls as well as from subjects with mild cognitive impairment (MCI) and AD. Combined analysis of the four EV-associated biomarkers yielded high diagnostic accuracy, with areas under the receiver operating characteristic curves (AUCs) of 0.932 for MCI and 0.923 for AD. This clinically accessible single-vesicle method enables multiplexed and sensitive EV profiling for early AD diagnosis, accurate disease stratification and longitudinal monitoring, facilitating timely intervention thus promoting better patient prognosis.},
}

@article {pmid41546910,
year = {2026},
author = {Elyasi, L and Wężyk, M},
title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {119001},
doi = {10.1016/j.biopha.2026.119001},
pmid = {41546910},
issn = {1950-6007},
abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.},
}

@article {pmid41546373,
year = {2026},
author = {Massoumzadeh, P and Tiemann-Powles, S and Naghashzadeh, M and Rizzo, J and Hu, J and Yaeger, LH and Alkelani, H and Wang, Q and Chen, G and Dolatshahi, M and Joseph-Mathurin, N and Benzinger, TLS},
title = {Sex Differences in Alzheimer's Disease: A Systematic Review of Two Decades of Neuroimaging Research.},
journal = {The British journal of radiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/bjr/tqag011},
pmid = {41546373},
issn = {1748-880X},
abstract = {OBJECTIVES: Given the heterogeneous nature of Alzheimer's Disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain.

METHODS: : This systematic review investigates sex differences in AD and summarizes key findings from neuroimaging studies over the past two decades to examine how genetics, hormones, and lifestyle factors influence neuroimaging biomarkers and their correlation with cognitive decline and AD progression. A comprehensive literature search was conducted across several databases for human studies from 2004 to 2024 related to AD, biological sex differences, and neuroimaging.

RESULTS: : After a three-step review process, the final extraction included 120 peer-reviewed studies using various neuroimaging modalities, such as Magnetic Resonance Imaging (MRI), amyloid-beta Positron Emission Tomography (PET), tau-PET, and Fluorodeoxyglucose (FDG) PET, to investigate sex as a biological predictor variable in adults with or at risk for AD. Over 90% of the reviewed studies identified clear sex-specific patterns of imaging biomarkers related to cognitive reserve, hormonal changes, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle factors. Machine learning studies increasingly incorporate sex as a key variable, revealing sex-specific biomarkers and improving model performance in predicting disease status and progression.

CONCLUSIONS: Considering biological sex in AD research is essential for improving diagnostic accuracy, tailoring interventions, and health outcomes.

ADVANCES IN KNOWLEDGE: This systematic review identifies sex-specific patterns in neuroimaging biomarkers of Alzheimer's Disease, influenced by cognitive reserve, hormones, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle. Recognizing these differences is crucial for understanding, diagnosis, and treatment efficacy.},
}

@article {pmid41546055,
year = {2026},
author = {Ramezani, N and Granberg, S and Kihlgren, A and Baudin, K and Lindner, H},
title = {The use of care home environments to meet culture-specific needs of culturally and linguistically diverse residents with dementia: an integrative review using the ICF framework.},
journal = {International journal for equity in health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12939-025-02748-0},
pmid = {41546055},
issn = {1475-9276},
abstract = {BACKGROUND: Increasing global migration creates new challenges for multicultural societies in providing equitable care. Culturally and linguistically diverse (CALD) people who move into care homes find themselves in an environment where health professionals do not speak their language and the access to cultural activities is limited. This may increase loneliness and social isolation. When designing care home environments for CALD residents with dementia, culture is a key consideration. The aim of this integrative review is to highlight what elements of the care home environment are reported to meet culture-specific needs of CALD residents with dementia, and how.

METHODS: A search strategy which included terms for care homes, forms of dementia and CALD people was developed, and a systematic search was carried out in six databases. Eligible articles were original peer-reviewed studies published between 2013 and 2024 and contained examples of how care home environments have been used to meet culture-specific needs of CALD residents. All screenings and extractions were carried out by two independent researchers.

RESULTS: The search resulted in 4311 records. After the screening process, 27 articles met the eligibility criteria. The review findings are categorized according to components of the WHO's International classification of functioning, disability and health (ICF). Results linked to the ICF component Activities and participation stress the importance of communication in the resident's preferred language, social and supportive relationships and culturally relevant activities, while the component Environmental factors highlights the significance of ethnic food and support from culturally competent care professionals and family members.

CONCLUSIONS: This integrative review underlines the complexity of using environments to meet culture-specific needs of CALD residents with dementia. The findings highlight the importance of bilingual staff, culturally relevant activities and inclusive environments in enhancing communication, building interpersonal relationships and reducing frustration among CALD residents. Collaborations between culturally competent staff, family members and members of cultural communities also facilitate meeting social and cultural needs of these residents. This review offers suggestions on how environments in care homes can be adapted for CALD residents and encourages further research to find practical solutions for equitable care.

REGISTRATION: A study protocol is registered on Prospero (CRD42023492906).},
}

@article {pmid41545942,
year = {2026},
author = {Sun, W and Luan, H and Li, S and Wang, P and Gong, J and Xu, C and Han, X and Wen, B and Lv, S and Wei, C},
title = {Circulating adipokines level and the risk of neurodegenerative diseases: a two‑sample mendelian randomization study and proteomic analysis.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04636-8},
pmid = {41545942},
issn = {1471-2377},
support = {2017YFC1310103//the National Key Research and Development Program of China/ ; 2021ZD0201802//the STI2030-Major Projects/ ; },
}

@article {pmid41545891,
year = {2026},
author = {Singh, SK and Antoine, C and Tse, C and Ji, L and Reed, M and Carter, WG and Trezza, V and Bid, HK},
title = {Therapeutic potential of acidic cannabinoids: an update.},
journal = {Journal of cannabis research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s42238-026-00387-y},
pmid = {41545891},
issn = {2522-5782},
support = {U54CA118638/CA/NCI NIH HHS/United States ; DICRIDG-21-072-01-DICRIDG//American Cancer Society/ ; },
abstract = {Cannabis sativa yields a wide range of bioactive compounds, including terpenes, flavonoids, and cannabinoids. Tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and cannabichromenic acid (CBCA) are the acidic biosynthetic precursors of the neutral cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which have been the subject of much research. This review examines the biosynthesis, decarboxylation, molecular pharmacology, and therapeutic significance of acidic cannabinoids, intending to address a significant knowledge gap. Peer-reviewed literature from major scientific databases was used in a systematic narrative review with an emphasis on investigations of acidic cannabinoid chemistry, pharmacology, pharmacokinetics, and disease-specific applications. According to the reviewed data, acidic cannabinoids exhibit unique biological activities that distinguish them from their neutral counterparts. These include neuroprotective, anti-inflammatory, anticonvulsant, and anti-proliferative actions, which are mediated by molecular targets such as serotonin 5-HT1A receptors, cyclooxygenase-2 (COX-2), transient receptor potential (TRP) channels, and peroxisome proliferator-activated receptor-γ (PPARγ). Acidic cannabinoids are more appealing for therapeutic usage in children and the elderly, considering that they are not intoxicating like THC; however, this distinction applies primarily to non‑heated consumption. Chemical instability, low bioavailability, and a dearth of controlled human trials impede clinical translation despite their potential. According to the findings, acidic cannabinoids are an underutilized yet potentially valuable class of precision medicines. In this study, we outline existing understanding on acidic cannabinoids, discuss their production and transformation, and identify research needs that could influence cannabis science research.},
}

@article {pmid41545748,
year = {2026},
author = {Wang, L and Liu, Y and Li, F and Li, X and Li, L and Zhang, J and Xu, Y},
title = {CX3CL1 in Early Detection of Alzheimer's Disease: Plasma Dynamics Across Age and Disease Stages.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70320},
pmid = {41545748},
issn = {2328-9503},
support = {CSTB2024NSCQ-MSX0945 to YX//the Natural Science Foundation of Chongqing/ ; },
abstract = {BACKGROUNDS: Alzheimer's disease (AD) is characterized by amyloid-beta plaques, tau tangles, and neuroinflammation. C-X3-C motif chemokine ligand 1 (CX3CL1, also known as fractalkine), a neuroimmune chemokine implicated in AD pathogenesis, shows inconsistent alterations in plasma/serum across studies. Specifically examining age-dependency and diagnostic utility, we investigated plasma CX3CL1 levels across the cognitive continuum (cognitively normal [CN], amnestic mild cognitive impairment [aMCI], AD) in a Chinese cohort.

METHODS: A total of 443 participants, including 130 patients with AD, 72 patients with aMCI, and 99 age-and sex-matched CN controls, as well as a cohort of 142 CN subjects of different ages, were enrolled from Chongqing General Hospital. Plasma CX3CL1 levels were determined using Enzyme-Linked Immunosorbent Assay (ELISA). Apolipoprotein E genotypes (APOE) were performed. The correlations between Plasma CX3CL1 levels and cognition test scores or age were analyzed. The optimal diagnostic sensitivity and specificity were determined using receiver operating characteristic curve analysis.

RESULTS: Plasma CX3CL1 levels significantly increased with age in CN individuals. No significant sex difference was found. Plasma CX3CL1 levels did not differ significantly between APOE ε4 carriers and non-carriers. Stepwise elevation across continuum: CX3CL1 levels showed a significant stepwise increase: CN controls (1.73 ± 0.51 ng/mL) < aMCI (2.40 ± 1.06 ng/mL) < AD (4.15 ± 1.24 ng/mL) (p < 0.001 between all groups). This pattern persisted in both male and female subgroups, between the AD group and the aMCI group, between the AD group and the CN control group (p < 0.001), between the aMCI group and the CN control group, and between the male and female subgroups (p < 0.05). CX3CL1 levels negatively correlated with Mini-Mental State Examination (MMSE) scores and positively correlated with age.

CONCLUSIONS: Plasma CX3CL1 levels exhibit a significant age-dependent increase in cognitively normal individuals, peak in midlife (40-49 years), and demonstrate a stepwise elevation across the AD continuum (CN → aMCI → AD). Strong inverse correlations with cognitive scores in disease groups and high diagnostic accuracy for AD, particularly against CN, support its role as a biomarker reflecting both physiological aging and AD-related pathological decline. Its regulation appears independent of APOE ε4 status. The midlife peak suggests potential relevance for preclinical processes, warranting further investigation of CX3CL1 as a biomarker and therapeutic target.},
}

@article {pmid41545552,
year = {2026},
author = {Shivahare, BD and Rajadurai, H and K, D and Kansal, S and Mathivanan, SK and S K B, S},
title = {An attention-augmented multimodal classification of alzheimer's disease and parkinson's disease vs healthy controls using MRI, EEG, and SNP data.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32274-6},
pmid = {41545552},
issn = {2045-2322},
abstract = {Due to the late manifestation of structural symptoms and symptomatic overlap, neurodegenerative diseases such as Parkinson's Disease (PD) and Alzheimer's Disease (AD) remain difficult to diagnose accurately. In order to categorize AD and PD in comparison to Healthy Controls (HC), this study suggests a multimodal classification framework that combines genetic Single Nucleotide Polymorphism (SNP) data, structural Magnetic Resonance Imaging (MRI), and functional Electroencephalography (EEG). To improve the model's accuracy and interpretability, the method makes use of an uncertainty estimate module and a novel cross-modality attention mechanism. The framework strives for diagnosis, concentrating on detecting Parkinson's disease (PD) and Alzheimer's disease (AD) in individuals exhibiting modest motor symptoms or early cognitive impairments, which are indicative of the prodromal stage of both conditions. A dataset of 2,500 MRI images, 1,500 EEG recordings, and SNP data for 1,000 subjects drawn from OpenNeuro, PPMI, and the UK Biobank was utilized in extensive analyses. The developed model was contrasted with recent unimodal and multimodal techniques. Our findings exhibit statistically significant increases of 6-12% compared to similar methods, with 95.6% average classification accuracy on AD and 94.8% on PD. The importance of the attention mechanism and both modalities to overall performance is quantified using ablation studies. Quantification of uncertainty also improves interpretability for possible clinical use. These results demonstrate the proper neurodegenerative disease diagnosis when explainable AI elements are paired with stable multimodal fusion.},
}

@article {pmid41545521,
year = {2026},
author = {},
title = {GLP-1s surprise failure in Alzheimer's.},
journal = {Nature biotechnology},
volume = {44},
number = {1},
pages = {7},
doi = {10.1038/s41587-025-02985-2},
pmid = {41545521},
issn = {1546-1696},
}

@article {pmid41545124,
year = {2026},
author = {Cucinotta, L and Pavarino, M and Cannizzaro, F and Sgorbini, B and Rubiolo, P and Sciarrone, D and Mondello, L},
title = {A novel "cut and sew" procedure for the natural reconstitution of essential oils prior to biological assays.},
journal = {Analytica chimica acta},
volume = {1386},
number = {},
pages = {345045},
doi = {10.1016/j.aca.2025.345045},
pmid = {41545124},
issn = {1873-4324},
mesh = {*Oils, Volatile/chemistry/isolation & purification/pharmacology ; Chromatography, Gas/methods ; Butyrylcholinesterase/metabolism ; Biological Assay ; *Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification ; Mentha piperita/chemistry ; },
abstract = {BACKGROUND: Given the increasing interest in natural compounds for therapeutic applications, understanding the contribution of individual components within complex essential oils (EOs) is crucial. The isolation is often achieved through bio-guided fractionation, typically using flash chromatography to target chemical classes. To refine this, some methods rely on customized reconstitution using reference standards, which is challenging due to issues with preserving natural abundances and enantiomeric ratios.

RESULTS: This study compares conventional flash chromatography with an advanced preparative multidimensional gas chromatography (prep-GC) system, equipped with a novel collection setup. This prep-GC approach enabled the isolation of sub-fractions at the milligram scale for biological assays. Critically, it preserved the natural distribution of chiral components, eliminating the need for standard-based reconstitution and its associated challenges. Mentha × piperita L. EO, known for its inhibitory activity against butyrylcholinesterase (BChE), an enzyme relevant to Alzheimer's disease, was chosen as a case study. The novel approach allowed for a comprehensive investigation by isolating the oxygenated fraction devoid of menthol. This facilitated a direct comparison of the biological activity of the whole EO against the total oxygenated fraction (from flash chromatography) and the menthol-devoid fraction (from prep-GC), as well as pure (-)-menthol, pure (-)-menthone, and their mixture.

SIGNIFICANCE: The results clearly indicate that (-)-menthol, (-)-menthone, and other terpenes within the oxygenated fraction jointly contribute to the overall BChE inhibitory activity. These findings highlight the complex interplay among Mentha × piperita L. EO constituents. Furthermore, this study underscores the potential of this new prep-GC technology for uncovering the biological roles of minor constituents in complex natural mixtures, by removing the contribution of the main representative components.},
}

*Oils, Volatile/chemistry/isolation & purification/pharmacology
Chromatography, Gas/methods
Butyrylcholinesterase/metabolism
Biological Assay
*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification
Mentha piperita/chemistry

@article {pmid41544694,
year = {2026},
author = {van Rooij, JRA and van den Berg, M and Van Vosselen, M and Calus, E and Vasilkovska, T and Kosten, L and Van Spilbeeck, I and Van Audekerke, J and Van Dam, D and Bertoglio, D and Adhikari, MH and Verhoye, M},
title = {Long-term dietary interventions fail to mitigate functional connectivity loss and cognitive decline in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115647},
doi = {10.1016/j.expneurol.2026.115647},
pmid = {41544694},
issn = {1090-2430},
abstract = {Short-term caloric restriction (CR) and resveratrol (Rsv) supplementation have shown potential in preserving brain function in aging and neurodegenerative diseases such as AD. However, there is a lack of knowledge regarding the potential benefits of long-term CR or Rsv on brain health in context of AD. Therefore, we aimed to assess the effects of short-term (1 month) CR and Rsv administration on resting-state functional connectivity (rs-FC), as well as the effect of long-term (8 months) CR or Rsv supplementation on rs-FC, spatial memory, amyloid burden, and neuroinflammation in male and female TgF344-AD (Tg) and wild-type (WT) rats. In Tg rats, short-term CR decreased rs-FC in female rats, while long-term CR decreased rs-FC and modestly improved spatial memory in male rats. Long-term CR and Rsv altered regional amyloid burden, and CR decreased IBA-1 in males without affecting GFAP. Overall, long-term CR and Rsv failed to mitigate FC loss and cognition, underscoring the potentially limited impact of these dietary interventions in AD.},
}

@article {pmid41544692,
year = {2026},
author = {Gu, Y and Zhang, B and Lei, C and Guan, Y and Fan, B and Xu, W and Jin, A and Deng, Q and Xue, R and Yang, X and Zhu, X},
title = {The metabolic reprogramming of lactate in the nervous system.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115643},
doi = {10.1016/j.expneurol.2026.115643},
pmid = {41544692},
issn = {1090-2430},
abstract = {Lactate, a critical energetic substrate and signaling molecule in the central nervous system (CNS), plays a pivotal role in maintaining neurophysiological homeostasis and driving the pathogenesis of neurodegenerative disorders through metabolic reprogramming. Herein, this review systematically summarizes recent progress in molecular mechanisms governing lactate metabolic reprogramming as well as its multiple biological functions in the central nervous system. Under physiological conditions, lactate regulates energy distribution via the astrocyte-neuron lactate shuttle, while mediates neural communication through receptors including G Protein-Coupled Receptor 81 and N-Methyl-d-Aspartate Receptor, thereby modulating synaptic plasticity and memory consolidation. In neurodegenerative pathologies (such as Alzheimer's and Parkinson's diseases), dysregulated lactate reprogramming is observed in the form of dynamic lactate imbalance, altered expression of monocarboxylate transporters and lactate dehydrogenase, and defective mitochondrial energy coupling. These perturbations further enhance neuronal damage by triggering neuroinflammation and perturbing epigenomic homeostasis (e.g., histone lactylation). Critical knowledge gaps remain unresolved: (1) The temporal dynamics of lactate flux during disease progression remain uncharacterized; (2) The spatial heterogeneity of lactate distribution across brain nuclei and its regulatory mechanisms are debated; (3) Consensus is lacking regarding functional alterations of core lactate metabolic components; and (4) The precise signaling cascades through which lactate modulates neurodegeneration require elucidation. By integrating contemporary research on central nervous system lactate reprogramming, this work provides novel perspectives on neurodegenerative disease mechanisms and establishes a theoretical framework for developing targeted therapeutic strategies that modulate lactate metabolism.},
}

@article {pmid41544613,
year = {2026},
author = {Renna, M and Bonavita, R and Dixon, G and Verdicchio, LV and Fleming, A},
title = {The interplay between autophagy and unconventional secretion in neurodegeneration.},
journal = {Cell chemical biology},
volume = {33},
number = {1},
pages = {10-32},
doi = {10.1016/j.chembiol.2025.12.007},
pmid = {41544613},
issn = {2451-9448},
mesh = {*Autophagy ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; },
abstract = {Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer's disease) and alpha-synuclein in Parkinson's disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.},
}

*Autophagy
Humans
*Neurodegenerative Diseases/metabolism/pathology
Animals
alpha-Synuclein/metabolism
tau Proteins/metabolism

@article {pmid41544446,
year = {2026},
author = {Hodgins, ML and Maxwell, SP and Howlett, SE and Rockwood, K},
title = {Blood biomarkers of frailty and cognition: A scoping review.},
journal = {Neurobiology of aging},
volume = {161},
number = {},
pages = {14-30},
doi = {10.1016/j.neurobiolaging.2026.01.003},
pmid = {41544446},
issn = {1558-1497},
abstract = {Frailty increasingly is recognized as a factor that modifies the relationship between disease biomarkers, including neuropathology, and dementia expression. The mechanisms underlying the relationship between frailty and dementia remain unclear, but blood biomarkers can offer insight into these mechanisms. We completed a scoping review of research examining the associations between blood biomarkers, frailty, and cognition. Three online databases were searched to identify original research examining blood biomarkers in the context of frailty and/or cognitive decline that accounted for the other condition in the analysis through stratification or inclusion in the model. Five of the 76 unique biomarkers identified -A disintegrin and Metalloproteinase 10 (ADAM10), fibrinogen, interleukin (IL)-6, neurofilament light chain (NfL) and vitamin D- were significantly and independently associated with both frailty and cognition. All five biomarkers could contribute to aging mechanisms, including disrupted proteostasis, chronic inflammation, dysregulated metabolism and/or deregulated nutrient sensing. These biomarkers could thus be common pathways of frailty and cognitive decline. Despite the Alzheimer-defining roles of β-amyloid and phosphorylated tau, these biomarkers typically are reported without considering the degree of frailty. Future biomarker research in cognitive decline and frailty should seek a clearer understanding of their relationship.},
}

@article {pmid41544372,
year = {2026},
author = {Rosenberg, A and Solomon, A and Bonnard, A and Daniilidou, M and Hagman, G and Hall, A and Matton, A and Öhlund-Wistbacka, U and Westman, E and Kivipelto, M},
title = {Preparing for the implementation of anti-amyloid therapies in Europe: Assessing real-world eligibility for lecanemab and donanemab in a Swedish memory clinic.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100476},
doi = {10.1016/j.tjpad.2025.100476},
pmid = {41544372},
issn = {2426-0266},
abstract = {Lecanemab and donanemab are the first anti-Aβ treatments to receive approval in Europe. Eligibility criteria are strict, eg., APOE ε4/4 carriers are excluded. Successful implementation in public healthcare hinges on accurate estimates of eligibility rates in settings which will be the first to roll out the treatments (specialized memory clinics with early disease stages). We applied the appropriate use recommendations (AUR) to assess treatment eligibility in a Swedish tertiary memory clinic where Aβ and APOE assessments are routinely performed. Of the full cohort (N = 410), 26 and 25 patients met the AUR criteria for lecanemab and donanemab, respectively (6 %; partial overlap between the groups). After excluding APOE ε4/4 carriers in line with the European guidelines, only 14 and 13 patients remained eligible (3 %). In clinics with younger populations, a significant percentage of potentially eligible patients are likely to have the APOE ε4/4 genotype. These findings are important to inform the implementation of anti-Aβ treatments.},
}

@article {pmid41544353,
year = {2026},
author = {Li, Z and Han, R and Fan, Y and Wang, Z and Wang, H and Jiang, D and He, X and Xiang, J and Yu, H and Huang, S},
title = {Interaction effects of extreme temperature events and air pollutants on neurodegenerative disease mortality: A case-crossover study in a cold-winter, hot-summer region of China.},
journal = {Ecotoxicology and environmental safety},
volume = {309},
number = {},
pages = {119732},
doi = {10.1016/j.ecoenv.2026.119732},
pmid = {41544353},
issn = {1090-2414},
abstract = {Extreme temperature events (ETEs) and air pollutants are both linked to neurodegenerative diseases, yet their interactions remain underexplored. This case-crossover study examined the effects of ETEs and six ambient air pollutants (PM10, PM2.5, O3, SO2, NO2, and CO) on mortality due to neurodegenerative diseases in a cold-winter, hot-summer region of China (2014-2021). Using a conditional logistic regression model combined with a distributed lag non-linear model, we found that heat wave and cold spell significantly increased overall neurodegenerative disease mortality, with peak effects at lag 0-14 days for heat wave (OR=1.77[95 %CI: 1.58, 1.98]) and lag 0-8 days for cold spell (OR=1.25[95 %CI: 1.10, 1.42]). All six air pollutants were significantly associated with mortality during the warm season, with PM2.5 and SO2 posing higher risks. Positive interactions were observed between heat wave and four air pollutants (PM10, PM2.5, SO2, CO), particularly with SO2 (interaction OR = 1.84[95 %CI: 1.68, 2.01]). The strongest interaction effects were found for Alzheimer's disease mortality across all subcategories. Vulnerable groups included females, individuals aged > 80 years, and those without a spouse. These findings highlight the compounded risks of ETEs and air pollution on neurodegenerative disease mortality, emphasizing the need for synergistic warning systems and targeted control measures. SYNOPSIS: This study provides evidence for the interaction between short-term exposure to extreme temperature events and air pollutants on neurodegenerative disease mortality.},
}

@article {pmid41544088,
year = {2026},
author = {Oludiran, A and Lewis, B and Pudwill, C and Chukkapalli, S and Ahmadi, H and Bannova, D and Linares, A and Burks, J and Hillman, JD and Dunn, WA and Progulske-Fox, A},
title = {Investigation of a viable but non-culturable state in Porphyromonas gingivalis and host cell invasion.},
journal = {PloS one},
volume = {21},
number = {1},
pages = {e0340605},
pmid = {41544088},
issn = {1932-6203},
mesh = {*Porphyromonas gingivalis/pathogenicity/physiology/drug effects/growth & development ; Humans ; *Microbial Viability/drug effects ; Hydrogen Peroxide/pharmacology ; Oxidative Stress/drug effects ; Endothelial Cells/microbiology ; Biofilms ; },
abstract = {Porphyromonas gingivalis (P. gingivalis) is a gram-negative, black-pigmented, anaerobic pathogen known for its biofilm formation and its central role in periodontal disease. More recently, P. gingivalis has been implicated in various systemic conditions, including atherosclerosis, Alzheimer's disease, and certain types of cancer, such as pancreatic and oral cancer. This bacterium employs several mechanisms to evade environmental stress, thereby contributing to its pathogenicity. The viable but non-culturable (VBNC) state is characterized by bacteria that remain viable but have reduced metabolic activity and are unable to form colonies on conventional culture media. To induce the VBNC state in P. gingivalis, we subjected the bacterium to oxidative stress using H2O2 and subsequently resuscitated it from this state with sodium pyruvate. We utilized viability staining, confocal microscopy, and flow cytometry (FC) to count live and dead bacteria, confirming the presence of significant numbers of viable P. gingivalis cells both before and after stress induction. Despite being viable, the stressed P. gingivalis failed to form colonies on blood agar plates after seven days of incubation, indicating it had entered the VBNC state. We were then able to resuscitate the VBNC P. gingivalis by adding sodium pyruvate, and the growth of the resuscitated bacteria on plates was comparable to that of control P. gingivalis. Investigation into the invasiveness of P. gingivalis in the VBNC state was conducted using human coronary artery endothelial cells (HCAECs). P. gingivalis in the VBNC state demonstrated the ability to invade and based on live/dead staining, showed that a substantial proportion of the VBNC P. gingivalis remained viable within the host cells for extended periods. In this study, we explore the VBNC survival strategy previously described in many aerobic bacteria but not previously reported in anaerobes such as P. gingivalis. The objectives of this study are to verify the VBNC state in P. gingivalis, determine whether this state can be reversed and assess the extent to which it impacts the ability of P. gingivalis to invade host cells. Understanding the VBNC and resuscitation states will be instrumental in guiding the development of more effective therapies for periodontitis and other diseases associated with P. gingivalis infection.},
}

*Porphyromonas gingivalis/pathogenicity/physiology/drug effects/growth & development
Humans
*Microbial Viability/drug effects
Hydrogen Peroxide/pharmacology
Oxidative Stress/drug effects
Endothelial Cells/microbiology
Biofilms

@article {pmid41544026,
year = {2026},
author = {Zahedipour, M and Saniee Abadeh, M and Shojaei, S},
title = {Alzheimer's disease prediction via an explainable CNN using genetic algorithm and SHAP values.},
journal = {PloS one},
volume = {21},
number = {1},
pages = {e0337800},
pmid = {41544026},
issn = {1932-6203},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Algorithms ; Magnetic Resonance Imaging/methods ; *Neural Networks, Computer ; Brain/diagnostic imaging ; Aged ; Male ; Female ; Genetic Algorithms ; },
abstract = {Convolutional neural networks (CNNs) are widely recognized for their high precision in image classification. Nevertheless, the lack of transparency in these black-box models raises concerns in sensitive domains such as healthcare, where understanding the knowledge acquired to derive outcomes can be challenging. To address this concern, several strategies within the field of explainable AI (XAI) have been developed to enhance model interpretability. This study introduces a novel XAI technique, GASHAP, which integrates a genetic algorithm (GA) with SHapley Additive exPlanations (SHAP) to improve the explainability of our 3D convolutional neural network (3D-CNN) model. The model is designed to classify magnetic resonance imaging (MRI) brain scans of individuals with Alzheimer's disease and cognitively normal controls. Deep SHAP, a widely used XAI technique, facilitates the understanding of the influence exerted by various voxels on the final classification outcome (Lundberg SM, Lee SI. A unified approach to interpreting model predictions. In: Advances in Neural Information Processing Systems, 2017. 4765-74. https://doi.org/10.5555/3295222.3295230). However, voxel-level representation alone lacks interpretive clarity. Therefore, the objective of this study is to provide findings at the level of anatomically defined brain regions. Critical regions are identified by leveraging their SHAP values, followed by the application of a genetic algorithm to generate a definitive mask highlighting the most significant regions for Alzheimer's disease diagnosis (Shahamat H, Saniee Abadeh M. Brain MRI analysis using a deep learning based evolutionary approach. Neural Netw. 2020;126:218-34. https://doi.org/10.1016/j.neunet.2020.03.017 PMID: 32259762). The research commenced by implementing a 3D-CNN for MRI image classification. Subsequently, the GASHAP technique was applied to enhance model transparency. The final result is a brain mask that delineates the pertinent regions crucial for Alzheimer's disease diagnosis. Finally, a comparative analysis is conducted between our findings and those of previous studies.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Algorithms
Magnetic Resonance Imaging/methods
*Neural Networks, Computer
Brain/diagnostic imaging
Aged
Male
Female
Genetic Algorithms

@article {pmid41543852,
year = {2026},
author = {Yu, L and Wang, T and Du, L and Bennett, DA and Schneider, JA and Boyle, PA},
title = {Neuropathologic Profiles and Associated Cognitive Trajectories in Community-Living Older Adults.},
journal = {JAMA network open},
volume = {9},
number = {1},
pages = {e2554354},
pmid = {41543852},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; Aged ; Aged, 80 and over ; *Independent Living ; Alzheimer Disease/pathology ; *Brain/pathology ; *Aging/pathology ; *Cognition/physiology ; Cohort Studies ; *Cognitive Dysfunction/pathology ; },
abstract = {IMPORTANCE: Mixed neuropathologies are common, and yet the full extent to which these pathologies coexist is not entirely clear.

OBJECTIVES: This study aims to identify distinct neuropathologic profiles in community-dwelling older adults and to examine associated cognitive trajectories over time.

This study included participants in 2 community-based cohort studies of aging and dementia. Participants were older adults without known dementia at enrollment who agreed to annual evaluations and brain donation. The Religious Orders Study started in 1994, and the Rush Memory and Aging Project started in 1997. Both studies are ongoing. Data were analyzed in May 2025.

EXPOSURES: Annual uniform detailed evaluations for up to 30 years and brain autopsy and neuropathologic evaluation after death.

MAIN OUTCOMES AND MEASURES: Neuropathologic evaluations assessed Alzheimer disease neuropathologic change (ADNC), Lewy bodies, limbic-predominant age-related transactive response DNA-binding protein 43 kDa encephalopathy neuropathologic change (LATE-NC), hippocampal sclerosis, infarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis. Annual cognitive scores were derived from a battery of 19 tests that assessed multiple cognitive domains. Latent neuropathologic profiles were identified using hierarchical clustering, and longitudinal cognitive trajectories associated with each profile were estimated using functional mixed-effects models.

RESULTS: A total of 1633 older adults were included in the study. The mean (SD) age at death was 90.4 (6.4) years, 1156 (70.8%) were female, and the mean (SD) years of education was 16.2 (3.6) years. A total of 46 participants (2.8%) self-reported as Black, 42 (2.6%) as Hispanic, and 1579 (96.6%) as White. More than 80% of individuals had mixed neuropathologies at autopsy, and 280 unique combinations of copathologies were identified. Hierarchical clustering revealed 5 distinct neuropathologic profiles: profile 1 (259 participants [15.9%]) was characterized by a high burden of infarcts and vessel diseases, profile 2 (201 participants [12.3%]) by high LATE-NC and hippocampal sclerosis, profile 3 (355 participants [21.7%]) by high Lewy bodies, profile 4 (159 participants [9.7%]) by high ADNC and amyloid angiopathy, and profile 5 (659 participants [40.4%]) by low pathology overall. Cognitive trajectories differed across profiles in terms of both the rate of decline and the timing of the onset of decline with fastest decline observed for profile 2 and 4.

CONCLUSIONS AND RELEVANCE: In this cohort study, mixed neuropathologies were extremely common and complex. Compared with vascular conditions, degenerative pathologies clustered into distinct profiles. Profiles characterized by high burdens of ADNC and separately, LATE-NC and hippocampal sclerosis, had the most potent associations with cognitive decline.},
}

Humans
Female
Male
Aged
Aged, 80 and over
*Independent Living
Alzheimer Disease/pathology
*Brain/pathology
*Aging/pathology
*Cognition/physiology
Cohort Studies
*Cognitive Dysfunction/pathology

@article {pmid41543797,
year = {2026},
author = {Konat, GW},
title = {Dysfunctional respiration as a risk factor for Alzheimer disease: a hypothesis.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {21},
pmid = {41543797},
issn = {1573-7365},
}

@article {pmid41543776,
year = {2026},
author = {Li, X and Zhang, L and Xia, J and Zheng, M and Zhou, Z and Cai, J},
title = {Multi-omics Mendelian randomization and machine learning identify candidate therapeutic targets for Alzheimer's and Parkinson's diseases.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {37},
number = {1},
pages = {24},
pmid = {41543776},
issn = {1432-1777},
support = {82474605//National Natural Science Foundation of China/ ; XJG20230163//Natural Science Foundation of Fujian/ ; },
mesh = {*Machine Learning ; *Parkinson Disease/genetics/drug therapy ; Animals ; *Alzheimer Disease/genetics/drug therapy ; *Mendelian Randomization Analysis ; Humans ; Mice ; Genome-Wide Association Study ; Quantitative Trait Loci ; Disease Models, Animal ; Molecular Docking Simulation ; Transcriptome ; Multiomics ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are major public health challenges lacking effective therapies. To identify potential drug targets, we integrated large-scale genome-wide association studies with expression, methylation, protein, and splicing QTL datasets using Mendelian Randomization (MR) and summary-data-based MR (SMR). Colocalization analysis and machine learning were applied to prioritize candidate genes, followed by in silico druggability evaluation through molecular docking and molecular dynamics (MD) simulations. In animal models, candidate genes identified by transcriptomic analysis were further validated using integrative molecular and functional experiments. We identified several genes with potential causal links to AD (e.g., IQCE, HDHD2, ALPP) and PD (e.g., IL15, STK3, CHRNB1). Transcriptomic analyses indicated a consistent downregulation of IL-15 in PD model mice, corroborated by subsequent Western blot and immunohistochemical validation. Among predicted compounds, Prednisolone (ALPP), Sirolimus (IL15), and CHEMBL379975 (STK3) showed favorable binding affinities and stable MD trajectories, suggesting promising therapeutic relevance. Collectively, these findings highlight 12 QTL-regulated genes as promising molecular targets for further investigation in the context of NDDs. While the computational results provide a useful basis for hypothesis generation, experimental validation will be essential to determine the biological relevance and therapeutic potential of these candidate genes and compounds.},
}

*Machine Learning
*Parkinson Disease/genetics/drug therapy
Animals
*Alzheimer Disease/genetics/drug therapy
*Mendelian Randomization Analysis
Humans
Mice
Genome-Wide Association Study
Quantitative Trait Loci
Disease Models, Animal
Molecular Docking Simulation
Transcriptome
Multiomics

@article {pmid41543642,
year = {2026},
author = {Blandi, L and Del Riccio, M},
title = {From breath to brain: influenza vaccination as a pragmatic strategy for dementia prevention.},
journal = {Aging clinical and experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40520-026-03323-5},
pmid = {41543642},
issn = {1720-8319},
abstract = {Aging populations require scalable strategies to delay or prevent dementia. Beyond the prevention of neurological injury associated with seasonal influenza, vaccination may help mitigate vascular and neuroinflammatory injury underlying cognitive impairment. Influenza infection can cause a marked short‑term increase in myocardial infarction risk, and acute infections have also been associated with transient increases in stroke risk. Experimental models show prolonged microglial activation and synaptic loss even from non-neurotropic strains - processes likely modulated by vaccination. Epidemiologic data consistently support this evidence; a 2023 meta-analysis, including observational studies, of ~ 2.09 million adults identified a 31% lower risk of incident dementia; US matched cohorts demonstrated 40% lower risk of Alzheimer's disease (absolute decrease 3.4%); Veterans Health data showed a 0.86 hazard ratio for dementia; and UK Biobank data showed lower risk for all-cause (0.83 h), and vascular dementia (0.58 h) with a dose-response association by vaccination term. Randomized trials suggest fewer adverse cardiovascular events in vaccine recipients giving even more biological plausibility to this concept. Despite that, prevention through influenza vaccination is not fully realized in older adults due to low levels of perceived risk, vaccine confidence, and variations in clinical practice guidance. This public health perspective reviews the physiopathological and epidemiological evidence in support of influenza vaccination as a pragmatic, dementia risk-modifying intervention within healthy aging strategies and encourages the inclusion of vaccination status in hospital discharge and chronic-care pathways, integration of cognitive outcomes in monitoring, and equity-centered research to eliminate barriers to behavioral and implementation.},
}