@article {pmid41428471,
year = {2025},
author = {Tian, Y and Liu, X and Baiheti, B and Pang, H and Li, Z and Zhang, H and Yuchi, Y and Liao, W and Tang, X and Zhao, J and Ahmad, F and Li, L and Zhao, X and Wang, C},
title = {Prevalence and healthy life expectancy among elderly with mild cognitive impairment in Chinese rural areas.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251405904},
doi = {10.1177/13872877251405904},
pmid = {41428471},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI), as an early manifestation of Alzheimer's disease and dementia, not only diminishes quality of life for the elderly but also imposes a substantial disease burden on society.ObjectiveThis study aims to investigate the epidemiological characteristics and influencing factors of MCI among rural elderly, and to utilize life expectancy (LE) and healthy life expectancy (HLE) as metrics to assess quality of life.MethodsThis study involved 14,549 participants aged 60 years and older from the Henan Rural Cohort Study. Cognitive function was assessed using the Mini-Mental State Examination. LE and HLE were calculated using the Sullivan method. A meta-analysis, which included 16 published studies, was conducted to validate the findings from the cross-sectional survey.ResultsThe crude and age-standardized prevalence of MCI were 32.96% and 34.14%, respectively. The prevalence of MCI was increased with age and was significantly higher among women than men. The results of the meta-analysis support the cross-sectional findings. Older age, being women, living alone, low income, low-level physical activity, insufficient fruit and vegetable intake, night sleep duration ≥8 h, hypertension, dyslipidemia, T2DM, cardiovascular diseases, depression, anxiety, and underweight are associated with an increased risk of MCI. The HLE/LE ratio declined with increasing age, and the HLE/LE ratio of women in each age group is lower than men.ConclusionsMCI is highly prevalent with multiple influencing factors. The HLE/LE ratio of elderly could increase from the reduction of MCI. Future research should focus on targeted screening and intervention approaches for MCI.},
}

@article {pmid41428469,
year = {2025},
author = {Vazquez, JP and Allali, G and Beauchet, O and Callisaya, M and Doi, T and Kumar, VP and Milman, S and Shimada, H and Srikanth, V and Verghese, J and Blumen, HM},
title = {Cerebral small vessel disease unveils a vascular pathway to motoric cognitive risk in aging.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251405448},
doi = {10.1177/13872877251405448},
pmid = {41428469},
issn = {1875-8908},
abstract = {BackgroundMotoric cognitive risk (MCR) syndrome is characterized by subjective cognitive complaints and slow gait and confers a higher risk of dementia. Cerebral small vessel disease (CSVD) is associated with poor cognitive, functional, and survival outcomes in aging. Markers of CSVD seen on magnetic resonance imaging (MRI) include white matter hyperintensities (WMHs) and lacunes.ObjectiveTo examine associations between imaging markers of CSVD and the MCR syndrome.MethodsCross-sectional data from 4 cohorts in 4 countries were examined. WMHs and lacunes were quantified from brain MRIs manually, using a standardized grading scale. Regression models examined the associations between WMH and lacunes and MCR, gait speed, slow gait, and cognitive complaints. We also compared the prevalence of the outcomes of interest between participants with "confluent or diffuse" or "no or mild" WMH. Statistical models were adjusted for age, sex, study site, and vascular risk factors.ResultsData from 1772 participants (M Age = 71.1 years, 49.9% female) was analyzed. Higher global WMH scores were associated with MCR (aOR = 1.07, p = 0.015). Frontal and basal ganglia WMH scores were associated with MCR (aOR = 1.23, p = 0.007, aOR = 1.31, p = 0.023, respectively). Participants with "confluent-diffuse" WMH had significantly higher prevalence of MCR (30.2% versus 19.2%, p = 0.003). Basal ganglia lacunes were associated with MCR (aOR = 1.57, p = 0.018).ConclusionsIn this multi-cohort study of older adults without cognitive impairment, we show that WMH and lacunes independently predict increased risk of MCR, after adjusting for key confounders. Our findings, based on a large multi-ethnic cohort, reveal region-specific CSVD patterns linked to MCR and related outcomes.},
}

@article {pmid41428468,
year = {2025},
author = {Li, Z and Hong, X and Zhang, X and Li, Z and Liu, Y},
title = {Association between dietary nutrient density patterns and cognitive function: A latent class analysis of NHANES 2011-2014.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251407108},
doi = {10.1177/13872877251407108},
pmid = {41428468},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and cognitive decline are major global health challenges. The impact of dietary nutrient density, particularly in the context of ultra-processed, fortified foods, on cognitive function remains uncertain.ObjectiveTo examine associations between dietary nutrient density patterns and cognitive performance in U.S. older adults and to evaluate effect modification by key subgroups.MethodsWe analyzed data from 2991 adults aged ≥60 years in NHANES 2011-2014. Nutrient density patterns were derived by latent class analysis of 24-h dietary recalls. Cognitive function was assessed with the CERAD Word Learning, Animal Fluency, and Digit Symbol Substitution Tests. Multivariable linear regression estimated associations between nutrient density patterns and cognitive scores, adjusting for sociodemographic, lifestyle, and clinical factors; stratified analyses assessed effect modification.ResultsFour distinct nutrient density patterns were identified. A High-Nutrient, Ultra-Processed pattern, characterized by high intake of processed foods and relatively lower plant-based nutrients, was associated with poorer cognitive performance, particularly on memory tasks (β = -0.43, p = 0.018), and these associations persisted after full adjustment. Associations were stronger among participants with hypertension or diabetes.ConclusionsDietary nutrient density patterns are independently associated with cognitive function in older adults, with ultra-processed, fortified dietary profiles linked to worse performance, especially in those with cardiometabolic conditions. Targeted dietary strategies that emphasize nutrient-dense, minimally processed foods may help preserve cognitive health in vulnerable subgroups.},
}

@article {pmid41428467,
year = {2025},
author = {Chen, J and Dillon-Rossiter, K and Grigsby-Duffy, L and Morava, A and Novic, A and Salmani, B and Smith, S and Prapavessis, H and Gardiner, PA},
title = {Individual sedentary activities and cognitive function in middle-aged and older adults: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394751},
doi = {10.1177/13872877251394751},
pmid = {41428467},
issn = {1875-8908},
abstract = {BackgroundThe influence of lifestyle factors on cognitive health, particularly among middle-aged and older adults, has garnered significant attention in gerontology and cognitive neuroscience. Currently, over 55 million people worldwide are living with dementia, including Alzheimer's disease with nearly 10 million new cases annually. Although sedentary behavior has been associated with cognitive decline, these studies often treat sitting time as a homogeneous entity, without considering the specific nature of sedentary activities.ObjectiveThis systematic review aims to examine associations of individual sitting activities with cognitive function in middle-aged and older adults.MethodsData were searched using eight electronic databases (EMBASE, Web of Science, PsycINFO, CINAHL, Medline, SPORTDiscus, PubMed, and Scopus) from inception to September 2024. Qualitative studies, reviews, conference abstracts, theses, and book chapters were excluded. The methodological quality of included studies was assessed using the QualSyst tool.ResultsA total of 85 studies (n = 1,575,657) were included in this review. Of the 43 studies examining television viewing, 28 (65%) reported a negative association between prolonged television viewing and cognitive function. Conversely, among the 58 studies that included active sedentary activities, only five (8.6%) reported negative associations.ConclusionsThe cognitive effects of sedentary behavior depend on the type of activity performed. Promoting cognitively engaging sedentary activities may support healthy cognitive aging, while excessive passive behaviors may increase risk of cognitive decline and Alzheimer's disease. Future research should focus on further clarifying the mechanisms behind these associations and explore interventions to enhance cognitive health in aging populations.},
}

@article {pmid41428464,
year = {2025},
author = {Ablona, KAG and Cenina, ARF},
title = {Diagnostic accuracy of Alzheimer's Questionnaire in identifying dementia among Filipinos in a tertiary hospital.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251405290},
doi = {10.1177/13872877251405290},
pmid = {41428464},
issn = {1875-8908},
abstract = {BackgroundDementia, most often due to Alzheimer's disease, is a growing concern in the Philippines. The Alzheimer's Questionnaire (AQ), an informant-based screening tool, may be particularly useful in this setting, where strong familial and caregiving ties exist. Establishing its diagnostic accuracy in Filipinos is crucial for early detection and improved care.ObjectiveTo determine the diagnostic accuracy of the AQ among Filipinos by comparing it with physician diagnoses and established cognitive assessment tools.MethodsThis retrospective cohort study included 190 Filipino patients who underwent cognitive assessments, including the AQ, Mini-Mental State Examination (MMSE-F), and Montreal Cognitive Assessment (MoCA-P), between 2022 and 2024. Diagnostic accuracy was measured using sensitivity, specificity, predictive values, and area under the curve (AUC). Cohen's Kappa assessed agreement between AQ classifications and physician diagnoses.ResultsClinico-demographic analysis suggested that age and work status may influence dementia risk, while gender and common comorbidities showed no significant associations. The AQ demonstrated high specificity (92.47%) and strong diagnostic accuracy (AUC = 0.923) in distinguishing dementia from non-dementia, performing comparably to MoCA and MMSE. However, it was less effective in detecting mild cognitive impairment (MCI).ConclusionsThe AQ is a reliable and accurate tool for dementia screening in Filipinos, though limited for MCI detection. Incorporating AQ into routine cognitive screening may enhance early dementia identification. Further studies should refine cultural adaptations and validate its role in the Philippine healthcare context.},
}

@article {pmid41428410,
year = {2025},
author = {Gravelsins, L and Gervais, NJ and Brown, A and Ramana, S and Zhao, S and Nicoll, G and Bernardini, MQ and Jacobson, M and Einstein, G},
title = {Younger midlife females with bilateral salpingo-oophorectomy: respiratory disturbances during sleep.},
journal = {Climacteric : the journal of the International Menopause Society},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13697137.2025.2595987},
pmid = {41428410},
issn = {1473-0804},
abstract = {OBJECTIVE: There are many menopauses; bilateral oophorectomy is associated with the worst cognitive outcomes. Compared to females with intact ovaries, females with bilateral oophorectomy experience early, abrupt ovarian hormone loss and are at increased risk for later-life Alzheimer's disease. They also have double the odds of developing later-life sleep disordered breathing (SDB) - a modifiable Alzheimer's risk factor. With respect to bilateral oophorectomy, it is unknown when respiratory disturbances occur or whether estradiol therapy (ET) ameliorates them. Also unknown is whether SDB influences cognition in this group.

METHOD: Females with risk-reducing bilateral salpingo-oophorectomy (BSO) taking ET (BSO+ET, n = 19) or not (BSO, n = 16) and premenopausal age-matched controls (AMC, n = 17) were assessed for SDB markers using take-home polysomnography and for working memory performance.

RESULTS: The BSO group showed signs of respiratory disturbance compared to the AMC group. Memory performance was uncorrelated with respiratory metrics. While the BSO+ET group showed an intermediate sleep phenotype, estrone glucuronide levels correlated with improved respiratory metrics.

CONCLUSION: The results suggest that respiratory disturbances manifest as early as 5 years post-BSO in younger females; ET offers some amelioration. The close relationship between sleep disruption and Alzheimer's risk emphasizes the importance of SDB screening post-BSO for early intervention.},
}

@article {pmid41428317,
year = {2025},
author = {Tinauer, C and Sackl, M and Stollberger, R and Schmidt, R and Ropele, S and Langkammer, C},
title = {Skull-stripping induces shortcut learning in MRI-based Alzheimer's disease classification.},
journal = {Insights into imaging},
volume = {16},
number = {1},
pages = {283},
pmid = {41428317},
issn = {1869-4101},
support = {P30134//Austrian Science Fund/ ; P35887//Austrian Science Fund/ ; },
abstract = {OBJECTIVES: High classification accuracy of Alzheimer's disease (AD) from structural MRI has been achieved using deep neural networks, yet the specific image features contributing to these decisions remain unclear. In this study, the contributions of T1-weighted (T1w) gray-white matter texture, volumetric information, and preprocessing-particularly skull-stripping-were systematically assessed.

MATERIALS AND METHODS: A dataset of 990 matched T1w MRIs from AD patients and cognitively normal controls from the ADNI database was used. Preprocessing was varied through skull-stripping and intensity binarization to isolate texture and shape contributions. A 3D convolutional neural network was trained on each configuration, and classification performance was compared using exact McNemar tests with discrete Bonferroni-Holm correction. Feature relevance was analyzed using Layer-wise Relevance Propagation, image similarity metrics, and spectral clustering of relevance maps.

RESULTS: Despite substantial differences in image content, classification accuracy, sensitivity, and specificity remained stable across preprocessing conditions. Models trained on binarized images preserved performance, indicating minimal reliance on gray-white matter texture. Instead, volumetric features-particularly brain contours introduced through skull-stripping-were consistently used by the models.

CONCLUSION: This behavior reflects a shortcut learning phenomenon, where preprocessing artifacts act as potentially unintended cues. The resulting Clever Hans effect emphasizes the critical importance of interpretability tools to reveal hidden biases and to ensure robust and trustworthy deep learning in medical imaging.

CRITICAL RELEVANCE STATEMENT: We investigated the mechanisms underlying deep learning-based disease classification using a widely utilized Alzheimer's disease dataset, and our findings reveal a reliance on features induced through skull-stripping, highlighting the need for careful preprocessing to ensure clinically relevant and interpretable models.

KEY POINTS: Shortcut learning is induced by skull-stripping applied to T1-weighted MRIs. Explainable deep learning and spectral clustering estimate the bias. Highlights the importance of understanding the dataset, image preprocessing and deep learning model, for interpretation and validation.},
}

@article {pmid41428270,
year = {2025},
author = {Verma, S and Kumari, K and Kesharwani, P and Verma, K and Dwivedi, J and Paliwal, S and Sharma, S},
title = {Is the Era of One-Size-Fits-All Alzheimer's Treatment Officially Over?.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {1},
pages = {3},
pmid = {41428270},
issn = {1559-1166},
mesh = {*Alzheimer Disease/drug therapy/therapy/metabolism ; Humans ; Animals ; Precision Medicine ; Biomarkers ; },
abstract = {Alzheimer's disease (AD) is prevalent in more than 55 million worldwide, a figure estimated to almost triple by 2050, highlighting the need for highly effective treatments. However, despite the large expenditure of research over several decades, over 90% of clinical trials-countless amyloid-β-targeted drugs among them-have failed, stressing the shortcomings of reductionist, one-target approaches. More and more, AD is viewed as a complex systems disorder, resulting from interlinked disruptions in proteostasis, neuroinflammation, vascular integrity, synaptic plasticity, and metabolic regulation. Such an understanding has transformed the therapeutic paradigm toward precision, multimodal treatment, integrating disease-modifying agents with biomarker-based diagnosis and patient stratification. Improved blood- and imaging-based biomarkers, new molecular targets, and drug-delivery technologies offer the hope for earlier intervention and more personalized treatment. Looking to the future, the way forward will rely on the integration of systems biology, computational modeling, and translational neuroscience into adaptive trial design able to tackle the heterogeneity of the disease. These developments combined constitute the progressive shift away from "one-size-fits-all" treatments towards a future of personalized, mechanism-based therapies in Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/therapy/metabolism
Humans
Animals
Precision Medicine
Biomarkers

@article {pmid41428168,
year = {2025},
author = {Babu, PR and Turner, C and Ryznar, R},
title = {Cross-seeding of IAPP and Aβ42: A review of the molecular link between type 2 diabetes and Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {8},
pmid = {41428168},
issn = {1573-7365},
}

@article {pmid41428114,
year = {2025},
author = {Zhang, H and Li, C and Song, Y and Wu, Y and Xu, B and Cao, F},
title = {Genetic Evidence Linking Lactylation-Related Gene Expression To Dementia Risk.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {1},
pmid = {41428114},
issn = {1559-1174},
support = {LQ23H090019//the Natural Science Foundation of Zhejiang Province/ ; LMS25H290004//the Natural Science Foundation of Zhejiang Province/ ; 2024KY675//the Medical Health Science and Technology Project of Zhejiang Province/ ; 2021KY472//the Medical Health Science and Technology Project of Zhejiang Province/ ; 2024ZL291//the Traditional Chinese Medicine Science and Technology Initiative of Zhejiang Province/ ; 2025ZL335//the Traditional Chinese Medicine Science and Technology Initiative of Zhejiang Province/ ; 2026ZL0407//the Traditional Chinese Medicine Science and Technology Initiative of Zhejiang Province/ ; 2023ZYC-Z01//the Key Project of Clinical Medical Research Special Fund of Zhejiang Medical Association/ ; 82205012//National Natural Science Foundation of China (NSFC) - Young Scientists Fund/ ; },
mesh = {Humans ; Mendelian Randomization Analysis ; *Dementia/genetics/metabolism/classification ; Alzheimer Disease/genetics ; Genome-Wide Association Study ; Frontotemporal Dementia/genetics ; Quantitative Trait Loci ; Lewy Body Disease/genetics ; Sirtuin 1/genetics ; Polymorphism, Single Nucleotide ; Parkinson Disease/genetics ; Dementia, Vascular/genetics ; Genetic Predisposition to Disease ; Gene Expression ; Epigenesis, Genetic ; *Protein Processing, Post-Translational ; Gene Expression Regulation ; },
abstract = {Lactylation has been identified as a novel epigenetic modification involved in neuroinflammation, mitochondrial dysfunction, and tau pathology. Although its relevance has been suggested in Alzheimer's disease (AD), its causal contribution to distinct dementia subtypes remains unclear. We conducted a two-sample Mendelian randomization (MR) study to investigate whether the genetically predicted expression of 15 lactylation-related genes is causally associated with the risk of five dementia subtypes: Alzheimer's disease (AD), Parkinson's disease with dementia (PDD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and vascular dementia (VaD). Gene expression instruments were selected from whole-blood eQTL data (n = 31,684), and outcome data were derived from large-scale GWASs. The inverse-variance weighted (IVW) method served as the primary analytical approach, with Bonferroni correction (α = 0.05/15) applied for multiple testing. After correction, six gene-dementia associations remained statistically significant. Increased expression of EP300 and PFKP was associated with higher AD risk, while SIRT1 and LDHC showed protective effects against PDD. NUP50 was associated with increased FTD risk, and STMN1 with reduced risk of DLB. No significant associations were detected for VaD. All findings were robust in sensitivity analyses and supported by brain expression evidence from GTEx. Genetic evidence was provided for a causal relationship between lactylation-related gene expression and dementia subtype risk, offering potential mechanistic insights and therapeutic targets.},
}

Humans
Mendelian Randomization Analysis
*Dementia/genetics/metabolism/classification
Alzheimer Disease/genetics
Genome-Wide Association Study
Frontotemporal Dementia/genetics
Quantitative Trait Loci
Lewy Body Disease/genetics
Sirtuin 1/genetics
Polymorphism, Single Nucleotide
Parkinson Disease/genetics
Dementia, Vascular/genetics
Genetic Predisposition to Disease
Gene Expression
Epigenesis, Genetic
*Protein Processing, Post-Translational
Gene Expression Regulation

@article {pmid41428086,
year = {2025},
author = {Buchman, AS and Yu, L and Oveisgharan, S and Tickotsky, N and de Paiva Lopes, K and Zammit, AR and VanderHorst, V and Klein, HU and Nag, S and Bennett, DA},
title = {Associations of pathologic Parkinson's disease (PD) and co-pathologies with cognitive decline and progression of parkinsonian signs in decedents with subclinical disease.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {1},
pmid = {41428086},
issn = {1432-0533},
mesh = {Humans ; Male ; Female ; Disease Progression ; Aged ; *Parkinson Disease/pathology/complications/psychology ; *Cognitive Dysfunction/pathology ; Aged, 80 and over ; Lewy Bodies/pathology ; *Parkinsonian Disorders/pathology/complications ; Middle Aged ; *Brain/pathology ; Substantia Nigra/pathology ; Neuropsychological Tests ; },
abstract = {To advance the nosology of pathologic Parkinson's disease (PD), we examined the associations of Lewy bodies (LBs), nigral neuronal loss (NNL), and co-pathologies with cognitive decline and progression of parkinsonian signs in older decedents without clinical PD during life. Nineteen cognitive tests and 26 Unified Parkinson's Disease Rating Scale items were measured annually. We measured both elements of pathologic PD, i.e., LBs and NNL, and eight other Alzheimer's disease and related dementias (ADRD) co-pathologies in 1717 brains. A semiquantitative scale (0-3) was used to assess NNL. Pathologic PD was based on the presence of LBs plus moderate or severe NNL. Possible pathologic PD was based on LBs alone or LBs with mild NNL. A series of bivariate linear mixed effect models jointly quantified cognitive decline and progressive parkinsonian signs in each decedent. Almost 30% of decedents without a diagnosis of clinical PD showed elements of pathologic PD [pathologic PD (8%); possible pathologic PD (19%)]. On average, pathologic PD accounted for 4.9% of the variance of cognitive decline and 9.4% of the variance of progression of parkinsonian signs controlling for ADRD pathologies. Adding another term for possible pathologic PD accounted for an additional 1.8% variance of cognitive decline but did not account for additional variance of progressive parkinsonian signs. Co-pathologies accounted for an additional 19% of cognitive decline and 7% of progressive parkinsonism. Thirty-three percent of the association of LBs with cognitive decline was attributable to NNL. In contrast, more than 70% of its association with progressive parkinsonism was attributable to NNL. Subclinical pathologic PD in older adults is heterogeneous. The associations of LBs with cognition and parkinsonism may vary with the severity of NNL and together with its co-pathologies account for a minority of late-life progressive parkinsonism and cognitive decline. Synucleinopathies in older adults without clinical PD may be underestimated.},
}

Humans
Male
Female
Disease Progression
Aged
*Parkinson Disease/pathology/complications/psychology
*Cognitive Dysfunction/pathology
Aged, 80 and over
Lewy Bodies/pathology
*Parkinsonian Disorders/pathology/complications
Middle Aged
*Brain/pathology
Substantia Nigra/pathology
Neuropsychological Tests

@article {pmid41428075,
year = {2025},
author = {Jellinger, KA},
title = {Is there a link between multiple sclerosis and Alzheimer disease? A critical note.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41428075},
issn = {1435-1463},
abstract = {Multiple sclerosis (MS) and Alzheimer disease (AD) are two neurological disorders that represent a major health problem, as they pose an enormous burden to the patients' quality of life. Although no cure is available, due to recent therapeutic advancements that significantly extend the lifespan, increased prevalence of AD is seen in elderly MS patients. Although cognitive dysfunction affects 40-60% of people with MS, little is known about the co-occurrence of these two conditions and their pathogenetic relationship. About 125 cases of comorbid MS and AD necessitate an evaluation of the literature on the overlaps between AD and MS. Although the etiology of both disorders is unknown, with the emerging recognition that demyelination plays a role in the risk and progression of AD, it has been proposed that both MS and AD share genetic and environmental factors inducing immune cell dysfunctions, inflammation, and neurodegeneration. These mechanisms may be triggered by an early viral infection, Epstein-Barr virus infection being a major risk factor. Both MS and AD show signs of amyloid pathology in the brain and impaired Aβ metabolism in CSF, suggesting overlapping pathobiology. Recent studies revealed similar polygenicity of AD and MS, providing molecular genetic insight into the immune mechanisms involved in both diseases, with similar patterns of microglial activation promoting neuroinflammation. The accumulating damage leads to demyelination, amyloid dysfunction, and damaged blood-brain barrier, together with mitochondrial impairment and other molecular mechanisms leading to neurodegeneration and development of dementia later in life. This short review highlights the overlapping pathophysiological processes promoting the development of AD pathology in progressed MS.},
}

@article {pmid41428074,
year = {2025},
author = {Huang, Y and Ikawa, M and Nogami, M and Mori, T and Makino, A and Kitazaki, Y and Mizuno, T and Kosaka, H and Kiyono, Y and Nishiyama, Y and Okazawa, H},
title = {Evaluation of increased oxidative stress in the brain of patients with early Alzheimer's disease by [64]Cu-ATSM PET/MRI.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41428074},
issn = {1435-1463},
support = {18H02763//Japan Society for the Promotion of Science/ ; 22H03017//Japan Society for the Promotion of Science/ ; 22K19505//Japan Society for the Promotion of Science/ ; 23K06924//Japan Society for the Promotion of Science/ ; 25K02600//Japan Society for the Promotion of Science/ ; },
abstract = {We aimed to compare brain oxidative stress (OS) levels between patients with early Alzheimer's disease (eAD) and age-matched cognitively normal (CN) individuals using [64]Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([64]Cu-ATSM) PET/MRI. Thirty-seven patients with eAD (71.8±8.0 years) and 14 CN (71.1±7.7 years) were included in this study. They underwent PET/MRI using Pittsburg compound-B ([11]C-PiB) and [64]Cu-ATSM on separate days. Each standardized uptake value (SUV) image was converted to an SUV ratio (SUVR) image using the individual cerebellar SUV as a reference. [11]C-PiB centiloid (CL) scale was calculated from a whole-brain image and compared with other biomarkers. The Patlak plot method was used to calculate the influx rate constant (Kin) image of [64]Cu-ATSM to evaluate the global and regional brain OS levels. Hippocampal volume was also evaluated using three-dimensional T1-weighted MRI. All eAD patients showed positive PiB accumulation, whereas all CN individuals showed negative accumulation. Significant group differences were found in the Mini-Mental State Examination score, Clinical Dementia Rating (CDR) score, Alzheimer's Disease Assessment Scale (ADAS), hippocampal volume, and PiB-CL. [64]Cu-ATSM Kin images showed significant positive correlations with PiB-CL in the hippocampus and posterior cingulate cortex of eAD patients. [64]Cu-ATSM SUVR in the hippocampus was negatively correlated with hippocampal volume, CDR score. A significant positive correlation between [64]Cu-ATSM Kin and PiB-CL was observed in the regions responsible for eAD, suggesting that increased OS levels in the brain are associated with the progression of amyloid deposition. These findings indicate [64]Cu-ATSM PET is a useful and promising OS evaluation tool.},
}

@article {pmid41427920,
year = {2025},
author = {Wang, Y and Wang, Y and Xu, Y and Yang, H and Huang, Y and Cheng, H and Wang, C},
title = {Development of a Novel PET Radioligand for Imaging the Adenosine A2A Receptor in the Brain.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00827},
pmid = {41427920},
issn = {1948-7193},
abstract = {The adenosine A2A receptor (A2AAR) is implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, due to its involvement in neuroinflammatory processes and synaptic function. However, suitable positron emission tomography (PET) radioligands for direct imaging of A2AAR in the living brain remain limited. In this study, we describe the synthesis and preclinical evaluation of [[11]C]2, a novel PET radioligand developed to target A2AAR with moderate affinity and selectivity. [[11]C]2 was synthesized with high radiochemical purity and satisfactory molar activity. In vivo PET imaging in wild-type mice demonstrated that [[11]C]2 efficiently crossed the blood-brain barrier and distributed throughout the brain. Blocking studies with unlabeled compound 2 confirmed the specificity of [[11]C]2 binding in vivo. In vitro autoradiography further revealed regional binding patterns in both wild-type and Alzheimer's disease model mice. Slightly higher in vitro signals in AD model mice suggest a potential link to neuroinflammatory mechanisms, although further investigation is required. Notably, during the initial 0.5-2.5 min after injection, striatal uptake was modestly higher than in other brain regions; however, this advantage became indistinct at later time points. Thus, while [[11]C]2 enables very early phase mapping of A2AAR distribution, the transient nature of its striatal preference indicates that further structural optimization is required to enhance sustained striatal selectivity and overall imaging performance.},
}

@article {pmid41427844,
year = {2026},
author = {Shader, RI},
title = {Question: Should I be Advising My Patients to Drink More Lithium-Containing Bottled Water to Possibly Prevent Alzheimer Disease?.},
journal = {Journal of clinical psychopharmacology},
volume = {46},
number = {1},
pages = {126-127},
pmid = {41427844},
issn = {1533-712X},
}

@article {pmid41427617,
year = {2026},
author = {You, W and Coventry, BJ and Henneberg, M},
title = {Cancer and dementia incidence are strongly correlated worldwide: evidence from cross-national regression analyses.},
journal = {Future science OA},
volume = {12},
number = {1},
pages = {2602336},
doi = {10.1080/20565623.2025.2602336},
pmid = {41427617},
issn = {2056-5623},
abstract = {BACKGROUND: Cancer and dementia are two major global health challenges influenced by population aging and socioeconomic transitions. Both impose substantial burdens, yet their relationship at the population level is insufficiently explored. This study investigated the global association between cancer incidence and dementia incidence, while accounting for developmental, demographic, and healthcare-related factors.

METHODS: Data were obtained from the Institute for Health Metrics and Evaluation. Covariates included economic affluence, urbanization, reduced selection opportunity, and life expectancy e(60). Analyses across 204 countries employed correlations, partial correlations, principal component analysis, and multiple linear regression (enter and stepwise). Subgroup analyses were stratified by income level, development status, WHO regions, and geopolitical groupings.

RESULTS: Cancer incidence was strongly correlated with dementia incidence worldwide (r = 0.873; ρ = 0.938, p < 0.001). Associations remained consistent across regions, particularly in upper-middle-income and developing countries. Partial correlations showed the relationship persisted after adjustment, with cancer explaining 59.8% of dementia variance. Regression models revealed that socioeconomic and demographic factors explained 51.7% of the variance, rising to 80.1% with cancer included.

CONCLUSION: Cancer incidence is a dominant independent predictor of dementia incidence globally, surpassing traditional factors. Findings highlight shared determinants and emphasize the importance of integrated chronic disease strategies, especially in low-resource settings.},
}

@article {pmid41427519,
year = {2025},
author = {Pei, T and Liu, Y and Zhang, W and Guo, G and Wang, X and Zhao, Y},
title = {Immuno-MSN-MTs Based Multiplex Biomarker Analysis: A Multimodal Mass Spectrometry Approach for Alzheimer's Disease Detection in Diverse Biospecimens.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e11311},
doi = {10.1002/smll.202511311},
pmid = {41427519},
issn = {1613-6829},
support = {22327805//National Natural Science Foundation of China/ ; 22204002//National Natural Science Foundation of China/ ; 22206008//National Natural Science Foundation of China/ ; },
abstract = {Multiplex protein biomarker detection plays a crucial role in the risk assessment and early diagnosis of Alzheimer's disease (AD). However, conventional mass spectrometry (MS) methods exhibit limited sensitivity for the direct detection of protein biomarkers. In this study, we developed an immuno- mesoporous silica nanoparticle -mass tags (immuno-MSN-MTs) technology based on mass spectrometry signal amplification for the detection of AD biomarkers in blood and brain tissues. When coupled with paper spray ionization mass spectrometry (PSI MS), this method enables highly sensitive quantitative analysis of AD biomarkers in plasma at the picogram per milliliter (pg/mL) level. Normalization of the mass tag signals using internal standards allows for the quantitative determination of protein biomarkers in AD mice across different months. Furthermore, the combination of immuno-MSN-MT with desorption electrospray ionization (DESI) imaging enables the simultaneous detection of protein biomarkers and small-molecule metabolites. This not only facilitates the localized detection of protein biomarkers in the brain tissues of AD mice but also enables the investigation of metabolite differences in lesion areas. These findings provide a theoretical basis for the early diagnosis of AD and the elucidation of the micro-mechanisms underlying Aβ aggregation, while offering a multi-scale perspective for AD pathological research.},
}

@article {pmid41427497,
year = {2025},
author = {Roehri, N and De Stefano, P and Spinelli, L and Marquis, R and Lagarde, S and Momjian, S and Seeck, M and Vulliemoz, S},
title = {Scalp-negative medial temporal interictal epileptic discharges alter large-scale brain networks: A simultaneous high-density electroencephalographic and intracranial electroencephalographic study.},
journal = {Epilepsia},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi.70061},
pmid = {41427497},
issn = {1528-1167},
support = {//PHOCEO/ ; 10004348//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; 163398//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; 180365//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; 192749//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; 209120/WT_/Wellcome Trust/United Kingdom ; 209470/WT_/Wellcome Trust/United Kingdom ; //Ligue Française Contre l'Epilepsie/ ; },
abstract = {OBJECTIVE: Interictal epileptiform discharges (IEDs) observed on scalp electroencephalography (EEG) serve as a diagnostic hallmark of epilepsy. However, only a small fraction of IEDs recorded by intracranial EEG (iEEG) are detectable on the scalp; the vast majority remain invisible on scalp recordings. Nevertheless, epilepsy is associated with important brain network alterations and cognitive symptoms between seizures. Our study aims to investigate the impact of these scalp-negative IEDs on the whole-brain network, particularly those produced in medial temporal regions, given their consistent involvement across patients, their potential implications in cognitive deficit, and their relevance in both epilepsy and Alzheimer disease. To achieve this, we leveraged simultaneous iEEG and high-density EEG (hdEEG) recordings.

METHODS: We analyzed IEDs occurring solely in the medial temporal regions, not visible on the scalp, in nine patients with drug-resistant epilepsy during simultaneous iEEG-hdEEG recordings. These scalp-negative IEDs were compared to epochs without any epileptic activity recorded in either modality. Spectral and network characteristics were investigated at the region of interest (ROI) for both modalities in different canonical frequency bands.

RESULTS: ROI time courses reconstructed with hdEEG during IEDs exhibited sharp wave characteristics (cluster-based corrected time-frequency analysis), confirming that some information time-locked to iEEG IEDs reached the scalp. Our findings revealed a significant frequency-dependent, large-scale increase in power and network features during scalp-negative IEDs compared to epochs without IEDs, at the whole-brain level and within specific ROIs, including the ipsilateral hippocampus (p < .05, false discovery rate corrected).

SIGNIFICANCE: Despite being localized in medial temporal regions, these IEDs have a widespread impact on functional brain networks, potentially contributing to cognitive impairment in epilepsy. This study lays the groundwork for examining their real-time effects on cognition, including in neurodegenerative conditions such as Alzheimer disease, where these IEDs can be present and difficult to detect.},
}

@article {pmid41427478,
year = {2025},
author = {Neumann, D and Razlighi, QR and Stern, Y and Devanand, DP and Jamison, KW and Kuceyeski, A and Tozlu, C},
title = {Disrupted Energetic and Entropic Landscape in Individuals With Mild Cognitive Impairment: Insights From Network Control Theory.},
journal = {Human brain mapping},
volume = {46},
number = {18},
pages = {e70427},
doi = {10.1002/hbm.70427},
pmid = {41427478},
issn = {1097-0193},
support = {FG-2008-36976//National Multiple Sclerosis Society/ ; TA-2204-39428//National Multiple Sclerosis Society/ ; R01 NS102646-01A1/NH/NIH HHS/United States ; R21 NS104634-01/NH/NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/physiopathology/metabolism ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; Entropy ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology/metabolism ; *Connectome/methods ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/physiopathology/metabolism ; tau Proteins/metabolism ; Aged, 80 and over ; },
abstract = {The energetic and entropic organization of the brain's functional activity in mild cognitive impairment (MCI) has yet to be fully characterized. Network Control Theory (NCT) is a multi-modal approach that captures alterations in the brain's energetic landscape by combining the brain's functional activity and the structural connectome. Entropy is another complementary metric that can quantify the complexity and predictability in a neural time series, offering insights into the brain's dynamic functional activity. Our study aims to explore the differences in the brain's energetic and entropic landscape between people with MCI and healthy controls (HC). Four hundred ninety-nine HC and 55 MCI patients were included. First, k-means clustering was applied to functional MRI (fMRI) time series to identify commonly recurring brain activity states. Second, NCT was used to calculate the minimum energy required to transition between these brain activity states, otherwise known as transition energy (TE). The entropy of the fMRI time series as well as PET-derived amyloid beta (Aβ) and tau deposition were measured for each brain region. The TE and entropy were compared between MCI and HC at the network, regional, and global levels using linear models where age, sex, and intracranial volume were added as covariates. The association of TE and entropy with Aβ and tau deposition was investigated in MCI patients using linear models where age, sex, and intracranial volume were controlled. Commonly recurring brain activity states included those with high (+) and low (-) amplitude activity in visual (+/-), default mode (+/-), and dorsal attention (+/-) networks. Compared to HC, MCI patients required lower transition energy in the limbic network (adjusted p = 0.028). Decreased global entropy was observed in MCI patients compared to HC (p = 7.29e-7). There was a positive association between TE and entropy in the frontoparietal network (p = 7.03e-3). Increased global Aβ was associated with higher global entropy in MCI patients (ρ = 0.632, p = 0.041). Lower TE in the limbic network in MCI patients may indicate either neurodegeneration-related neural loss and atrophy or a potential functional upregulation mechanism in this early stage of cognitive impairment. Future studies that include people with Alzheimer's Disease (AD) are needed to better characterize the changes in the energetic landscape in the later stages of cognitive impairment.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/physiopathology/metabolism
Male
Female
Aged
Magnetic Resonance Imaging
Entropy
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology/metabolism
*Connectome/methods
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/physiopathology/metabolism
tau Proteins/metabolism
Aged, 80 and over

@article {pmid41427477,
year = {2025},
author = {Hwang, J and Clore, MF and Blasco Tavares Pereira Lopes, F and Ayati, M and Schlatzer, D and Qi, X and Wang, R and Koyuturk, M and Chance, MR},
title = {Redox Stoichiometry at the Single-Residue Level Using Mass Spectrometry Reveals Dynamic Methionine Sulfoxide Speciation in Actin and Calmodulin during Brain Aging.},
journal = {Journal of proteome research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jproteome.5c00715},
pmid = {41427477},
issn = {1535-3907},
abstract = {Methionine oxidation to methionine sulfoxide (MSox) is often viewed as a nonspecific modification from reactive oxygen species. However, oxidation at specific methionine sites, such as Met44/47 in actin and Met77 in calmodulin, can be reversed by methionine sulfoxide reductase (Msr) and other enzyme families. This study uses liquid chromatography coupled with mass spectrometry to comprehensively investigate actin and calmodulin-based MSox speciation within the mouse hippocampus in an Alzheimer's disease (AD) model (5XFAD), reflecting neuroinflammation and oxidative stress. Concurrent detection of both oxidized and unmodified peptides enabled direct calculation of absolute oxidation stoichiometry and protein-normalized % occupancy ─an analytical dimension seldom attainable for most post-translational modification studies. Our results indicate age-dependent but not AD-dependent redox dynamics. In actin, D-loop Met44/47 declined from ∼9 to ∼5% between 3 and 6 months and then rose to ∼14% by 9 months, while H-loop Met269 remained stable at ∼5% MSox. In calmodulin, linker Met77 climbed steadily with age (but not AD), whereas C-lobe Met145/146 fell sharply from 20 to ∼8% MSox from 3 to 9 months. These findings highlight dynamic, age-related methionine oxidation patterns in actin and calmodulin within the mouse hippocampus, likely relevant to brain development and aging.},
}

@article {pmid41427410,
year = {2025},
author = {Chen, K and Pineau, E and Koletar, M and Trevisiol, A and He, JS and Hill, M and Goubran, M and Sled, J and McLaurin, J and Stefanovic, B},
title = {Stable neuronal representations to repeated stimulation underlie cognitive resilience in Alzheimer's disease pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.05.692431},
pmid = {41427410},
issn = {2692-8205},
abstract = {While Alzheimer's Disease (AD) typically triggers cognitive decline, some individuals with significant AD pathology maintain normal cognition into late life. Understanding the neuronal underpinnings of such cognitive resilience would propel the development of interventions for delaying dementia. To this end, we used cognitive testing to identify a subset of cognitively resilient 13-month-old TgF344-AD rats (established AD) and their non-transgenic littermates, followed by Neuropixels recording from 8500 neurons during repeated somatosensory stimulation. Cognitively resilient TgF344-AD rats recruited fewer neurons yet displayed more stable neuronal representations during repeated stimulations in cortical excitatory and hippocampal inhibitory ensembles, with reduced excitatory spike burstiness during network activation and a distinct pattern of functional synaptic connectivity. These associations existed independently of amyloid and tau levels. For the first time, our study revealed neuronal population-level hallmarks of maintained cognition that may serve as a novel neurophysiological biomarker of cognitive resilience and a target for stabilizing cognition.},
}

@article {pmid41427392,
year = {2025},
author = {LaGrow, TJ and Itkyal, V and Watters, H and Jensen, KM and Ballem, R and Pan, WJ and Iraji, A and Calhoun, VD and Keilholz, S},
title = {Spatiotemporal Network Dynamics Reveal Alzheimer's Disease Progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.09.692653},
pmid = {41427392},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by progressive disruptions in large-scale brain networks that precede cognitive decline, yet conventional functional connectivity analyses often fail to detect disruptions in coordination among large-scale brain networks that may be critical for early detection. This study leverages quasi periodic patterns (QPPs) and complex principal component analysis (cPCA) to characterize spatiotemporal network alterations across longitudinally stable (normal cognitive, mild cognitive impairment, dementia of Alzheimer's type) and transitioning (normal cognitive to mild cognitive impairment, mild cognitive impairment to dementia of Alzheimer's type) cohorts from the Alzheimer's Disease Neuroimaging Initiative using resting state fMRI. QPPs were used to derive recurrent spatiotemporal templates and network integrity measures at the intrinsic connectivity network level, while cPCA decomposed Hilbert transformed time series into complex valued patterns that capture amplitude and phase relationships. Nonparametric group comparisons revealed a structured trajectory in which limbic, subcortical, and higher cognition networks, including triple network components, are affected early, followed by progressive disruption in visual, cerebellar, sensorimotor, and additional triple network systems. Transitioning cohorts showed many of these alterations before formal diagnostic conversion, indicating that spatiotemporal signatures carry preclinical information. QPP based metrics were particularly sensitive to limbic and subcortical degradation, whereas cPCA emphasized changes in higher order, visual, and cerebellar patterns, revealing complementary aspects of the same underlying pathology. These findings extend prior QPP only work and highlight the utility of combining QPP and cPCA based measures as a dynamic, network-level biomarker framework for AD progression. with potential applications in early detection, characterizing disease trajectories, and treatment monitoring.},
}

@article {pmid41427315,
year = {2025},
author = {Peña-Ramos, O and Gedam, M and Zhang, X and Wang, S and Qi, C and Huang, TH and Rajpurohit, CS and Dunlap, M and Deng, Y and Auld, N and Jung, SY and Li, H and Li, J and Luo, L and Peng, J and Cheng, C and Zheng, H},
title = {Astrocyte cell-surface proteomics identified CD44 as an OPN/SPP1 receptor regulating lipid metabolism and glial crosstalk in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.05.692670},
pmid = {41427315},
issn = {2692-8205},
abstract = {The development of β-amyloid (Aβ) pathology in Alzheimer's disease (AD) is accompanied by profound changes in astrocytes and microglia. How these responses are orchestrated by cell surface proteins, key mediators of cell-cell communication, remain unclear. Using in situ astrocyte cell-surface proteome profiling in 5xFAD mice, we identified a set of dysregulated surface proteins induced by Aβ pathology, including CD44. CD44 was selectively upregulated in plaque-adjacent astrocytes and interacted with osteopontin (OPN), encoded by the disease-associated microglia gene Spp1 , to promote lipid accumulation, and this effect is γ-secretase dependent. Astrocytic CD44 in turn regulated Spp1 expression and microglial activity. Conditional deletion of Cd44 in adult astrocytes of 5xFAD mice attenuated glial reactivity, reduced Aβ pathology, and improved cognition. These findings define a plaque-proximal OPN-CD44 axis that controls astrocyte lipid metabolism and glial activity, positioning CD44 as a surface-accessible therapeutic target in AD.},
}

@article {pmid41427303,
year = {2025},
author = {Yang, X and Li, Y and Bibic, A and Wang, J and Wan, M and Duan, W and Lu, H and Wei, Z},
title = {Vascular Microbleeds Without Brain Atrophy: A Microvascular Signature of Mid-Stage 5xFAD Pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.08.692809},
pmid = {41427303},
issn = {2692-8205},
abstract = {Cerebral microbleeds are increasingly recognized as a downstream manifestation of vascular injury in Alzheimer's disease (AD), arising secondary to cerebral amyloid angiopathy (CAA). Here, we examined the pathological specificity of microbleeds by comparing an amyloidosis mouse model (5xFAD) with a small-vessel disease (SVD) model characterized by vascular smooth-muscle cell loss. In vivo multimodal MRI, including gradient-echo, spin-echo, and diffusion-weighted imaging, was complemented by ex vivo high-resolution anatomical scans for validation. Both in vivo and ex vivo gradient-echo MRI consistently revealed hippocampal microbleeds in the 5xFAD model without macroscopic atrophy or ventricular enlargement, whereas no microbleeds or blood-brain barrier disruption were detected in the SVD model. Diffusion-weighted MRI further showed region-specific alterations in apparent diffusion coefficient within the midbrain of 5xFAD mice, but not in other regions or in the SVD cohort. These findings indicate that microbleeds are a pathology-specific marker of amyloid-related vascular injury. The imaging evidence underscores the potential of microbleeds as a disease-specific biomarker for detecting amyloid-driven vascular fragility and refining diagnostic and therapeutic strategies for AD.},
}

@article {pmid41427298,
year = {2025},
author = {Song, JY and Akkentli, F and Jo, H and Park, J and Ha, S and Redding-Ochoa, J and Troncoso, JC and Kang, SU and Dawson, VL and Dawson, TM},
title = {Neuronal PARIS-STAT3 axis drives tau pathology and glial activation in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.06.692741},
pmid = {41427298},
issn = {2692-8205},
abstract = {PARIS, a substrate of Parkin, accumulates in Parkinson's disease and promotes disease progression. Here, we demonstrate that PARIS also contributes to Alzheimer's disease by elevating STAT3 transcriptional activity, thereby inducing tau pathology, hippocampal atrophy, and glial activation. Genetic depletion of Paris reduced tau phosphorylation and cognitive decline in tauopathy mice, whereas neuron-specific PARIS overexpression caused tau accumulation, gliosis, and memory impairment. In contrast, astrocyte-specific overexpression did not induce pathology, indicating that PARIS acts in neurons to drive tau phosphorylation and glial activation. The pathological features induced by neuronal PARIS overexpression were rescued by STAT3 inhibition, demonstrating that PARIS-STAT3 signaling underlies these effects. Moreover, Paris knockout did not alter pathology in the amyloid-driven mouse model, highlighting specificity for tau pathology. Together, these findings reveal PARIS as a neuronal regulator of STAT3 signaling that exacerbates tau-mediated neurodegeneration and identify the PARIS-STAT3 pathway as a potential therapeutic target in Alzheimer's disease.},
}

@article {pmid41427297,
year = {2025},
author = {Sun, L and Hu, M and Lyu, J and Zhu, D and Gao, F and Pan, M and Zhang, J and Chen, C},
title = {Selective Inactivation of Astrocytic Monoacylglycerol Lipase for Alzheimer's Disease Therapy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.04.692105},
pmid = {41427297},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly, yet effective therapies remain lacking. Here, we identify monoacylglycerol lipase (MAGL), the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, specifically in astrocytes as a promising therapeutic target for AD. APP transgenic (TG) mice with astrocyte-specific MAGL deletion (TG-aKO), but not neuron-specific deletion (TG-nKO), exhibit markedly reduced Aβ pathology, neurodegeneration, and neuroinflammation, along with preserved synaptic structure and function and improved cognition. These benefits are recapitulated in TG mice by AAV-mediated silencing of astrocytic MAGL, whereas MAGL overexpression exacerbates neuropathology and accelerates synaptic and cognitive decline. Transcriptomic analyses reveal that dysregulated synapse-, inflammation-, and AD-related gene expression profiles are reversed in TG-aKO mice. MAGL expression is elevated in astrocytes from both AD patients and TG mice. Remarkably, a single intracerebroventricular (ICV) injection of AAV-MAGL-shRNA administered at either presymptomatic or postsymptomatic stages prevents or reverses neuropathology and synaptic and cognitive impairments in TG mice, providing preclinical evidence that astrocytic MAGL silencing represents an effective therapeutic strategy for AD.},
}

@article {pmid41427288,
year = {2025},
author = {Barr, HJ and Caldwell, SK and Reimertz, JM and Depp, C and Walker, AJ and Marsh, SE and Gupte, AS and Hingerl, M and Patel, J and Park, SO and Ferraro, S and Lipton, J and Stevens, B},
title = {The circadian clock regulates scavenging of fluid-borne substrates by brain border-associated macrophages.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.08.693074},
pmid = {41427288},
issn = {2692-8205},
abstract = {Circadian disruptions perturb the brain and immune system and increase the risk of developing Alzheimer's Disease (AD), yet whether this involves dysregulation of brain immunity remains less clear. Here, we perform single-cell RNA sequencing of the brain immune compartment around the day-night cycle and identify brain border-associated macrophages (BAMs) as highly rhythmic cells. During the rest phase, we find that BAMs exhibit coordinated upregulation of endocytic genes and enhanced uptake of extracellular fluid-borne material including amyloid-beta (Aβ). Rhythmicity in BAM scavenging is regulated by the clock gene Bmal1 , mediated by the endocytic receptor CD206, and perturbed with age. In a mouse model of AD, we show that deletion of Bmal1 in BAMs worsens perivascular and leptomeningeal Aβ plaque burden. Our results identify endocytosis as a specialized and rhythmic BAM function and identify perturbed timing of brain border immune functions as a potential mechanism by which circadian disruptions precipitate amyloidosis.},
}

@article {pmid41427267,
year = {2025},
author = {Finney, CA and An, L and Winchester, LM and Vogel, J and Wilkins, HM and Burns, JM and Swerdlow, RH and Slawson, C and Rothstein, JD and , and Lutz, MW and Saloner, R and Shvetcov, A},
title = {Mapping the circulating proteome across neurodegeneration: A harmonized, consortium-scale framework for uncovering molecular pathophysiology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.09.693329},
pmid = {41427267},
issn = {2692-8205},
abstract = {Large-scale plasma proteomics offers unprecedented opportunities to investigate the systemic biology of neurodegeneration, yet technical heterogeneity, site-specific artifacts, and clinical confounding remain major barriers to reproducible discovery. Leveraging data from 13,733 individuals with Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), amyotrophic lateral sclerosis (ALS), and non-impaired controls in the Global Neurodegeneration Proteomics Consortium (GNPC), we present a scalable and generalizable analytical framework for harmonizing and interpreting consortium-scale proteomic datasets. Using a high-dimensional perturbation framework, we systematically benchmark five commonly used batch correction methods across a range of realistic confounding structures, including site-disease imbalance, nonlinear effects, and heteroskedasticity. Empirical Bayes modelling via limma consistently emerged as the most robust method, optimally balancing removal of site-related technical variance with retention of disease-relevant biological signal. On this harmonized foundation, we resolve neurodegenerative disease plasma signatures, including a shared immune-metabolic axis in AD and PD, neuromuscular disruption in ALS, and proteostatic imbalance in PD. Tissue and cell-type enrichment highlight widespread immune-endocrine involvement in AD and hematopoietic activation in PD. Demographically matched analyses nominate distinct, candidate biomarkers across diseases, including lipid, redox, and complement factors in AD, lysosomal and cytoskeletal proteins in PD, and muscle-derived markers in ALS. This study establishes a scalable analytical framework for integrating real-world proteomic data and provides a disease-resolved catalogue of circulating signatures to inform biomarker development and targeted intervention across neurodegenerative diseases.},
}

@article {pmid41427244,
year = {2025},
author = {Balagurusamy, B and Ganesan, V and Gopi, V and Ilayaperumal, P},
title = {Liposomal and Nanomaterial-Based Strategies for Targeted Alzheimer's Disease Therapy.},
journal = {ACS omega},
volume = {10},
number = {49},
pages = {60004-60019},
pmid = {41427244},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder with limited therapeutic options. Liposomal drug delivery has emerged as a promising strategy to enhance drug bioavailability and targeted delivery across the blood-brain barrier. This review explores the role of liposomes and nanomaterials in AD therapy, focusing on their versatility for drug delivery, including intranasal formulations, gene therapy, and reactive oxygen species (ROS)-responsive systems. Various liposomal formulations, such as mannose-modified, antibody-targeted, exosome-like, and biomaterial-based carriers, have shown significant potential in improving therapeutic efficacy. Natural compound-loaded liposomes, including polyphenols, tannic acid, and plant extracts, offer neuroprotective benefits. Furthermore, the inhibition of amyloid-β (Aβ) aggregation, a key pathological feature of AD, is addressed through innovative liposomal approaches, including peptide-conjugated, chiral-modified, and transferrin-targeted liposomes. This review highlights the synergistic role of glymphatic clearance and microglial phagocytosis in reducing the amyloid burden. Liposomal-based strategies are promising for advancing AD treatment by improving drug stability, specificity, and brain-targeting efficiency.},
}

@article {pmid41427231,
year = {2025},
author = {Borrego-Sánchez, A and García-Frutos, EM and Darder, M and Sainz-Díaz, CI},
title = {Molecular Insights of 7‑Azaindole Drugs and Their Intercalation in the Confined Space of Montmorillonite.},
journal = {ACS omega},
volume = {10},
number = {49},
pages = {60287-60297},
pmid = {41427231},
issn = {2470-1343},
abstract = {Two derivatives of the group of 7-azaindoles, 1-benzyl-3-(piperidin-1-ylmethyl)-1H-pyrrolo [2,3-b] pyridine, and 1-benzyl-5-methoxy-3-(piperidin-1-ylmethyl)-1H-pyrrolo [2,3-b] pyridine as mono-oxalate salts are studied in this work as potential neuroprotective drugs for the treatment of Alzheimer's disease. Previously, we studied the use of a natural montmorillonite clay mineral as a candidate for a drug delivery system, finding that these drugs can be intercalated into the confined interlayer space of montmorillonite and subsequently released in a human medium for therapeutic use. However, some aspects of this study could not be explained. This work has studied this process at the atomic and molecular levels by using the Interface force field (FF). Initially, this methodology was validated in this work, reproducing the experimental crystal structure of these 7-azaindole drugs. Then, this FF was applied to calculate the intercalation of these drugs by cation exchange into montmorillonite according to the experimental results. Our calculations have reproduced this intercalation at the cation exchange capacity at the molecular level, finding that the experimental structure can only be justified with the intercalation of five drug molecules per 4 × 2 × 1 supercell of clay mineral inside the confined interlayer space. In addition, this intercalation does not produce a monolayer disposition postulated initially from experiments. On the contrary, our molecular dynamics simulations show that the intercalated molecules adopt a disordered disposition with a certain tendency to form a bilayer configuration in the confined interlayer space of montmorillonite. Besides, the spectroscopic infrared properties are useful for monitoring the preparation and encapsulation processes of pharmaceutical drugs. Then, these properties were studied experimentally and calculated theoretically. The calculated frequencies of the crystal structure of these 7-azaindole drugs allowed assignments of the experimental FT-IR spectra. This collaborative work with experimental and theoretical research enhances the knowledge for a promising drug delivery system for anti-Alzheimer therapy.},
}

@article {pmid41427113,
year = {2025},
author = {Garai, S and Vo, S and Blank, L and Xu, F and Chen, J and Duong-Tran, D and Zhao, Y and Brown, BC and Shen, L},
title = {H-VIP: quantifying regional topological contributions of the brain network to cognition.},
journal = {Frontiers in radiology},
volume = {5},
number = {},
pages = {1686780},
pmid = {41427113},
issn = {2673-8740},
abstract = {INTRODUCTION: Understanding the role of various brain regions of interest (ROIs) in various cognitive functions or tasks, across healthy or neurodegenerative conditions and multiple degrees of separation, remains a key challenge in neuroscience. Conventional network measures can only capture localized or quasi-localized features of brain ROIs. Topological data analysis (TDA), particularly persistent homology, provides a threshold-free, mathematically rigorous framework for identifying topologically salient features in complex networks. In this paper, we introduce a new metric, the Homological Vertex Importance Profile (H-VIP), designed to assess the relevance of vertices that participate in persistent topological structures (e.g., connected components, cycles or cavities) in brain networks. The H-VIP quantifies the topological features of the network at the ROI (node) level by compressing its higher-order connectivity profile using homological constructs.

METHODS: Leveraging homological constructs of brain connectomes, we extend two of our previously defined network-level measures-average persistence and persistence entropy-to an ROI-level measure, i.e., the H-VIP. We then applied the H-VIP to two independent datasets: structural connectomes from the Human Connectome Project and functional connectomes from the Alzheimer's Disease Neuroimaging Initiative. Persistent homology was computed for each network, and H-VIP scores were derived to evaluate vertex-level contributions. Finally, H-VIP scores were used for the prediction of multiple cognitive measures.

RESULTS: In both anatomical and functional brain networks, H-VIP values demonstrate predictive power for various cognitive measures. Notably, the connectivity of the frontal lobe exhibited stronger correlations with cognitive performance than the whole-brain network.

DISCUSSION: H-VIP offers a robust and interpretable means to locate, quantify, and visualize region-specific contributions to network's topological, higher-order landscape. Its ability to detect potentially impaired connectivity at the individual level suggests possible applications in personalized medicine for neurological diseases and disorders. Beyond brain connectomics, the H-VIP can be used for other types of complex networks where topological features are of importance, such as financial, social, or ecological networks.},
}

@article {pmid41427105,
year = {2026},
author = {Custodio, N and Soto-Añari, M and Montesinos, R and Malaga, M and Custodio, B and Chambergo-Michilot, D and Bustamante-Paytan, D and Yauri, Z and Agüero, K and Verastegui, G and Lanata, S and Butler, C and Tosto, G},
title = {The modified Rowland Universal Dementia Assessment Scale for dementia screening in the Peruvian population.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e2025377},
pmid = {41427105},
issn = {1980-5764},
abstract = {UNLABELLED: Dementia cases are rising globally, particularly in low- and middle-income countries like those in Latin America.

OBJECTIVE: The aim of the study was to enhance diagnostic accuracy in diverse populations; modifications to brief cognitive tools may be necessary.

METHODS: This cross-sectional study involved 197 participants who underwent neurocognitive assessments with both the Peruvian version of the Rowland Universal Dementia Assessment Scale (RUDAS-PE) and a modified version of RUDAS-PE (mRUDAS-PE). Statistical analyses, including chi-square tests and receiver-operator curves, were used to compare the diagnostic performance of the original and modified RUDAS.

RESULTS: The mRUDAS-PE showed improved performance in the visuospatial construction domain, with more participants achieving top scores, especially among controls and Alzheimer's disease patients. The judgment domain also yielded higher scores for controls. Only the judgment domain modifications do not change the diagnostic accuracy.

CONCLUSION: Judgment modifications could be considered to improve the diagnostic performance of RUDAS-PE. Further testing in populations with different educational levels from rural areas is needed to assess their broader impact.},
}

@article {pmid41427064,
year = {2025},
author = {Tregub, PP and Kolotyeva, NA and Chekulayev, PA and Groshkov, AA and Illarioshkin, SN and Salmina, AB and Piradov, MA},
title = {Protein Misfolding in the Pathogenesis and Diagnosis of Neurodegenerative Diseases (Review).},
journal = {Sovremennye tekhnologii v meditsine},
volume = {17},
number = {4},
pages = {60-77},
pmid = {41427064},
issn = {2309-995X},
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Protein Folding ; *tau Proteins/metabolism ; *alpha-Synuclein/metabolism ; *Amyloid beta-Peptides/metabolism ; *Proteostasis Deficiencies/diagnosis/metabolism ; },
abstract = {This review systematizes existing data on protein misfolding in the pathogenesis of neurodegenerative diseases (with a focus on α-synuclein, β-amyloid, and tau protein). Modern laboratory and neuroimaging methods used for clinical diagnosis and scientific research of proteinopathies are discussed. The paper describes promising protein amplification techniques that enable the detection of ultra-low concentrations of aberrant protein forms in biological fluids. The challenges and prospects of early diagnosis of neurodegenerative diseases through protein misfolding detection are also shown.},
}

Humans
*Neurodegenerative Diseases/diagnosis/metabolism
*Protein Folding
*tau Proteins/metabolism
*alpha-Synuclein/metabolism
*Amyloid beta-Peptides/metabolism
*Proteostasis Deficiencies/diagnosis/metabolism

@article {pmid41427057,
year = {2025},
author = {Leung, YY and Kuksa, PP and Carter, L and Cifello, J and Greenfest-Allen, E and Valladares, O and Boateng, L and Laub, S and Tulina, N and Moura, S and Ramirez, A and Celis, K and Jin, F and Feng, R and Wang, G and De Jager, P and Vance, JM and Wang, L and Grant, SFA and Schellenberg, GD and Chesi, A and Wang, LS},
title = {Integrated genomic analysis and CRISPRi implicates EGFR in Alzheimer's disease risk.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {42},
pmid = {41427057},
issn = {3005-1940},
abstract = {Genome-wide association studies (GWAS) have identified numerous loci linked to late-onset Alzheimer's disease (LOAD), but the pan-brain regional effects of these loci remain largely uncharacterized. To address this, we systematically analyzed all LOAD-associated regions reported by Bellenguez et al. using the FILER functional genomics catalog across 174 datasets, including enhancers, transcription factors, and quantitative trait loci. We identified 41 candidate causal variant-effector gene pairs and assessed their impact using enhancer-promoter interaction data, variant annotations, and brain cell-type-specific gene expression. Notably, the LOAD risk allele of rs74504435 at the SEC61G locus was computationally predicted to increase EGFR expression in LOAD-related cell types: microglia, astrocytes, and neurons. Functional validation using promoter-focused Capture C, ATAC-seq, and CRISPR interference in the HMC3 human microglia cell line confirmed this regulatory relationship. Our findings reveal a microglial enhancer regulating EGFR in LOAD, suggesting EGFR inhibitors as a potential therapeutic avenue for the disease.},
}

@article {pmid41427016,
year = {2025},
author = {Jiang, A and Shi, D and Que, X and Lin, Z and Chen, Y and Huang, Y and Liu, C and Wen, Y and Zhang, S and Huang, W},
title = {Development of a novel diagnostic model for Alzheimer's disease based on glymphatic system and metabolism-related genes.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1585761},
pmid = {41427016},
issn = {2296-889X},
abstract = {OBJECTIVES: Alzheimer's disease (AD), a common neurodegenerative disorder, is characterized by its complex pathogenesis and challenging early diagnosis; however, the role of the glymphatic system and metabolism-related genes (GS&MetabolismRGs) in AD remains poorly understood. Therefore, this study aimed to explore a potential diagnostic model and the molecular mechanisms of GS&MetabolismRGs in AD.

MATERIALS AND METHODS: We obtained glymphatic system and metabolism-related differentially expressed genes (GS&MetabolismRDEGs) associated with AD by integrating of GEO and GeneCards databases. Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and gene set enrichment analysis were performed to investigate the roles of GS&metabolismRDEGs in AD-related biological processes. Hub genes were identified using machine learning methods, resulting in the construction and validation of AD diagnostic models. AD samples were further stratified into high-score and low-score groups based on the median value of glymphatic system and Metabolism Score to investigate the underlying pathogenesis. Finally, immune infiltration analysis was conducted to explore the relationship between immune cell frequencies and hub genes.

RESULTS: Six GS&MetabolismRDEGs were identified, which were predominantly enriched in biological processes, such as the PD-L1 expression, hyaluronan metabolic process, and the PD-1 checkpoint pathway in cancer. Further analysis identified six hub genes that were used to construct an AD diagnostic model. Immune infiltration analysis of the disease and control groups revealed significant associations among all eight immune cell types. The strongest negative correlation was found between the resting memory CD4[+] T cells and Tregs. Further analysis revealed a strong positive correlation between Tregs and NFKB1 in low-risk group and the most significant correlation between activated mast cells and TREM1 in high-risk group.

CONCLUSION: This study developed a novel diagnostic model based on six GS&MetabolismRDEGs, highlighting their potential as key biomarkers for early diagnosis and providing new insights into the molecular mechanisms driving AD.},
}

@article {pmid41426989,
year = {2025},
author = {Sagaro, GG and Amenta, F},
title = {Comparison of the effects of choline alphoscerate and citicoline in patients with dementia disorders: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1649661},
pmid = {41426989},
issn = {1664-2295},
abstract = {BACKGROUND: Over 44 million people worldwide live with dementia, affecting their quality of life and well-being. Choline alphoscerate and citicoline supplements are commonly used to improve cognitive function in dementia patients. However, their efficacy remains inconsistent.

OBJECTIVE: This systematic review aimed to investigate and compare the effects of choline alphoscerate and citicoline on cognitive impairments, behavioural symptoms, and other clinical conditions in patients with dementia disorders.

METHODS: PubMed and Scopus were searched to identify relevant studies. We calculated weighted mean differences (WMD) or standardized mean differences (SMD) and 95% confidence intervals (CI) for continuous outcomes and odds ratios (OR) and 95% CI for binary outcomes.

RESULTS: This review included data from 358 participants across three randomized controlled trials (RCTs). As measured by the Sandoz Clinical Assessment for Geriatric Patients (SCAG), choline alphoscerate significantly improved clinical conditions in patients with dementia disorders compared with citicoline at the end of treatment [WMD: -3.92 (95% CI: -7.41 to -0.42)]. Specifically, our pooled analysis revealed that choline alphoscerate showed significant improvements in cognitive function, interpersonal relationships, affective disorders, apathy, and somatic functioning compared to citicoline at the end of treatment, as measured by the SCAG. However, there was no significant difference between the choline alphoscerate and citicoline treatment groups on memory or word fluency tests (WFT). Dropout rates for choline alphoscerate and citicoline were 9.4 and 6.7%, respectively [OR: 1.44 (95% CI: 0.66 to 3.13)], indicating no significant differences in acceptability.

CONCLUSION: Our findings indicate that choline alphoscerate is more effective than citicoline in improving the clinical conditions of dementia patients.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42024626782, Identifier: CRD42024626782.},
}

@article {pmid41426983,
year = {2025},
author = {Kuroda, T and Mori, Y and Shoji, D and Kubota, S and Noguchi-Shinohara, M and Ono, K and Murakami, H},
title = {Limited utility of imaging-based (N) markers in predicting cerebral spinal fluid Alzheimer's disease biomarker positivity in lecanemab-eligible mild cognitive impairment.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1735548},
pmid = {41426983},
issn = {1664-2295},
abstract = {BACKGROUND: Early detection of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) is essential for the timely initiation of anti-amyloid β (Aβ) therapy. In clinical practice, cerebrospinal fluid (CSF) testing and amyloid positron emission tomography (PET) are not feasible for all patients; therefore, initial screening sometimes relies on imaging-based neurodegeneration (N) markers within the amyloid-tau-neurodegeneration AT(N) framework. However, the diagnostic accuracy of imaging-based (N) markers remains uncertain in real-world MCI cohorts being evaluated for anti-Aβ antibody therapy. We aimed to assess the utility of imaging-based (N) markers in predicting AD pathology in patients with MCI who may be eligible for lecanemab.

METHODS: Thirty-six patients with MCI who were potentially eligible for lecanemab underwent CSF biomarker testing and were subsequently classified as MCI unlikely due to AD (MCI non-AD; n = 14) or MCI due to AD (MCI-AD; n = 22). Demographics, general risk factors, neuropsychological test scores, and imaging-based (N) markers-medial temporal atrophy (MTA) on magnetic resonance imaging (MRI) and regional cerebral blood flow (CBF) reductions on single-photon emission computed tomography (SPECT)-were compared between groups.

RESULTS: MCI-AD was diagnosed in 22 patients (61%). Demographics, neuropsychological test scores, and most general risk factors did not differ between groups, except for diabetes, which was more frequent in the MCI non-AD group. Overall, 34 of 36 patients (94%) were classified as (N) + based on MRI or SPECT (91% MCI-AD; 100% MCI non-AD). There were no significant differences in mean MTA scores or the degree of CBF reduction between groups. In contrast, the proportion of MRI (N) + patients was significantly higher in the MCI non-AD group than in the MCI-AD group, and two patients with MCI-AD were (N) - on both MRI and SPECT.

CONCLUSION: Relying on imaging-based (N) markers to select MCI patients who may be eligible for lecanemab prior to CSF biomarker testing may lead to inefficient diagnostic pathways and may fail to identify patients who could benefit from anti-Aβ therapy.},
}

@article {pmid41426598,
year = {2025},
author = {Wu, H and Zhang, M and Zhang, L and Liu, H and Fan, H},
title = {Global trends and perspectives in mitophagy on neurodegenerative diseases: a scientometric analysis over 20 years.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1666909},
pmid = {41426598},
issn = {2296-858X},
abstract = {BACKGROUND: The investigation of mitophagy in neurodegenerative diseases has grown significantly, yet a comprehensive global insight remains limited. This study conducts a scientometric analysis to map the research landscape related to mitophagy in neurodegenerative diseases.

METHODS: We conducted a bibliometric analysis of 2,566 publications (2004 to 11 June 2025) from Web of Science Core Collection and Scopus. To mitigate bias in trend analyses, incomplete 2025 data were excluded from publication growth and curve fitting but retained for other analyses. Data were analyzed via Bibliometrix R package, VOSviewer, Scimago Graphica, and CiteSpace to map mitophagy research evolution.

RESULTS: The field showed exponential growth with peak productivity in 2021. The United States led publication output, with institutions from the USA, UK, and China forming the core of robust international collaborations, while maintaining the highest citation impact. Influential researchers included Tavernarakis, Nektarios and Reddy, P. Hemachandra, with prominent journals such as International Journal of Molecular Sciences, Cells and Autophagy, serving as key publication venues. Cluster analysis revealed thematic structures centered on "Parkinson's disease," "mitochondrial dysfunction," "oxidative stress," and "fission/fusion mechanisms", with additional focus on "Parkin-mediated mitophagy" and "neurodegenerative diseases." Research evolved from foundational studies through mechanistic exploration to translational applications. Emerging trends include "post-translational modifications (PTMs)," "chaperone-mediated autophagy," "gut microbiota," "mitochondrial quality control," and therapeutic investigations of compounds like "curcumin" and "melatonin."

CONCLUSION: This first comprehensive scientometric analysis underscores the expanding interest in mitophagy as a crucial molecular mechanism in neurodegenerative diseases. Our findings establish a framework for developing novel therapeutic interventions such as mitochondrial quality control modulators and compounds like curcumin and melatonin targeting mitophagy dysfunction in neurodegenerative disorders.},
}

@article {pmid41426524,
year = {2026},
author = {Yu, X and Zhang, J and Cao, C and Chen, T and Zhuang, Y and Chen, M and Lyu, Y and Zhang, L and Su, L and Liu, T and Zhu, D},
title = {Domain-Adaptive Diagnosis of Lewy Body Disease with Transferability Aware Transformer.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15966},
number = {},
pages = {184-193},
pmid = {41426524},
abstract = {Lewy Body Disease (LBD) is a common but understudied dementia that poses a significant public health burden. It shares similar clinical signs with Alzheimer's disease (AD), with both conditions progressing through stages of normal cognition, mild cognitive impairment, and dementia. A major obstacle in LBD diagnosis is data scarcity, which limits the effectiveness of deep learning models. In contrast, AD datasets are more abundant, offering a potential avenue for knowledge transfer. However, LBD and AD data are typically collected from different sites using varied machines and protocols, resulting in a distinct domain shift. To effectively leverage AD data while mitigating domain shift, we propose a Transferability Aware Transformer (TAT) that adapts knowledge from AD to enhance LBD diagnosis. Our method utilizes structural connectivity (SC) derived from structural MRI as training data. Built on the attention mechanism, TAT assigns high weights to disease-transferable features while suppressing domain-specific ones, effectively reducing domain shift and improving diagnostic accuracy on limited LBD data. The experimental results demonstrate the effectiveness of TAT. Our work serves as the first to explore domain adaptation from AD to LBD study under data scarcity and domain shift scenarios, providing a promising framework for domain-adaptive diagnosis of rare diseases.},
}

@article {pmid41426277,
year = {2025},
author = {Figueira, JAV and Ramírez, A and Monteros, MAEL and Santiesteban, RV and Parra, IDC and Romero-Sacoto, L and Cucalón, MJP},
title = {Erratum to "Psychometric evaluation of the Alzheimer's Disease Knowledge Scale in Ecuadorian university students".},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251408943},
doi = {10.1177/25424823251408943},
pmid = {41426277},
issn = {2542-4823},
abstract = {[This corrects the article DOI: 10.1177/2331216519862987.].},
}

@article {pmid41426276,
year = {2025},
author = {Sun, W and Bi, H and Qi, Z and Hu, M and Wang, W},
title = {Status and trends of transcranial magnetic stimulation research in Alzheimer's disease: A bibliometric and visual analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407542},
pmid = {41426276},
issn = {2542-4823},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive dysfunction and is the most common cause of dementia. In recent years, transcranial magnetic stimulation (TMS) has been widely used in the treatment of AD and has achieved better therapeutic results. In this study, from the perspective of bibliometrics, we used VOSviewer and CiteSpace software to visualize and analyze the research progress of TMS in AD in terms of scientific knowledge mapping, and to systematically review the current status and trend of the global research on TMS in the treatment of AD, in order to provide references and guides for future research in this field. Our bibliometric analysis of 605 publications (1999-2024) reveals three pivotal findings: The Italy dominate TMS-AD research output; repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus and dorsolateral prefrontal cortex (DLPFC) shows consistent cognitive benefits; Emerging technologies are reshaping therapeutic precision. Intermittent theta burst stimulation as an emerging TMS stimulation mode is gradually becoming a future research direction. In the future, more attention will be paid to individualized therapeutic solutions and more precise stimulation with the help of neuronavigation to improve the therapeutic effect of TMS.},
}

@article {pmid41426275,
year = {2025},
author = {Zhang, R and Kuang, Y and Yuan, Z and Luo, N and Qiu, S},
title = {Cognitive decline and neuroimaging correlates in comorbid type 2 diabetes and depression: A systematic review.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407106},
pmid = {41426275},
issn = {2542-4823},
abstract = {Background: The comorbid state of diabetes and depression increases the risk of developing Alzheimer's disease compared to a single disease, but the relationship between cognitive decline and brain imaging changes in this state remains unclear. Objective: To systematically review the association between brain imaging changes and mild cognitive impairment or cognitive decline in this comorbid state. Methods: We searched four databases until April 15, 2025, combining keyword searches with MeSH terms and free words, and supplemented relevant studies with reference back. Observational studies were included to assess the relationship between brain imaging changes and cognitive decline in diabetes and depression comorbid states. The Newcastle-Ottawa Scale was used to assess the quality of the included observational studies. Results: Thirteen studies with a total of 1509 participants were finally included. Imaging methods included structural MRI, magnetization transport imaging, diffusion tensor imaging, and functional MRI. Frequently reported affected brain regions included the frontal lobe, limbic system, and basal ganglia regions. Compared to type 2 diabetes mellitus patients, the comorbid state showed more alterations in brain structure and function, and these were associated with executive function and attentional impairment in cognitive decline. The brain functional connectivity findings were inconsistent. Conclusions: The comorbid state exhibits characteristic brain imaging alterations and is associated with cognitive impairment, indicating potential relevance to the risk of developing mild cognitive impairment and dementia. Further longitudinal and multimodal studies with more rigorous and standardized experimental designs are warranted to validate and extend these findings.},
}

@article {pmid41425927,
year = {2025},
author = {Qin, R and Li, C and Yuan, X and Chen, Y},
title = {Microbiome-targeted Alzheimer's interventions via gut-brain axis.},
journal = {Frontiers in microbiology},
volume = {16},
number = {},
pages = {1729708},
pmid = {41425927},
issn = {1664-302X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options, underscoring the need for novel therapeutic targets. The gut-brain axis has emerged as a critical bidirectional communication system, with growing evidence establishing gut dysbiosis as a causal factor in AD pathogenesis. This dysbiosis, characterized by a reduction in beneficial microbes and an increase in pro-inflammatory taxa, compromises intestinal and blood-brain barrier integrity, promoting systemic inflammation and the translocation of neurotoxic agents like lipopolysaccharide (LPS). Consequently, the balance of key microbial metabolites is disrupted, reducing neuroprotective short-chain fatty acids (SCFAs) and indoles while elevating inflammatory mediators, which collectively exacerbate neuroinflammation, amyloid-β (Aβ) deposition, and tau pathology. This review evaluates promising interventions, including probiotics, anti-inflammatory diets, exercise, and phytochemicals that can restore microbial balance, enhance barrier function, and improve cognitive outcomes in preclinical and early clinical studies. However, clinical translation is hindered by an overreliance on animal models, short-term studies, and insufficient mechanistic insight. Future research must prioritize large-scale human trials, multi-omics integration to elucidate signaling pathways, and personalized approaches that account for host genetics and baseline microbiome composition to fully harness the therapeutic potential of the gut-brain axis for AD.},
}

@article {pmid41425914,
year = {2025},
author = {Steinmaurer, A and Breit, L and Stögmann, E and König, T},
title = {Peripheral CHI3L1 expression is associated with APOE ε4 status in early-onset Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1730319},
pmid = {41425914},
issn = {1663-4365},
abstract = {BACKGROUND: YKL-40 (CHI3L1) is a glycoprotein secreted by reactive astrocytes and peripheral immune cells, implicated in inflammation and tissue remodeling in Alzheimer's disease (AD). While elevated CHI3L1 levels have been observed in cerebrospinal fluid and plasma, its expression at the transcript level in peripheral blood - and modulation by genetic risk factors such as APOE ε4 - remains poorly understood.

METHODS: We analyzed peripheral blood CHI3L1 mRNA expression in a well-characterized cohort comprising individuals with biomarker-confirmed AD (n = 34), mild cognitive impairment (MCI; n = 31), and cognitively healthy controls (HC; n = 21). CHI3L1 expression levels were compared across diagnostic groups and stratified by APOE ε4 status, age at onset (early-onset < 65 years; late-onset ≥ 65), and sex. Correlations were examined between CHI3L1 and inflammatory gene transcripts (IL1B, TNF, MMP9, LRP1, and TREM2).

RESULTS: Peripheral CHI3L1 expression was elevated in individuals with early-onset AD (EOAD), particularly among APOE ε4 carriers (EOAD APOE ε4+, n = 13 vs. EOAD APOE ε4-, n = 8; p = 0.026). Stratified analyses revealed an exploratory association between CHI3L1 expression, APOE genotype, and sex, with the highest levels observed in female ε4 carriers with EOAD. Across diagnostic groups, CHI3L1 levels positively correlated with transcripts of IL1B, MMP9, and LRP1, with the strongest associations again in APOE ε4 + individuals. Notably, these effects were more pronounced in the MCI and AD groups than in healthy controls, indicating early immune activation in at-risk individuals.

CONCLUSION: Our exploratory findings indicate that peripheral CHI3L1 expression may reflect APOE ε4-linked immune activity, with a trend toward higher expression in EOAD and in female ε4 carriers. The observed genotype- and sex-dependent expression patterns indicate preliminary differences in peripheral immune activity that warrant replication in larger cohorts. Peripheral CHI3L1 may thus serve as a hypothesis-generating marker of genotype-linked inflammatory phenotypes rather than a validated biomarker.},
}

@article {pmid41425905,
year = {2025},
author = {Zhang, J and Lyu, Y and Yu, X and Zhang, L and Cao, C and Chen, T and Chen, M and Zhuang, Y and Liu, T and Zhu, D},
title = {CLASSIFFICATION OF MILD COGNITIVE IMPAIRMENT BASED ON DYNAMIC FUNCTIONAL CONNECTIVITY USING SPATIO-TEMPORAL TRANSFORMER.},
journal = {Proceedings. IEEE International Symposium on Biomedical Imaging},
volume = {2025},
number = {},
pages = {},
pmid = {41425905},
issn = {1945-7928},
abstract = {Dynamic functional connectivity (dFC) using resting-state functional magnetic resonance imaging (rs-fMRI) is an advanced technique for capturing the dynamic changes of neural activities, and can be very useful in the studies of brain diseases such as Alzheimer's disease (AD). Yet, existing studies have not fully leveraged the sequential information embedded within dFC that can potentially provide valuable information when identifying brain conditions. In this paper, we propose a novel framework that jointly learns the embedding of both spatial and temporal information within dFC based on the transformer architecture. Specifically, we first construct dFC networks from rs-fMRI data through a sliding window strategy. Then, we simultaneously employ a temporal block and a spatial block to capture higher-order representations of dynamic spatio-temporal dependencies, via mapping them into an efficient fused feature representation. To further enhance the robustness of this feature representations by reducing the dependency of labeled data, we also introduce a contrastive learning strategy to manipulate different brain states. Experimental results on 345 subjects with 570 scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) demonstrate the superiority of our proposed method for MCI (Mild Cognitive Impairment, the prodromal stage of AD) prediction, highlighting its potential for early identification of AD. The code is available at: https://github.com/Nancy-Zhang-0/MCI_dFC_STT.},
}

@article {pmid41425897,
year = {2025},
author = {Huang, J and Wang, S and Mok, VCT and Song, W and Ko, H and Zhang, Y},
title = {Integrating GLP-1 receptor agonists with anti-amyloid immunotherapy for Alzheimer's disease: a phased clinical roadmap.},
journal = {Life medicine},
volume = {4},
number = {6},
pages = {lnaf036},
pmid = {41425897},
issn = {2755-1733},
}

@article {pmid41425599,
year = {2025},
author = {Yi, Y and Jia, P and Xie, P and Peng, X and Zhu, X and Yin, S and Luo, Y and Deng, Y and Wan, L},
title = {Beyond oxidative stress: Ferroptosis as a novel orchestrator in neurodegenerative disorders.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1683876},
pmid = {41425599},
issn = {1664-3224},
mesh = {*Ferroptosis/drug effects ; Humans ; *Neurodegenerative Diseases/metabolism/etiology/drug therapy/pathology ; *Oxidative Stress ; Animals ; Iron/metabolism ; Lipid Peroxidation ; },
abstract = {Neurodegenerative diseases are a group of disorders characterized by progressive loss of neuronal function due to degenerative damage to neural cells. Ferroptosis, a newly identified form of regulated cell death, is pathologically defined by iron-dependent accumulation of lipid peroxides, mitochondrial shrinkage, and increased mitochondrial membrane density. Unlike apoptosis or necrosis, ferroptosis is driven by a combination of factors, including excessive lipid peroxidation, disruption of iron homeostasis, and depletion of antioxidant defenses such as glutathione (GSH) and glutathione peroxidase 4 (GPX4). The ferroptotic process engages multiple biological functions-such as iron metabolism, lipid metabolism, oxidative stress, mevalonate signaling, transsulfuration pathways, heat shock protein activation, glutamate/cystine transport, and GSH biosynthesis. While initial studies focused on its role in cancer, accumulating evidence now links ferroptosis to neurological disorders. Ferroptosis has been implicated in the pathophysiology of stroke, traumatic brain injury, and major neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Several small-molecule inhibitors-including ferrostatin-1, liproxstatin-1, and iron chelators such as deferoxamine (DFO)-have demonstrated efficacy in animal models by attenuating neuronal damage and improving behavioral outcomes through the suppression of ferroptosis. In addition, natural compounds have emerged as promising candidates for targeting ferroptosis due to their structural diversity, low toxicity, and multitarget regulatory properties. These agents offer potential leads for developing novel neuroprotective therapeutics. Neurodegenerative diseases remain a significant global health burden, with limited effective treatments available to date. Modulation of ferroptosis presents a new conceptual framework for therapeutic intervention, offering hope for disease-modifying strategies. This review summarizes recent advances in understanding the role of ferroptosis in neurodegenerative disease mechanisms, focusing on its contribution to pathological progression, molecular regulation, and therapeutic interventions. By integrating current findings, we aim to provide theoretical insights into novel pathogenic mechanisms and scientific guidance for the development of targeted therapies that modulate ferroptosis to slow or halt disease progression.},
}

*Ferroptosis/drug effects
Humans
*Neurodegenerative Diseases/metabolism/etiology/drug therapy/pathology
*Oxidative Stress
Animals
Iron/metabolism
Lipid Peroxidation

@article {pmid41425509,
year = {2025},
author = {Jenkins, MR and Fleming, VL and Schworer, EK and Dong, Y and Tudorascu, DL and Handen, BL and Hartley, SL},
title = {Role of leisure and sleep in promoting daily physical activity in adults with down syndrome.},
journal = {Health psychology and behavioral medicine},
volume = {13},
number = {1},
pages = {2521418},
pmid = {41425509},
issn = {2164-2850},
abstract = {Background: Adults with Down syndrome (DS) are at an elevated risk of chronic health conditions (e.g. obesity, Alzheimer's disease). Although physical activity can mitigate the effects of these conditions, adults with DS spend more time sedentary relative to the adult general population. This study examined how daily fluctuations in two lifestyle factors, sleep and leisure, affect physical activity in adults with DS. Method: For 7 days, a sample of adults with DS (N = 109) wore a GT9X ActiGraph accelerometer to collect movement and sleep data and completed a daily diary to record leisure engagement. Movement variables included time spent sedentary, in light physical activity, and in moderate-to-vigorous physical activity. Sleep variables included total sleep time (TST) and sleep efficiency (SE). Time spent in and total count of cognitively stimulating leisure (e.g. reading, experiential activities) and social leisure (e.g. visiting friends, attending club meetings) were based on 22 items from the Victoria Longitudinal Study activity questionnaire. Mixed linear models examined between - and within-person associations for sleep and physical activity, and leisure and physical activity. Models controlled for sociodemographics, day of week, and weekend (vs. weekday). Results: At the between-person level, more TST was associated with more time sedentary (ps < .05) and less physical activity (ps < .001). More SE was associated with less time sedentary (ps < .001) and more physical activity (ps < .05). At the within-person level, participants with more physical activity than typical predicted greater TST (and less SE) that night (ps < .01). More cognitively stimulating and social leisure were associated with more physical activity at the within-person level (ps < .05). Conclusions: Findings can inform health programs seeking to increase physical activity in adults with DS. Interventions should consider the function of sleep and leisure in everyday life for long-term sustainability of physical activity.},
}

@article {pmid41425321,
year = {2025},
author = {Pillai, VVS and Smeding, T and Meng, JX and Klenerman, D and Ruggeri, FS},
title = {Single-Oligomer Characterization of Tau Phosphorylation and Mechanical State.},
journal = {ACS measurement science au},
volume = {5},
number = {6},
pages = {951-962},
pmid = {41425321},
issn = {2694-250X},
abstract = {Post-translational modifications have emerged as a key biomolecular process in the onset of neurodegenerative disorders, such as the hyperphosphorylation of tau protein in Alzheimer's disease (AD). High levels of phosphorylation are related to tau malfunction, self-assembly into amyloids forming neurofibrillary tangles in the brain, and cellular toxicity. These molecular processes are also reflected in human biofluids, allowing us to use tau phosphorylation as a biomarker of the disease onset and progression. However, it is not yet clear what structural changes the tau protein undergoes upon phosphorylation and what the early self-assembly steps are that lead to the formation of the final amyloid species. This knowledge gap is related in large part to the experimental challenge in achieving a multiparametric physical-chemical characterization of nanoscale size and heterogeneous amyloid at the single-molecule level. Here, we employ high-resolution and advanced atomic force microscopy methods to study the effect of phosphorylation on the tau pathway of self-assembly and on the physical-chemical properties of the heterogeneous amyloid species formed, down to the single-oligomer level. We report the correlative analysis of single-oligomer structural and chemical properties and achieve, for the first time, the quantitative determination of their phosphorylation state. Our findings reveal that hyperphosphorylation results in the formation of smaller, stiffer, and more adhesive oligomers, which might be critical for their pathological role in AD. This nanoresolved information might be, in turn, useful to understand the early molecular mechanisms of disease, as well as to improve the detection of pathological tau species in biofluids as diagnostic biomarkers.},
}

@article {pmid41425260,
year = {2026},
author = {Lyu, Y and Zhang, J and Zhang, L and Ruan, W and Liu, T and Zhu, D},
title = {Oblique Genomics Mixture of Experts: Prediction of Brain Disorder With Aging-Related Changes of Brain's Structural Connectivity Under Genomic Influences.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15963},
number = {},
pages = {348-358},
pmid = {41425260},
abstract = {During the process of brain aging, the changes of white matter structural connectivity are closely correlated with the cognitive traits and brain function. Genes have strong controls over this transition of structural connectivity-altering, which influences brain health and may lead to severe dementia disease, e.g., Alzheimer's disease. In this work, we introduce a novel deep-learning diagram, an oblique genomics mixture of experts(OG-MoE), designed to address the prediction of brain disease diagnosis, with awareness of the structural connectivity changes over time, and coupled with the genomics influences. By integrating genomics features into the dynamic gating router system of MoE layers, the model specializes in representing the structural connectivity components in separate parameter spaces. We pretrained the model on the self-regression task of brain connectivity predictions and then implemented multi-task supervised learning on brain disorder predictions and brain aging prediction. Compared to traditional associations analysis, this work provided a new way of discovering the soft but intricate inter-play between brain connectome phenotypes and genomic traits. It revealed the significant divergence of this correlation between the normal brain aging process and neurodegeneration.},
}

@article {pmid41425086,
year = {2025},
author = {Sato, K and Niimi, Y and Ihara, R and Ikeuchi, T and Ishii, K and Ito, K and Iwata, A and Kasuga, K and Kato, T and Kowa, H and Nakase, T and Senda, M and Suzuki, K and Tomita, N and Tsukamoto, T and Yoshiyama, K and Iwatsubo, T},
title = {Immediate reactions to amyloid PET disclosure in Japanese older adults without dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70167},
pmid = {41425086},
issn = {2352-8737},
abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) has become increasingly important for detection of early Alzheimer's disease (AD) and eligibility for emerging disease-modifying therapies. While North American and European studies report limited short-term psychological harm following disclosure of amyloid status in asymptomatic individuals, evidence in non-North American and European contexts is scarce. We evaluated the immediate psychological impact of amyloid PET disclosure in a large Japanese cohort without dementia.

METHODS: We analyzed data from 630 cognitively unimpaired Clinical Dementia Rating global score (CDR-GS of 0, 70%) or mild cognitive impairment (CDR-GS of 0.5, 30%) participants 50-85 years of age enrolled in the Japanese Trial-Ready Cohort onsite study across seven centers between July 2020 and January 2024. Amyloid PET positivity was defined by visual read or Centiloid ≥12. Psychological outcomes-Future Time Perspective (FTP), and Concerns about AD-were assessed immediately before and after disclosure; Impact of Event Scale (IES) was also measured via telephone 1-3 days post-disclosure. Mixed-effects Poisson and linear regression models, adjusted for site, participant, and baseline covariates, evaluated the effects of PET positivity on post-disclosure outcomes.

RESULTS: Twenty-six percent of participants were PET positive. PET-positive individuals experienced greater distress (median IES 8 vs 3) compared with PET-negative peers, whereas FTP improved similarly irrespective of PET status. Concerns about AD increased modestly in PET-positive participants (+4.8%) but decreased in PET-negative individuals (-5.5%; interaction p < 0.001). Female sex and higher baseline depression and anxiety predicted larger distress responses.

DISCUSSION: Consistent with North American and European findings, amyloid PET disclosure in this Japanese cohort was generally well-tolerated, eliciting only modest increases in distress and concerns among PET-positive individuals. These results support the feasibility and ethical acceptability of structured disclosure protocols across cultural settings and highlight the importance of tailored counseling for at-risk subgroups.

HIGHLIGHTS: Immediate impact of amyloid disclosure in a Japanese cohort without dementia.Amyloid-positive individuals had higher distress (Impact of Event Scale) after disclosure.Future Time Perspective improved similarly regardless of amyloid positron emission tomography (PET) results.Concerns about Alzheimer's disease slightly rose in PET-positive participants.Female sex and higher baseline depression and anxiety predicted larger distress.},
}

@article {pmid41425084,
year = {2025},
author = {Pérez-Martínez, DA and Jarry, AC and Martino, G and Pesce, G and Pieniazek, I and Presto, J and Miernik, P and Casciano, R and Frederiksen, KS},
title = {Uncovering barriers to early diagnosis of Alzheimer's disease: a European perspective.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70178},
pmid = {41425084},
issn = {2352-8737},
abstract = {INTRODUCTION: Timely and accurate diagnosis of early Alzheimer's disease (AD) is critical to maximizing the potential benefits of disease-modifying therapies; however, it remains a challenge in clinical practice.

METHODS: A double-blind survey was conducted among general practitioners (GPs; n = 52) and AD specialists (neurologists, psychiatrists, geriatricians, and others; n = 75) across five European countries to evaluate healthcare practitioners' (HCPs) perceptions of diagnosing AD. Data from all countries were pooled and presented overall.

RESULTS: GPs are usually the first point of contact for patients with mild cognitive impairment (MCI)/AD. Only 30% of patients received a formal diagnosis of AD during the MCI stage, and it took patients 15.2 months from symptom onset to their first primary care visit. The most common challenges identified by HCPs were referral times, lack of effective treatment, and resource and time constraints.

DISCUSSION: Systemic reforms are required to remove barriers in early AD diagnosis, including tailored training and coordinated care between GPs and AD specialists.

HIGHLIGHTS: Timely diagnosis of eAD remains a major challenge in clinical practice.Only one-third of patients received a formal diagnosis of AD during the MCI stage.It took patients 15.2 months from symptom onset to first primary care visit.Key diagnostic barriers include referral delays and lack of effective treatments.Addressing these issues may improve eAD diagnosis and timely intervention.},
}

@article {pmid41425078,
year = {2025},
author = {Xu, W and Ren, B and Zhang, Z and Chen, C and Xu, T and Liu, S and Ma, C and Wang, X and Wang, Q and Cheng, F},
title = {Correction: Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1752611},
doi = {10.3389/fnins.2025.1752611},
pmid = {41425078},
issn = {1662-4548},
abstract = {[This corrects the article DOI: 10.3389/fnins.2022.943400.].},
}

@article {pmid41425077,
year = {2025},
author = {Mongan, KL and Sharma, TP},
title = {Neuritin: a multifaceted neuroprotective factor with emerging applications for neurodegeneration.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1698598},
pmid = {41425077},
issn = {1662-4548},
abstract = {Neuritin is a conserved, activity-regulated gene encoding a glycosylphosphatidylinositol-anchored protein, crucial for neural development, synaptic plasticity, and neuroprotection. Identified via activity-dependent gene screening in the rat hippocampus, neuritin promotes neurite outgrowth, dendritic arborization, and synaptic maturation with neural activity. In this review, we summarize recent findings regarding neuritin's signaling pathways, neuroprotective, neuroregenerative, and neuromodulatory properties, with a focus on its therapeutic potential to counter neurodegeneration in various conditions such as glaucoma, Alzheimer's disease, stroke, diabetic neuropathy, and neuropsychiatric disorders. Additionally, recent studies reveal roles in immunoregulation, angiogenesis, and cancer biology, highlighting neuritin as a versatile signaling molecule with broad therapeutic implications.},
}

@article {pmid41425072,
year = {2025},
author = {Gatto, RG and Gakh, O and Wilkins, JM and Carlos, AF and Youssef, H and Guo, Y and Whitwell, JL and Josephs, KA and Lucchinetti, CF},
title = {Fourier transform infrared spectroscopy detects distinct TAR DNA-binding protein 43 signatures in frontotemporal lobar degeneration.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1649433},
pmid = {41425072},
issn = {1662-4548},
abstract = {BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of cognitive impairment in young adults. A major pathological subtype of FTLD is characterized by positive expression of TAR DNA Binding Protein 43 (TDP-43), referred to as FTLD[TDP]. However, techniques that can be utilized to interrogate and distinguish between various subtypes of FTLD are limited. Herein, we evaluated the potential of Fourier transform infrared (FTIR) spectroscopy to inform on the biomolecular changes in FTLD and to discriminate this disease from other non-FTLD cases.

METHODS: Histopathologically confirmed cases from FTLD[TDP] and Alzheimer's disease (AD) autopsy cases were evaluated using FTIR spectroscopy. Formalin-fixed paraffin-embedded (FFPE) brain tissue sections from the superior and medial temporal lobes were obtained from a single control case, an AD case, an FTLD[TDP] case, and a comorbid FTLD[TDP] case that presented with AD pathology (tau and β-amyloid; FTLD[TDP] + AD). All samples were immunostained for pathological forms of tau, β-amyloid, and TDP-43. Myelin was assessed by proteolipid protein staining. Consecutive tissue sections were scanned by FTIR spectroscopy. Spectral maps were manually segmented, matching ten grey matter (GM) and ten white matter (WM) subregions per case for analysis. Peak-area ratios from lipid and amide functional groups as detected by FTIR spectroscopy were quantified and compared.

RESULTS: Relative to the control tissue, both FTLD cases and AD showed increased ratios of amide I/II, α-helix/unordered proteins, α-helix/phosphorylated proteins, and olefinic/lipid content in GM and WM. The α-helix/unordered ratio was significantly different between FTLD cases and AD, while α-helix/unordered and α-helix/phosphorylated ratios differed significantly between FTLD[TDP] and FTLD[TDP] + AD. Across all cases and brain subregions, FTIR spectroscopy-derived amide I/II, olefinic/lipid, and carboxyl/lipid ratios significantly correlated positively with TDP-43 and tau immunoreactivity (p-value < 0.05).

CONCLUSION: Fourier transform infrared spectroscopy of FFPE brain tissue sections from FTLD[TDP] and AD captures disease-specific changes in the composition of proteins, lipids, and secondary structures. These findings suggest that FTIR spectroscopy can serve as a rapid and cost-effective tool for mapping and quantitating biomolecular alterations in FTLD.},
}

@article {pmid41425066,
year = {2025},
author = {Ohki, T and Kitamura, K and Tokutake, K and Saeki, S and Yamamoto, M and Takasu, M and Hirata, H},
title = {Depletion of CD169[+] border-associated macrophages induces Parkinson's disease-like behavior.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1688394},
pmid = {41425066},
issn = {1662-4548},
abstract = {Parkinson's disease (PD) and Alzheimer's disease (AD) present with complex behavioral symptoms that can arise in the absence of overt structural brain damage. Recent evidence suggests that border-associated macrophages (BAMs) located at the brain's interfaces regulate central nervous system function, yet the specific roles of distinct BAM subsets remain largely undefined. By reanalyzing single-nucleus RNA sequencing data from postmortem PD brains, we identified a BAM subset expressing CD169 that was significantly reduced in patients compared with controls. To examine their function, we employed CD169-DTR mice to selectively ablate CD169[+] BAMs and evaluated behavioral and histological changes. Depletion of CD169[+] BAMs induced tremors, abnormal hindlimb reflexes, and heightened anxiety-like behavior without dopaminergic neuron loss. Histological analysis revealed a pronounced reduction of mitral and tufted cells in the olfactory bulb, indicating disruption of olfactory-limbic circuitry. These findings demonstrate that CD169[+] BAMs are critical for maintaining neural network stability and motor function, and that their loss can elicit PD-like phenotypes in the absence of classical dopaminergic neurodegeneration. This work establishes a novel mouse model linking brain-border immune cell dysfunction to Parkinsonian pathology and highlights a neuroimmune mechanism that may contribute to the onset of PD-like disorders.},
}

@article {pmid41424971,
year = {2025},
author = {Zhao, J and Wang, X and Li, B},
title = {The Bidirectional Mechanism of Uric Acid Levels on Alzheimer's Disease: A Narrative Review.},
journal = {International journal of general medicine},
volume = {18},
number = {},
pages = {7639-7651},
pmid = {41424971},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD) is a central nervous system disorder marked by the extracellular accumulation of β-amyloid (Aβ) plaques in the cerebral cortex and the intracellular aggregation of hyperphosphorylated tau protein, manifesting as progressive cognitive decline and neurodegeneration. The pathological mechanisms of AD are intricate, in clinical treatment, cholinesterase inhibitors have been widely used for many years as symptomatic therapy, alleviating symptoms by improving neurotransmitter levels, but they cannot halt disease progression. Anti-Aβ monoclonal antibodies belong to disease-modifying therapies, although they have achieved breakthrough advances in recent years, strict monitoring requirements must be followed. In recent years, numerous studies have revealed a "U-shaped" association between uric acid (UA) levels and AD risk, along with population heterogeneity. Furthermore, fluctuations in UA levels exert a "bidirectional effect" on AD. At physiological concentrations, UA may confer neuroprotective benefits through antioxidant activity, inhibition of neuroinflammation, preservation of the blood-brain barrier (BBB), regulation of autophagy, and promotion of the clearance of Aβ and tau proteins. Conversely, abnormal UA levels may accelerate AD progression by inducing oxidative stress, activating inflammatory responses, and compromising the BBB. We conducted a comprehensive literature review across multiple medical databases, including PubMed, Embase, Cochrane Library, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI), and Wanfang Data. The selected articles underwent critical evaluation, summarization, and incorporation into this review to highlight research achievements in this domain. This narrative review summarizes current pharmacological treatments for AD and UA, encompassing traditional Chinese medicine (TCM) monomers, compounds, and Western medications. It also thoroughly explores and elucidates the complex mechanism underlying the "bidirectional effect" of UA levels and metabolic pathways on AD, offering insights and theoretical support for future AD drug development.},
}

@article {pmid41424816,
year = {2025},
author = {Wang, Y and Guiler, W and Patel, A and Pepper, S and Walpitage, N and Ratnayake, I and Honea, R and Mudaranthakam, DP},
title = {Predicting dementia risk using neuroimaging and cognitive assessment.},
journal = {JAR life},
volume = {14},
number = {},
pages = {100040},
pmid = {41424816},
issn = {2534-773X},
abstract = {INTRODUCTION: Dementia affects over 55 million people globally, with numbers expected to double in the coming decades. Early detection is critical, yet traditional risk assessments relying on age, family history, and basic cognitive tests often fall short. This study explores whether combining structural brain imaging with brief cognitive assessments can more accurately predict dementia risk.

METHOD: Using data from 312 older adults enrolled in the KU Alzheimer's Disease Center cohort, researchers evaluated two modeling approaches: one based on a single clinic visit and another using longitudinal data across multiple visits. Participants underwent cognitive testing and MRI scans, including measures of hippocampal volume, gray matter, and Alzheimer's disease signature regions. Depressive symptoms were also assessed using the Geriatric Depression Scale (GDS).

RESULTS: Results showed that models incorporating neuroimaging significantly outperformed those using demographics or cognitive scores alone. The best-performing model combined imaging and cognitive data, achieving 77.6% accuracy in predicting dementia status. Longitudinal models further improved prediction by capturing changes over time, with imaging features contributing most to explained variance. Key predictors included reduced hippocampal volume, lower gray matter, and higher GDS scores. These findings align with known patterns of neurodegeneration and suggest that depression may interact with brain changes to influence dementia risk.

CONCLUSION: Importantly, the study demonstrates that a compact, multimodal approaching standard MRI scans with brief cognitive tests-can generate individualized risk profiles suitable for clinical use. This method offers a scalable path to early intervention, trial enrollment, and personalized care planning. Future work will focus on validating these models in more diverse populations and integrating fluid biomarkers to enhance precision. Ultimately, this research supports the development of practical tools for forecasting dementia risk and advancing preventive strategies in aging populations.},
}

@article {pmid41424797,
year = {2025},
author = {Yang, H and Wang, Y and Xu, Y and Wang, C},
title = {CX3CR1: a potential microglia-specific PET imaging target in Alzheimer's and Parkinson's diseases.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1678159},
pmid = {41424797},
issn = {1663-9812},
abstract = {Microglia are the resident immune cells of the central nervous system (CNS), playing a crucial role in maintaining brain homeostasis and mediating neuroimmune responses. The chemokine receptor CX3CR1, predominantly expressed on microglia, regulates microglial function via interactions with its neuronal ligand CX3CL1. The CX3CR1-CX3CL1 signaling exhibits complex, context-dependent roles in neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD) animal models, CX3CR1 deficiency shows paradoxical outcomes, attenuating or exacerbating amyloid-β (Aβ) and tau pathologies in AD, while consistently worsening α-synuclein-induced neurodegeneration in PD. Although CX3CR1 emerges as a promising therapeutic and diagnostic target, its complex role in microglial dynamics remains incompletely understood. Positron emission tomography (PET) imaging provides a powerful, noninvasive method for investigating biological processes in vivo. There is an urgent need to develop and validate new PET tracers targeting microglial CX3CR1 in the CNS, further offering new opportunities for the diagnosis and treatment of neuroinflammation-associated neurodegenerative diseases.},
}

@article {pmid41424796,
year = {2025},
author = {Pirozhkov, SV and Vukolova, MN and Bulgakova, VV and Lutokhina, YA and Bolevich, SB and Sobolevsky, AI and Yelshanskaya, MV},
title = {Endothelium glutamate receptors in brain pathology.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1709274},
pmid = {41424796},
issn = {1663-9812},
abstract = {The endothelium in brain microcirculation functions not only as a barrier but also as a signal transduction component within a system that regulates multiple vascular processes, including muscle tone, permeability, and structural integrity. The control of local blood flow is vital to ensure adequate oxygen and nutrient supply, efficient removal of catabolic waste, and the maintenance of proper brain cell function. The role of endothelial glutamate receptors in brain pathology is an emerging area of research, particularly important for understanding how these receptors contribute to neurological diseases and disorders. Endothelial cells (ECs), which are considered active players in maintaining brain homeostasis, express glutamate receptors on their surface. Activation of these receptors can trigger a cascade of signaling events, including synthesis of nitric oxide (NO) and proinflammatory molecules. N-Methyl-D-Aspartate receptors (NMDARs) play a significant role in functional hyperemia, also known as neurovascular coupling (NVC), which is essential for maintaining the energy balance in brain cells. Growing evidence suggests that disturbance of this balance is implicated in several neurological diseases, such as Alzheimer's disease, stroke, and traumatic brain injury (TBI), where endothelial dysfunction may impair blood flow regulation, contributing to further neuronal damage and cognitive decline. This review focuses on the glutamate receptor-mediated alterations in endothelial permeability and the prevention of the brain pathology through direct modulation of these receptors. Notably, the metabotropic glutamate receptor mGluR1, along with NMDARs, may cause deleterious effects in brain ischemia, as their activation increases the permeability of the vessel wall. Stimulation of NMDARs may also lead to ferroptosis in ECs. EC dysfunction results in significant blood-brain barrier (BBB) disruption, allowing infiltration by inflammatory cells and the accumulation in brain of pathological proteins, such as amyloid-beta (Aβ) or autoantibodies. This contributes to neuronal dystrophy and apoptosis, as seen in Alzheimer's disease and autoimmune encephalopathy. Activated ECs generate proinflammatory mediators that attract leukocytes and sustain the neuroinflammatory response. Infiltrating peripheral white blood cells are key contributors to inflammatory damage following TBI. Regulation of ECs through glutamate receptors therefore represents a promising therapeutic strategy for treatment of neurodegenerative diseases, as well as ischemic and traumatic brain injuries.},
}

@article {pmid41424643,
year = {2026},
author = {Chen, T and Chen, M and Zhang, J and Zhuang, Y and Cao, C and Yu, X and Lyu, Y and Zhang, L and Su, L and Liu, T and Zhu, D},
title = {A Unified Continuous Staging Framework for Alzheimer's Disease and Lewy Body Dementia via Hierarchical Anatomical Features.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15962},
number = {},
pages = {13-23},
pmid = {41424643},
abstract = {Alzheimer's Disease (AD) and Lewy Body Dementia (LBD) often exhibit overlapping pathologies, leading to common symptoms that make diagnosis challenging and protracted in clinical settings. While many studies achieve promising accuracy in identifying AD and LBD at earlier stages, they often focus on discrete classification rather than capturing the gradual nature of disease progression. Since dementia develops progressively, understanding the continuous trajectory of dementia is crucial, as it allows us to uncover hidden patterns in cognitive decline and provides critical insights into the underlying mechanisms of disease progression. To address this gap, we propose a novel multi-scale learning framework that leverages hierarchical anatomical features to model the continuous relationships across various neurodegenerative conditions, including Mild Cognitive Impairment, AD, and LBD. Our approach employs the proposed hierarchical graph embedding fusion technique, integrating anatomical features, cortical folding patterns, and structural connectivity at multiple scales. This integration captures both fine-grained and coarse anatomical details, enabling the identification of subtle patterns that enhance differentiation between dementia types. Additionally, our framework projects each subject onto continuous tree structures, providing intuitive visualizations of disease trajectories and offering a more interpretable way to track cognitive decline. To validate our approach, we conduct extensive experiments on our in-house dataset of 308 subjects spanning multiple groups. Our results demonstrate that the proposed tree-based model effectively represents dementia progression, achieves promising performance in intricate classification task of AD and LBD, and highlights discriminative brain regions that contribute to the differentiation between dementia types. Our code is available at https://github.com/tongchen2010/haff.},
}

@article {pmid41424622,
year = {2025},
author = {Scher, CJ and Anderson, K and Zagorski, W and Siamdoust, S and Finik, J and Sadarangani, T},
title = {Identifying Person-Centered Outcome Measures for Use in Adult Day Services: An E-Delphi Consensus Study.},
journal = {Sage open aging},
volume = {11},
number = {},
pages = {30495334251408570},
pmid = {41424622},
issn = {3049-5334},
abstract = {Researchers and advocates recognize that adult day services (ADS) play a key role in delivering person-centered care to individuals living with Alzheimer's Disease and related dementias (ADRD). However, few ADS centers are routinely measuring person-centered outcomes, thereby limiting our ability to understand the impact of ADS on these key indicators of well-being. Guided by Kitwood's framework of person-centered dementia care, this study aimed to identify valid, reliable, and practical person-centered outcome measures that reflect ADRD quality-of-life domains. Twenty-two ADS practitioners and researchers (N = 22) participated in a two-round e-Delphi review to evaluate 10 potential outcome measures across four person-centered domains: meaning and purpose; engagement; social networks; and sense of belonging. Based upon scores on select characteristics in Round 1 of the e-Delphi review (e.g., ease of administration, relevance to population), consensus was reached in Round 2 (66.67% supermajority) on the following measures: the PROMIS Meaning and Purpose in Life Scale (76%); the Friendship Scale (76%); and the General Belongingness Scale (67%). Panelists could not reach consensus on the Life Engagement Test (52%) and the Engagement in Meaningful Activities Scale (48%), so both were retained for future evaluation. The scales identified in this e-Delphi review will now be incorporated into real-world data collection beta-testing to evaluate feasibility, practicality and impact of ADS on these person-centered outcomes.},
}

@article {pmid41424575,
year = {2026},
author = {Sharma, A and Sathiyanarayanan, L and Arulmozhi, S},
title = {Investigating the therapeutic potential of pinocembrin in Alzheimer's disease: insights from network pharmacology and molecular docking.},
journal = {In silico pharmacology},
volume = {14},
number = {1},
pages = {7},
pmid = {41424575},
issn = {2193-9616},
abstract = {The complicated neurodegenerative disease known as Alzheimer's disease (AD) is typified by neural malfunction, cognitive impairment, and gradual memory loss. Multi-target treatment approaches are desperately needed since AD etiology is complicated. Using network pharmacology, molecular docking, and in vitro experimental validation, this study explores the therapeutic potential of pinocembrin, a flavonoid recognized for its neuroprotective, antioxidant, and anti-inflammatory qualities. Network pharmacology study revealed nine important AD-associated targets of Pinocembrin, which are involved in neurotransmitter modulation, oxidative stress response, and neuronal protection. These targets include CA2, CYP1B1, CYP19A1, DPP4, ESR1, ESR2, HSP90AB1, MAOB, and SHBG. The relationship of these targets with important networks linked to AD, including PI3K-Akt signaling, estrogen signaling pathways, and neuroactive ligand-receptor interaction, was further validated by Gene Ontology (GO) and KEGG pathway enrichment analysis. According to ADMET study, Pinocembrin has good pharmacokinetic characteristics, such as low anticipated toxicity, intermediate blood-brain barrier permeability, and high gastrointestinal absorption. Strong and consistent binding affinities were shown by molecular docking studies, especially with CYP1B1 (-8.1 kcal/mol), DPP4 (-7.3 kcal/mol), and CA2 (-7.6 kcal/mol), indicating possible inhibitory effects on these targets. The compound's medicinal property was further supported by in vitro validation. Pinocembrin's safety profile was validated by the MTT assay, which demonstrated high cell survival (>90%) in PC12 neuronal cells at all tested dosages. In comparison to donepezil as a reference, pinocembrin also demonstrated moderate acetylcholinesterase (AChE) inhibitory action, with an IC50 of 50 µM. Furthermore, DPPH, ABTS, and H2O2 scavenging assays were used to indicate antioxidant activity. The IC50 values for these assays were 150 µg/mL, 78.6 µg/mL, respectively, and total reducing power was 46.5 mg EAA/g. All of these results point to the possibility of pinocembrin as a multi-target therapy drug for Alzheimer's disease. To verify its effectiveness and refine its pharmacological profile for therapeutic use, more in vivo research and molecular dynamics simulations are necessary.},
}

@article {pmid41424454,
year = {2025},
author = {Egba, SI and Edeh, MO and Uchenna, NO and Igwe, MC and Ogbodo, JO},
title = {Nasal Delivery of Phytochemicals Using Nanocarriers: Therapeutic Opportunities and Translational Challenges.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {15017-15041},
pmid = {41424454},
issn = {1178-2013},
mesh = {Humans ; *Phytochemicals/administration & dosage/pharmacokinetics/chemistry/therapeutic use ; Administration, Intranasal ; Animals ; *Nanoparticles/chemistry ; Nasal Mucosa/metabolism ; *Drug Carriers/chemistry ; Curcumin/administration & dosage/pharmacokinetics ; *Nanoparticle Drug Delivery System/chemistry ; *Drug Delivery Systems/methods ; Biological Availability ; Nanotechnology ; },
abstract = {The integration of phytochemicals with nanotechnology represents a promising approach to enhance nasal drug delivery, improving therapeutic efficacy and targeted brain delivery. This review explores recent advances in phytochemical-nanotechnology formulations and their applications in managing neurodegenerative diseases, respiratory disorders, and cancers. Phytochemicals such as curcumin, resveratrol, and quercetin exhibit potent pharmacological properties but suffer from poor solubility and limited bioavailability. Nanotechnology-based systems-including nanoparticles, liposomes, and nanoemulsions-overcome these drawbacks by improving stability, absorption, and controlled release. However, challenges such as nasal mucosa irritation, formulation complexity, regulatory barriers, and scalability still impede clinical translation. Notably, encapsulation of curcumin in polymeric nanoparticles has been shown to enhance its solubility and bioavailability, producing improved therapeutic outcomes in preclinical Alzheimer's models. Overall, this review underscores the synergistic potential of phytochemicals and nanotechnology in developing innovative nasal delivery platforms capable of providing targeted, effective, and patient-friendly treatment options for a range of medical conditions.},
}

Humans
*Phytochemicals/administration & dosage/pharmacokinetics/chemistry/therapeutic use
Administration, Intranasal
Animals
*Nanoparticles/chemistry
Nasal Mucosa/metabolism
*Drug Carriers/chemistry
Curcumin/administration & dosage/pharmacokinetics
*Nanoparticle Drug Delivery System/chemistry
*Drug Delivery Systems/methods
Biological Availability
Nanotechnology

@article {pmid41424314,
year = {2025},
author = {Barron, AE and Lin, JS and Ryder, MI and Bergman, P},
title = {The dysregulation of innate immunity by Porphyromonas gingivalis in the etiology of Alzheimer's disease.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70060},
pmid = {41424314},
issn = {1365-2796},
support = {1DP1OD029517/NH/NIH HHS/United States ; //SENS Research Foundation/ ; //Cisco University Research Program Fund/ ; //Stanford University's Discovery Innovation Fund/ ; //Truchard Foundation/ ; },
abstract = {The etiology of Alzheimer's disease (AD) remains under active debate. In this perspective, we explore the hypothesis that a primarily infection-caused chronic dysregulation and weakening of human innate immunity via the underexpression, degradation, and inactivation of innate immune proteins necessary for direct antimicrobial effects and regulation of host defense and autophagy could lead to AD. Key evidence relates to the fact that important innate immune proteins such as LL-37-which can bind Aβ and block amyloid formation-as well as Apolipoprotein E, antiviral interferons, and TNF-α can be degraded and deactivated by enzymes produced by the common oral anaerobic pathogen Porphyromonas gingivalis (Pg). Pg produces numerous virulence factors; of particular importance for AD are Pg's gingipain cysteine proteases. Deleterious effects of chronic Pg infection and gingipains include a systemic downregulation and paralysis of the interferon response, particularly the antiviral interferon-lambda response, which enables replication of endemic herpesviruses. The result is a chronic, low-level viral infectious assault on gut, nerves, and brain causing the production of Aβ antimicrobial peptides, accumulation of Aβ plaques, phosphorylation of Tau, progressive neuroinflammation, and neurodegeneration. The resultant innate immune system dysregulation, as an AD etiology, ties together the well-known amyloid cascade hypothesis and the infectious theory of AD into a unified explanation of the pathology and cause of AD. If this theory holds true, it suggests preventative approaches: (1) test for and eradicate Pg from oral flora, and/or directly deactivate the gingipains; and (2) reduce Herpesvirus exacerbations by the use of antiviral drugs and/or vaccines (e.g., Bacillus Calmette-Guérin).},
}

@article {pmid41424310,
year = {2025},
author = {Nwakasi, C and Nweke, C},
title = {Does Grit Moderate the Association Between Health and Subjective Cognitive Decline Among Middle-Age and Older Nigerians Living With HIV?.},
journal = {Research on aging},
volume = {},
number = {},
pages = {1640275251409700},
doi = {10.1177/01640275251409700},
pmid = {41424310},
issn = {1552-7573},
abstract = {This study investigated the effects of subjective health status and grit (a personality trait) on subjective cognitive decline (SCD) in adult people living with HIV (PLWH) in Nigeria, as previous research suggested that these factors may predict cognitive functioning. A total of 150 PLWH (Mage = 55.19) completed paper-based questionnaires at a teaching hospital in Nigeria. Multiple linear regression showed that better subjective health status was negatively associated with SCD. Grit-components (consistency of interest and perseverance of effort) moderated the association between subjective health and SCD. Higher consistency of interest strengthened the protective effect of positive subjective health on SCD, while low perseverance of effort amplified this protective association. The role of personality traits on health and cognitive decline in adults living with HIV in Nigeria warrants more studies to help inform cognitive health intervention programs for middle-aged and older adults with HIV.},
}

@article {pmid41424289,
year = {2025},
author = {Bartolić, M and Bosak, A},
title = {BACE1: Biological Functions and Involvement in the Pathophysiology of Alzheimer's Disease and Other Neurological Disorders.},
journal = {BioFactors (Oxford, England)},
volume = {51},
number = {6},
pages = {e70071},
doi = {10.1002/biof.70071},
pmid = {41424289},
issn = {1872-8081},
support = {HrZZ-IP-2020-02-9343//Hrvatska Zaklada za Znanost/ ; KK.01.1.1.02.0007//European Regional Development Fund/ ; BioMolTox//Next Generation EU/ ; },
mesh = {Humans ; *Amyloid Precursor Protein Secretases/metabolism/genetics/antagonists & inhibitors ; *Alzheimer Disease/genetics/enzymology/pathology/physiopathology/drug therapy/metabolism ; *Aspartic Acid Endopeptidases/genetics/metabolism/antagonists & inhibitors ; Animals ; Amyloid beta-Peptides/metabolism/genetics ; *Nervous System Diseases/genetics ; },
abstract = {β-Secretase (BACE1) is the key enzyme responsible for generating amyloid-β (Aβ) peptides, whose aggregation and plaque formation are major hallmarks of Alzheimer's disease (AD). Owing to its central role in Aβ production, BACE1 has become a widely studied therapeutic target in the search for disease-modifying treatments for AD. However, evidence of numerous physiological substrates indicates that BACE1 participates in diverse biological processes, from the development and maintenance of the nervous system through control of neuronal differentiation and axonal myelination to immune response mediation by promotion of cell-cell interactions. These functions prompted research into the enzyme's role in other neurodegenerative disorders such as Parkinson's disease, Niemann-Pick type C disease, and Creutzfeldt-Jakob disease, whose pathophysiology includes aberrant protein aggregation and/or cognitive decline leading to dementia as seen in AD, as well as in neurological conditions such as schizophrenia and epilepsy, which are characterized by impaired neurotransmission and seizures, respectively. This review summarizes current knowledge on BACE1 substrates involved in nervous system regulation and immune response, highlights its roles at the molecular and genetic levels across aforementioned disorders, and outlines outcomes from clinical trials of BACE1 inhibitors.},
}

Humans
*Amyloid Precursor Protein Secretases/metabolism/genetics/antagonists & inhibitors
*Alzheimer Disease/genetics/enzymology/pathology/physiopathology/drug therapy/metabolism
*Aspartic Acid Endopeptidases/genetics/metabolism/antagonists & inhibitors
Animals
Amyloid beta-Peptides/metabolism/genetics
*Nervous System Diseases/genetics

@article {pmid41424240,
year = {2025},
author = {Corrêa, MI and Siqueira, IOC and Souza, S and Bruera, E and Drummond-Lage, AP},
title = {Expanding the Boundaries of Palliative Care: Diseases of the Nervous System and Survival Prognosis in Home-Based Programs.},
journal = {The American journal of hospice & palliative care},
volume = {},
number = {},
pages = {10499091251411396},
doi = {10.1177/10499091251411396},
pmid = {41424240},
issn = {1938-2715},
abstract = {BackgroundHome-based palliative care (HBPC) is increasingly recognized as an essential strategy for managing patients with non-oncologic and life-limiting conditions. However, prognostic factors influencing survival in this population remain underexplored.ObjectivesTo evaluate the prognostic impact of the Palliative Performance Scale (PPS) and comorbidities on survival among non-oncologic patients receiving HBPC in Brazil.MethodsA retrospective cohort study was conducted, including 248 non-cancer patients enrolled in a publicly funded HBPC program in Caratinga, Brazil. Sociodemographic data, comorbidities, and PPS scores at admission were extracted from medical records. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards models, with model discrimination assessed by Harrell's C-index.ResultsDiseases of the nervous system (DNS) were the most frequent referral diagnoses (32.3%). Median survival was 78 days (95% CI: 46.0-98.0) for patients with DNS and 34 days (95% CI: 19.0-50.0) for those without (P = .014). In multivariate analysis, DNS (P = .0157) emerged as the strongest predictor of survival, whereas PPS at admission (P = .0629) was a weak predictor (model C-index = 0.60). Patients with Alzheimer's disease and related dementias demonstrated longer survival than those with other DNS or no DNS diagnoses (P < .014). Higher PPS scores were generally associated with longer survival, although predictive accuracy was limited.ConclusionsDNS conditions, particularly dementia, were associated with longer survival among non-oncologic HBPC patients. While PPS remains a useful tool, its discriminatory capacity was modest, underscoring the need for refined prognostic models in non-oncologic palliative care.},
}

@article {pmid41424213,
year = {2025},
author = {Perbet, R and Wiedmer, AE and Quitot, N and Bhavsar, H and Perrin, F and Gaona, A and Mate de Gerando, A and Gomez Isla, T and Frosch, MP and Das, S and Hyman, BT},
title = {Seed-competent tau oligomers' activity correlates with the rate of progression in sporadic Alzheimer's disease patients.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400798},
doi = {10.1177/13872877251400798},
pmid = {41424213},
issn = {1875-8908},
abstract = {BackgroundWhile it is clear that abnormal tau structures contribute to the clinical symptoms of Alzheimer's disease (AD), which of the many structural entities found in the AD brain underlie templated misfolding and progression of disease remains uncertain. However, their identification is crucial to target for more effective diagnostics and therapeutics.ObjectiveTo identify the most pathogenic tau species driving Alzheimer's disease progression.MethodsWe compared the biochemical and templated seeding properties of tau isolated from post-mortem brain tissue of patients with varying rates of clinical progression, categorized as rapid, slow, or typical, based on longitudinal decline in cognitive performance assessed by Clinical Dementia Rating Sum of Boxes scores. Sarkosyl-insoluble filamentous preparations were compared to aqueous-soluble preparations. Focusing on the aqueous-soluble proteins, we further characterized the most efficient seeding species using size-exclusion chromatography and quantifying oligomers using dot blot under both native and denaturing conditions.ResultsA rapidly progressive course corresponded to enhanced tau seeding behavior, with the strongest correlations observed in the aqueous-soluble fraction. Using size-exclusion chromatography, we demonstrated that the seeding activity of fractions containing oligomers, correlated most strongly with disease aggressiveness. Moreover, quantifying oligomers using dot blot under both native and denaturing conditions, we found that rapid progressors had higher levels of oligomeric tau, which was also more stable.ConclusionsAqueous-soluble oligomeric tau species may be an important driver of AD progression. Substantial heterogeneity was observed even in purified samples, suggesting that variations in tau conformers among patients may contribute to differences in clinical disease progression.},
}

@article {pmid41424206,
year = {2025},
author = {Royall, DR and Palmer, RF and , },
title = {Affliction class moderates the impact of neurodegeneration: Implications for A/T/N.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401200},
doi = {10.1177/13872877251401200},
pmid = {41424206},
issn = {1875-8908},
abstract = {BackgroundBiomarkers of amyloidopathy/tauopathy/neurodegeneration (A/T/N) are being invoked as evidence of Alzheimer's disease (AD). However, some individuals are resilient against their effects. We have developed a psychometric algorithm to distinguish resilient from afflicted persons, and have demonstrated it in relation to inflammation, adipokines and amyloidopathy.ObjectiveThis analysis addresses neurodegeneration.Methods1737 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were assigned to neurodegeneration affliction classes through a "Line of Identity (LOI)" approach. A neurodegeneration "N Factor" indicated by three biomarkers was constructed. A previously validated measure of dementia severity, "dTEL″, was regressed onto the N Factor. Affliction classes were defined by each subject's deviation from the LOI obtained from the correlation of dTEL's N-Factor-adjusted residual (CR) versus unadjusted dTEL scores. Moderation effects on the N Factor's association with dTEL were tested by Chi Square difference. Class effects on prospective conversion to clinical "AD" from non-demented baseline diagnoses (NC + MCI) were tested by survival analysis.Results49.4% of ADNI subjects were afflicted by neurodegeneration. The Afflicted class had greater dementia severity, lower (adverse) N factor composite scores and higher observed levels of CNS neurodegeneration. These differences reflected the unique effect of neurodegeneration. Affliction class was not associated with other AD-related biomarkers. Afflicted cases were more likely to convert to clinical "AD" over 48 months [by Cox's F: F (164, 356) = 3.65, p < 0.001.ConclusionsOur approach could allow for more accurate prediction of biomarker effects and guide precision interventions.},
}

@article {pmid41424194,
year = {2025},
author = {Osburn, SC and Easterday, DS and McEntee, CM and Latham, AS and Lark, DS and McGrath, S and Moreno, JA and LaRocca, TJ},
title = {Evidence of emerging transcriptome mediators of Alzheimer's disease in canine cognitive dysfunction.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70062},
doi = {10.1111/bpa.70062},
pmid = {41424194},
issn = {1750-3639},
support = {AG073137/AG/NIA NIH HHS/United States ; AG078859/AG/NIA NIH HHS/United States ; AG070562/AG/NIA NIH HHS/United States ; AG060302/AG/NIA NIH HHS/United States ; },
abstract = {Growing data suggest companion dogs may be a promising model of human brain aging and Alzheimer's disease (AD). However, although pathology is somewhat similar in canine cognitive dysfunction (CCD) and AD, the transcriptomic similarities between these two conditions have not been thoroughly evaluated. Two emerging transcriptome-related mechanisms of human brain aging and AD involve transposable elements (TEs) and microRNAs (miRNAs), which have the potential to be carried systemically and between cells by extracellular vesicles (EVs). To determine if evidence of these AD-related transcriptomic events might be present in CCD, we generated transcriptome (RNA-seq) data on prefrontal cortex tissue and plasma EVs from young, older, and older CCD dogs. We show that: (1) global transcriptome changes with CCD indicate reduced neuronal health; (2) TE transcripts increase with CCD in both the brain and plasma EVs; (3) brain- and disease-relevant miRNAs are present in the same EVs, and some of these miRNAs correlate with indices of cognitive function/CCD. Collectively, our data suggest that transcriptomic changes in CCD, including those related to novel RNA mechanisms of brain aging and AD, may be similar to those observed in humans.},
}

@article {pmid41424047,
year = {2025},
author = {Bao, L and Xu, Z and Xue, C and Tang, Y and Xiao, C and Peng, L and Dong, J},
title = {Characteristics of Hypothalamic Structural and Functional MRI Changes in Alzheimer's Disease Patients With Sleep Dysfunction.},
journal = {The European journal of neuroscience},
volume = {62},
number = {12},
pages = {e70367},
doi = {10.1111/ejn.70367},
pmid = {41424047},
issn = {1460-9568},
support = {YKK22145//Nanjing Medical Science and Technology Development Foundation/ ; LKM2024027//Jiangsu Geriatric Health Research Project/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging/complications/pathology ; Male ; Female ; Magnetic Resonance Imaging ; *Hypothalamus/diagnostic imaging/physiopathology/pathology ; Aged ; *Sleep Wake Disorders/physiopathology/diagnostic imaging/complications/pathology/etiology ; Middle Aged ; },
abstract = {Sleep dysfunction (SD) is common in Alzheimer's disease (AD) and associated with cognitive impairment. The hypothalamus regulates circadian rhythms and exhibits AD pathology; we investigated the abnormal alterations in the structure and function of the hypothalamus in AD patients with sleep dysfunction (ADSD). Twelve ADSD patients, 19 AD patients without sleep dysfunction (ADNSD), and 13 age- and sex-matched healthy controls (HCs) underwent neuropsychological assessments, including the Montreal Cognitive Assessment and Mini-Mental State Examination, and sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Hypothalamic volume and its subregional volumes were derived from T1-weighted magnetic resonance imaging (MRI), whereas resting-state functional MRI was used to assess functional connectivity (FC) with the hypothalamus. We found reduced volumes in the bilateral anterior inferior and left anterior superior hypothalamic subregions in both AD groups compared to HCs. Compared to HCs, the ADNSD group exhibited enhanced hypothalamic FC with the left middle frontal gyrus (MFG) and right inferior parietal lobule (IPL) and reduced FC with right MFG, whereas the ADSD group exhibited enhanced FC with the left MFG and right superior frontal gyrus and reduced FC with right IPL. Furthermore, the ADSD group exhibited reduced FC with the right IPL and enhanced FC with right MFG relative to the ADNSD group. Crucially, within the combined AD cohort, FC with the right IPL was negatively correlated with PSQI, whereas FC with the right MFG was positively correlated. These findings indicate the hypothalamus is a critical target for interventions to improve sleep quality and cognition in AD.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging/complications/pathology
Male
Female
Magnetic Resonance Imaging
*Hypothalamus/diagnostic imaging/physiopathology/pathology
Aged
*Sleep Wake Disorders/physiopathology/diagnostic imaging/complications/pathology/etiology
Middle Aged

@article {pmid41424017,
year = {2025},
author = {Sun, R and Zhang, Y and Xu, J and Chen, M and Liu, C and Liu, X and Zhou, Y and Tsao, R and Ito, Y and Li, S},
title = {Multi-Angle Bioactivity Cartography for Computational Screening and Mechanistic Analysis of AChE Inhibitors From Yellow Gastrodia elata.},
journal = {Archiv der Pharmazie},
volume = {358},
number = {12},
pages = {e70174},
doi = {10.1002/ardp.70174},
pmid = {41424017},
issn = {1521-4184},
support = {YDZJ202401457ZYTS//Natural Science Foundation of Jilin Province/ ; YJYKF-002//Natural Science Foundation of Changchun Normal University/ ; },
mesh = {*Cholinesterase Inhibitors/pharmacology/isolation & purification/chemistry ; Molecular Docking Simulation ; *Gastrodia/chemistry ; *Acetylcholinesterase/metabolism ; Molecular Dynamics Simulation ; Humans ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Butyrylcholinesterase/metabolism ; Network Pharmacology ; Alzheimer Disease/drug therapy ; },
abstract = {Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC50 values (0.0145 and 0.0148 mM). Molecular dynamics and network pharmacology analyses further revealed critical interactions between these compounds and key AD-related targets, including ACHE, BCHE, BACE1, and PTGS2. In summary, this work underscores the potential of YGE-sourced compounds, especially parishins A and G, as effective AChE inhibitors. The established integrative computational platform facilitates multi-dimensional bioactivity evaluation and enables hierarchical prioritization of candidate compounds, thereby offering a valuable framework for advancing natural product-derived therapeutics for AD.},
}

*Cholinesterase Inhibitors/pharmacology/isolation & purification/chemistry
Molecular Docking Simulation
*Gastrodia/chemistry
*Acetylcholinesterase/metabolism
Molecular Dynamics Simulation
Humans
Structure-Activity Relationship
Molecular Structure
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Butyrylcholinesterase/metabolism
Network Pharmacology
Alzheimer Disease/drug therapy

@article {pmid41423949,
year = {2025},
author = {Na, C and Lee, J and Suh, JM and Go, J and Kwak, J and Lee, J and Kim, KS and Lee, CH and Kim, M and Lim, MH},
title = {Positional Isomerism Tunes Molecular Reactivities and Mechanisms toward Pathological Targets in Dementia.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c14323},
pmid = {41423949},
issn = {1520-5126},
abstract = {Positional isomerism offers a powerful strategy to fine-tune molecular reactivity toward diverse pathogenic factors in complex diseases. Here, we show that positional isomerism in phenylene-based compact molecules bearing electron-donating groups at the para, ortho, or meta positions engineers distinct chemical reactivities with key pathological targets, including reactive oxygen species, metal-free amyloid-β (Aβ), and metal-bound Aβ, which are implicated in Alzheimer's disease (AD). Comprehensive mechanistic analyses reveal that specific isomers drive covalent adduct formation, oxidation, and oxidative cleavage toward metal-free and metal-bound Aβ, with their chemical transformations governed by electronic and metal-binding properties dictated by the substitution pattern. In AD transgenic mice, para- and ortho-substituted analogs display markedly different efficacies in attenuating hippocampal oxidative stress, lowering amyloid plaque burden, and improving cognitive performance. Our findings establish a structure-property-reactivity framework in which subtle positional changes elicit divergent chemical and biological outcomes, providing a principle for rationally designing multi-target-directed chemical modulators to probe and control multifactorial networks underlying neurodegeneration.},
}

@article {pmid41423697,
year = {2025},
author = {Jeong, H and Ren, J and Cheng, W and Volkow, ND and Ling, H and Zhu, D and Du, C and Pan, Y},
title = {Cortical layer multi-parameter analysis of neurovascular impairments in AD/ADRD rodent model with in vivo optical imaging.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {70},
pmid = {41423697},
issn = {2047-9158},
support = {2R01 DA029718//National Institute of Health/ ; R01AG064798//National Institute of Health/ ; R21DA042597//National Institute of Health/ ; R01AG064798//National Institute of Health/ ; },
mesh = {Animals ; *Alzheimer Disease/diagnostic imaging/physiopathology ; Mice ; Disease Models, Animal ; *Cerebrovascular Circulation/physiology ; *Cerebral Cortex/diagnostic imaging/blood supply ; Mice, Transgenic ; *Optical Imaging/methods ; Male ; Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND: Neurovascular biomarkers have the potential to enhance early diagnosis of Alzheimer's disease (AD) and AD-related dementias (ADRD), as cerebrovascular alterations often precede neurodegeneration. However, their clinical application remains challenging due to insufficient specificity, heterogeneity, and technical limitations.

METHODS: Here, we report that vessel- and cortical layer-specific parameters exhibit promising diagnostic sensitivity for neurovascular impairments in an AD/ADRD mouse model, apolipoprotein E (APOE) 4 knock-in (KI), compared to APOE3-KI at 12 months of age. Using two in vivo imaging modalities, 3D capillary-resolution optical Doppler tomography and laser speckle contrast imaging, we measured 36 morphological and functional vascular parameters and evaluated their diagnostic performance using a machine-learning Support Vector Machine classifier.

RESULTS: APOE4 mice showed significant alterations including reduced venular and arterial cerebral blood flow velocities and diameters, increased vascular tortuosity, layer-dependent decreases in vascular density, and impaired cerebrovascular reactivity. Venule- and microcirculation-related parameters and dynamic vasoactivity to brain stimuli demonstrated high diagnostic accuracy (~ 90%).

CONCLUSION: Together, these findings provide in vivo evidence for early, cortical layer-specific neurovascular dysfunction caused by APOE4 that increases the susceptibility to dementia and highlight the potential of combining neurovascular biomarkers from optical imaging with AI-based classifier for identification of increased AD/ADRD risk.},
}

Animals
*Alzheimer Disease/diagnostic imaging/physiopathology
Mice
Disease Models, Animal
*Cerebrovascular Circulation/physiology
*Cerebral Cortex/diagnostic imaging/blood supply
Mice, Transgenic
*Optical Imaging/methods
Male
Apolipoprotein E4/genetics

@article {pmid41423696,
year = {2025},
author = {Wang, J and Wang, S and Jin, C and Li, X and Mo, C and Zheng, J and Lu, X and Liang, F and Gu, D},
title = {Osteoporosis and risk of dementia among older adults: a population‑based cohort study.},
journal = {Bone research},
volume = {13},
number = {1},
pages = {104},
pmid = {41423696},
issn = {2095-4700},
mesh = {Humans ; Aged ; Male ; Female ; *Dementia/epidemiology/complications/etiology ; *Osteoporosis/complications/epidemiology ; Risk Factors ; Cohort Studies ; Aged, 80 and over ; China/epidemiology ; Osteoporotic Fractures/epidemiology ; Proportional Hazards Models ; },
abstract = {Evidence on the association between osteoporosis and dementia is not fully clear. This study aimed to investigate the potential association between osteoporosis and the subsequent risk of dementia among older adults. We performed a cohort study of 176 150 community-dwelling older adults aged ≥65 years and free of cognitive impairment between 2018 and 2022 using integrated healthcare data from Shenzhen, China. Diagnoses of osteoporosis, osteoporotic fractures, and dementia were identified through linked outpatient and inpatient medical records and death registration records. Multivariate Cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of incident dementia associated with osteoporosis and osteoporotic fractures. The mean (SD) age of the total study population was 70.7 (5.4) years, and 9 605 had a previous diagnosis of osteoporosis. Over a median follow-up of 2.2 (IQR: 1.8-4.3, maximum: 5.5) years, corresponding to 505 423 person-years at risk, 1 367 incident all-cause dementia cases, including 617 Alzheimer's disease and 298 vascular dementia cases, occurred. Physician-diagnosed osteoporosis was associated with a higher risk of all-cause dementia (HR: 1.80, 95% CI: 1.53-2.12). The increased dementia risk tended to be more prominent among patients with osteoporotic fractures (HR: 2.43, 95% CI: 1.83-3.23) than those without (HR: 1.63, 95% CI: 1.35-1.97). Results were similar for Alzheimer's disease and vascular dementia. This study provides evidence that older adults with osteoporosis, especially those with osteoporotic fractures, have an elevated risk of incident dementia. Effective prevention and management of osteoporosis among the older population may be promising to mitigate the dual burden of osteoporosis and dementia.},
}

Humans
Aged
Male
Female
*Dementia/epidemiology/complications/etiology
*Osteoporosis/complications/epidemiology
Risk Factors
Cohort Studies
Aged, 80 and over
China/epidemiology
Osteoporotic Fractures/epidemiology
Proportional Hazards Models

@article {pmid41423583,
year = {2025},
author = {Katuwawala, K and Bharadwaj, P and Martins, I and De Silva, BGDNK and Ho, V and Dissanayake, A and Martins, RN and Fernando, WMADB},
title = {Unraveling the Significance of Fecal MicroRNA Profile in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {319},
pmid = {41423583},
issn = {1559-1182},
mesh = {*Alzheimer Disease/genetics/diagnosis/metabolism/microbiology ; *MicroRNAs/genetics/metabolism ; Humans ; *Feces/chemistry ; Gastrointestinal Microbiome ; Animals ; },
abstract = {Alzheimer's disease (AD), a complex neurodegenerative disorder characterised by progressive cognitive decline, affects millions globally. With no current cure, treatment focuses on symptom management and slowing disease progression. Early identification is therefore crucial. Fecal microRNA (miRNA) analysis is emerging as a promising non-invasive diagnostic tool. Evidence suggests that miRNAs present in fecal samples may regulate gene expression linked to AD pathology, impacting cellular functions and disease progression. Dietary factors critically influence gut microbiota composition and diversity, affecting brain health via the gut brain axis. Macronutrients such as carbohydrates, proteins, and fats modulate miRNA expression and gut microbiota, influencing AD risk. High-fat diets can increase inflammation and contribute to AD. This review aims to provide a comprehensive overview of how diet-modulated fecal miRNAs and gut microbiota interplay may serve as novel, non-invasive indicators for early detection and intervention strategies in AD.},
}

*Alzheimer Disease/genetics/diagnosis/metabolism/microbiology
*MicroRNAs/genetics/metabolism
Humans
*Feces/chemistry
Gastrointestinal Microbiome
Animals

@article {pmid41423566,
year = {2025},
author = {Kong, D and Zhang, T and Hou, G and Liu, G and Qi, X and Xing, H},
title = {A novel method for acoustic modeling of cranial bone based on the porosity index.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33411-x},
pmid = {41423566},
issn = {2045-2322},
support = {2022YFS0048//Sichuan Science and Technology Program/ ; 82027808//National Natural Science Foundation of China/ ; 2020SCUNL210//Science Specialty Program of Sichuan University/ ; },
abstract = {Transcranial ultrasound stimulation (TUS) has emerged as a clinically validated neuromodulation technique. Particularly, phased array ultrasound can be applied in TUS to focus on the cortex or deep brain non-invasively, such as the ventral intermediate thalamic nucleus (VIM) and Precuneus (PCu) region for the treatment of essential tremor (ET) and Alzheimer Disease (AD). Current TUS treatment planning relies on computed tomography (CT)-derived skull porosity measurements, which involve patient radiation exposure and potential registration errors. This study proposes a Porosity Index (PI)-based method, derived from Ultrashort Echo Time (UTE) Magnetic Resonance (MR) images, for establishing skull acoustic models as a viable alternative, aiming to eliminate these limitations. Acoustic simulations using the K-Wave open-source platform were performed to validate the PI method's accuracy in predicting skull porosity and simulating focal distributions compared to CT. Focal spot characteristics were quantified using five metrics: peak intensity, target intensity, focal positioning error, Dice similarity coefficient, and Pearson correlation coefficient between CT- and PI-based simulation results. Statistical differences between these metrics were assessed using Tukey's multiple comparisons test. Quantitative comparisons against the gold-standard CT approach demonstrated comparable performance in peak focal intensity (deviation < 5%) and spatial pressure distribution patterns (Dice coefficient > 0.82). No significant differences (p > 0.05) were observed for any of the evaluated metrics. Our findings demonstrate that both the sound pressure distribution and prediction of the porosity are comparable with those from the reference CT. Using the PI to replace the traditional CT porosity has high feasibility and can achieve the purpose of reducing unnecessary radiation exposure and registration error for patients.},
}

@article {pmid41423556,
year = {2025},
author = {Sutnikiene, V and Audronyte, E and Pakulaite-Kazliene, G and Kaubrys, G},
title = {Silhouettes, number Location, and cube analysis tests from the VOSP battery reveal visual object and space perception deficits in early Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33126-z},
pmid = {41423556},
issn = {2045-2322},
}

@article {pmid41423431,
year = {2025},
author = {Zhao, MT and Gong, Q and Chen, R and Jiao, Y and , },
title = {Cortical Hierarchy Collapse in Alzheimer's Disease: Connectome Gradient Compression as a Potential Biomarker.},
journal = {Journal of neuroscience research},
volume = {103},
number = {12},
pages = {e70099},
doi = {10.1002/jnr.70099},
pmid = {41423431},
issn = {1097-4547},
support = {CXZX202219//the Jiangsu Provincial Medical Innovation Center/ ; 2242023 K5005//the Fundamental Research Funds for the Central Universities of China/ ; 62071158//the National Natural Science Foundation of China/ ; //Alzheimer's Disease Neuroimaging Initiative/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Connectome/methods ; Male ; Female ; Aged ; *Nerve Net/diagnostic imaging/physiopathology ; Middle Aged ; *Cerebral Cortex/diagnostic imaging/physiopathology ; Biomarkers ; Aged, 80 and over ; Magnetic Resonance Imaging ; Brain/physiopathology/diagnostic imaging ; },
abstract = {This investigation centered on Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory impairment and cognitive decline. Functional connectome gradient analysis was utilized to investigate alterations in the hierarchical architecture of brain networks in AD. The study cohort consisted of 222 subjects, encompassing 111 AD patients and 111 normal controls (NC). Connectome gradients were computed via a dimensionality reduction technique based on diffusion map embedding and analyzed at both the region of interest (ROI) and network levels. Additional connectome gradient metrics, including network median distance and gradient eccentricity, were calculated, and the relationship between connectome gradients and rich-club organization was assessed. These connectome gradient values were subsequently correlated with clinical cognitive scores. The results demonstrated a significant reduction in the principal gradient range in AD patients. At the network level, gradient values exhibited an increase in the somatomotor (SMN) and visual networks (VIS), while decreasing in the default mode (DMN) and frontoparietal networks (FPN) relative to controls. Analyzes of network mean distance and gradient eccentricity further revealed compression of the brain cortical hierarchy in AD patients. Furthermore, rich-club analyzes indicated a reduction in the gradient value difference between hub and peripheral nodes in AD patients. Finally, clinical correlation analysis revealed a positive correlation between the degree of cognitive impairment and the degree of compression of the brain cortical hierarchy. These findings provide a novel perspective on the study of brain network organization in AD patients, contributing to a more comprehensive understanding of the neural mechanisms underlying Alzheimer's disease.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology
*Connectome/methods
Male
Female
Aged
*Nerve Net/diagnostic imaging/physiopathology
Middle Aged
*Cerebral Cortex/diagnostic imaging/physiopathology
Biomarkers
Aged, 80 and over
Magnetic Resonance Imaging
Brain/physiopathology/diagnostic imaging

@article {pmid41423172,
year = {2025},
author = {Luo, J and Tan, Z and Shang, P and Huang, S and Liu, Y and Wang, Y and Xie, H and Chen, Q},
title = {Accelerated intermittent theta burst stimulation combined with cognitive training modulates cortical plasticity and brain activation in patients with amnestic mild cognitive impairment.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113009},
doi = {10.1016/j.exger.2025.113009},
pmid = {41423172},
issn = {1873-6815},
abstract = {Amnestic mild cognitive impairment (aMCI) is the prodromal period of Alzheimer's disease without effective treatment. This research aimed to investigate the effects of accelerated intermittent theta burst stimulation (iTBS) combined with adaptive cognitive training (COG) on cognitive function in aMCI patients and explore the underlying neural mechanisms. Twenty-four aMCI patients participated in either the real (n = 12) or sham (n = 12) stimulation group. Both groups received adaptive COG, which comprised three sessions of real or sham iTBS delivered on the left dorsolateral prefrontal cortex (DLPFC) once a day for 14 days. The primary outcomes were the Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores. Secondary outcomes were changes in cortical plasticity measured by transcranial magnetic stimulation and brain activation monitored by functional near-infrared spectroscopy (fNIRS). Patients were evaluated before and after the intervention. Patients with aMCI who received iTBS combined with COG had a significant improvement in cognitive performance, as assessed by the ADAS-Cog and N-back. In the iTBS+COG group, cortical plasticity measured 30 min post-intervention correlated with ADAS-Cog changes (r = -0.59, p = 0.043). Furthermore, this plasticity was associated with 1-back activation (r = -0.58, p = 0.050), and 2-back activation correlated with ADAS-Cog changes (r = -0.59, p = 0.042). Accelerated iTBS targeted to the left DLPFC combined with adaptive COG promoted cognitive improvement in aMCI patients more effectively by modulating cortical plasticity and brain activation. Cortical plasticity and brain activation might be valuable measurements for understanding cognitive function (Chinese Clinical Trial Registry: ChiCTR2400087943).},
}

@article {pmid41423157,
year = {2025},
author = {Liu, J and Yang, J and Liu, S and Sun, W and Xu, B and Liu, J and Wei, F},
title = {Renshen Shouwu Formula Alleviates Alzheimer's Disease Pathology by Modulating Tryptophan Metabolism and Activating the SIRT1 Signaling Pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121073},
doi = {10.1016/j.jep.2025.121073},
pmid = {41423157},
issn = {1872-7573},
abstract = {The Renshen Shouwu is a traditional Chinese medicine formula, whose active components have neuroprotective and multiple pharmacological effects. However, Alzheimer's disease (AD) is a complex neurodegenerative disorder, and the exact mechanism of its treating AD remains to be elucidated, and more in - depth research is needed.

AIM OF THE STUDY: The aim of this study is to elucidate the protective effect and potential molecular mechanisms of Renshen Shouwu Formula (RSSW) on AD.

MATERIALS AND METHODS: Using senescence-accelerated mouse prone 8 (SAMP8) mice as an AD model, the cerebral cortex morphology was assessed by H&E staining. Non-targeted and targeted metabolomics, together with 16S rRNA sequencing, were performed to analyze the effects of RSSW on metabolic changes and gut microbiota in SAMP8 mice. Furthermore, potential therapeutic targets of RSSW were predicted by network pharmacology and validated via western blot.

RESULTS: RSSW treatment significantly mitigated pathological damage in the cerebral cortex, and reduced pro-inflammatory cytokine levels in SAMP8 mice. Results of both non-targeted and targeted metabolomics analyses indicated that RSSW intervention could improve tryptophan metabolism in SAMP8 mice by elevating tryptophan levels, suppressing kynurenine pathway overactivation, and enhancing serotonin and indole derivative biosynthesis. Additionally, RSSW administration markedly increased the relative abundance of Lactobacillus in gut microbiota, which showed positive correlations with the levels of tryptophan, serotonin pathway metabolites, and neurotransmitters, and negatively with kynurenine pathway metabolites. Furthermore, network pharmacology identified that SIRT1 could serve as a potential target for RSSW in AD. Notably, RSSW upregulated SIRT1 protein levels and reduced levels of Ac-p53 and acetylated NF-κB proteins in the hippocampus of SAMP8 mice.

CONCLUSIONS: RSSW suppresses the progression of AD by regulating tryptophan metabolism, reshaping the gut microbiota, and activating SIRT1-mediated signaling pathways. These findings suggest that RSSW may be a promising therapeutic strategy for AD through multi-path action mechanisms.},
}

@article {pmid41423153,
year = {2025},
author = {Widziolek, M and Mieszkowska, A and Marcinkowska, M and Domagalska, A and Zawisza, M and Soltys, Z and Potempa, J and Chadzinska, M},
title = {Porphyromonas gingivalis induces neuroinflammation in a gingipain-dependent manner in zebrafish larvae.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106234},
doi = {10.1016/j.bbi.2025.106234},
pmid = {41423153},
issn = {1090-2139},
abstract = {Porphyromonas gingivalis (Pg), a keystone pathogen in the development of periodontitis, has been implicated in neurodegenerative diseases such as Alzheimer's disease (AD). The gingipains, Pg crucial virulence factors, have been detected in the brains of AD patients and suggested to be involved in neuroinflammation, which leads to neuronal death. However, the mechanisms underlying Pg brain invasion and its inflammatory effect remain poorly understood. In this study, using a zebrafish larval model, we investigated the gingipain-dependent effects of systemic and local hindbrain infection with Pg, on: (i) neuroinflammation and cell death, (ii) Pg phagocytosis and persistence in the brain, (iii) activation of microglia/macrophages, (iv) cerebral vasculature integrity, and (v) larval behavioural changes. Systemic infection with wild-type Pg W83, but not with the gingipain-null mutant (ΔK/R-ab), resulted in increased bacterial survival in the brain and upregulation of the expression of pro-inflammatory genes both in the brain and periphery. Furthermore, Pg W83 also induced microglia/macrophages activation, as indicated by morphological changes and upregulation of activation marker expression, however number of microglia was reduced upon Pg W83 systemic infection. Finally, alterations in cerebral vasculature and larval locomotor activity were also observed. In contrast, the ΔK/R-ab mutant was rapidly cleared and did not induce inflammatory responses, underscoring the pivotal role of gingipains in Pg survival, microglia activation and neuroinflammation. Interestingly, the direct hindbrain inoculation of Pg induced only a mild, transient inflammation, indicating that systemic dissemination and potentially peripheral inflammation is crucial in the affecting blood-brain barrier and neuroinflammation. In contrast to systemic infection, local infection with Pg W83 or injection of purified gingipains led to increased microglia/macrophages numbers but similarly to systemically administered bacteria, Pg W83 was more effective in activating the microglia/macrophages than the ΔK/R-ab mutant, which was rapidly phagocytosed and cleared. Moreover, during local infection Pg W83, but not ΔK/R-ab, was able to induce cell death in the brains of infected larvae. Collectively, these findings highlight the gingipain-dependent mechanisms of Pg-induced neuroinflammation and emphasize the importance of further investigation into the role of the oral-brain axis in neurodegenerative diseases. In addition, this study highlights the utility of zebrafish larvae as a powerful tool to investigate host immunity-pathogen interactions in the brain.},
}

@article {pmid41423142,
year = {2025},
author = {Li, X and Liu, C and Hu, H},
title = {The expanding role of Furin in human Disease: A comprehensive review.},
journal = {Gene},
volume = {},
number = {},
pages = {149969},
doi = {10.1016/j.gene.2025.149969},
pmid = {41423142},
issn = {1879-0038},
abstract = {Furin is a calcium-dependent serine endoprotease that activates multiple substrates by cleaving at polybasic motifs, playing a pivotal role in human physiology and pathology. This review summarizes the latest research progress regarding Furin's extensive involvement in infectious diseases, tumor diseases, cardiovascular diseases, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. This review offers an in-depth analysis of Furin's dual functions, which include promoting viral entry into host cells, driving oncogenesis via growth factors, metalloproteinases, and the Notch signaling pathway, and maintaining metabolic homeostasis and immune tolerance. Key pathophysiological mechanisms involve the dysfunction of Furin substrate activation in atherosclerosis, hypertension, Alzheimer's disease, diabetes, and other disorders. The review also highlights the potential value of Furin as a diagnostic and prognostic biomarker and therapeutic target, while pointing out the challenges encountered in developing its inhibitors.},
}

@article {pmid41423022,
year = {2025},
author = {Eldaly, ABM and Agadagba, SK and Verma, A and Li, K and Lim, LW and Chan, LL},
title = {Longitudinal brain-wide recordings reveal early neurophysiological alterations in memory-impaired mice.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.035},
pmid = {41423022},
issn = {1873-7544},
abstract = {Scopolamine, a muscarinic receptor antagonist, is widely utilized to pharmacologically model Alzheimer's disease (AD) due to its ability to mimic cholinergic deficits and induce memory impairments. Despite its common use to investigate behavioral and cognitive impairments in memory deficit animal models, the longitudinal brain-wide electrophysiological alterations associated with scopolamine administration alterations associated with scopolamine administration remain largely unexplored. This study integrated electrophysiological and behavioral analyses to investigate scopolamine-induced cognitive deficits in mice. Using a 16-channel intracranial electroencephalography (iEEG) array, we tracked brain-wide oscillatory changes and functional connectivity over 6 weeks during memory task-related and task-free activities. The mouse's pre-attentive sensory memory was assessed by auditory evoked potentials (AEP) within the passive oddball mismatch negativity (MMN) paradigm, and the mouse's spatial working memory was further evaluated using a Y-maze spontaneous alternation task. The auditory MMN responses indicated significant sensory discrimination impairments from Week 2 onward, and spontaneous theta oscillations demonstrated widespread disruptions by Week 3. Concurrently, scopolamine degraded the animal's Y-maze successful alternation rates. The decline in alternation performance was correlated with the observed electrophysiological alterations, revealing the progressive impact of scopolamine on cognitive and neural functions. Furthermore, this study identified early electrophysiological biomarkers of brain functional network changes associated with memory impairments, in which functional connectivity abnormalities were observed from the first week of scopolamine administration, suggesting they have diagnostic potential in preclinical AD research. By bridging behavioral outcomes with brain-wide iEEG metrics, this work emphasizes the translational relevance of scopolamine models for understanding AD-like pathology and evaluating therapeutic interventions.},
}

@article {pmid41422990,
year = {2025},
author = {Tan, YY and Leow, CY and Choo, CT and Tan, J and Ong, CT},
title = {Translated retained intron 11 sequence confers pathological properties to Tau in Alzheimer's disease.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102872},
doi = {10.1016/j.pneurobio.2025.102872},
pmid = {41422990},
issn = {1873-5118},
abstract = {A novel Tau11i isoform was previously found to be enriched in Alzheimer's disease (AD) brains. Further characterization showed that the 19-amino acid peptide encoded by retained intron 11 facilitates the formation of high-molecular-weight heterodimers and phase-separated liquid droplets, as well as enhances heparin-induced β-sheet aggregation and cellular seeding of Tau11i. Compared to full-length Tau441 isoform, expression of Tau11i in human neurons caused significant transcriptional changes that recapitulated single-cell molecular signatures of neurofibrillary tangle (NFT)-free excitatory AD neurons in the prefrontal cortex. Additionally, Tau11i-expressing neurons showed dysregulated levels of specific ribosomal proteins and p21. Unlike Tau441, Tau11i interacts with Pinin and Poly(A)-binding protein Cytoplasmic 1 (PABPC1) in cells lacking AD pathology, mimicking the sequestration of RNA-binding proteins (RBP) by pathological Tau in AD brains. Notably, PABPC1 colocalizes with Tau11i in AD temporal lobes and is enriched at the 3' untranslated regions of genes upregulated in Tau11i-expressing neurons. These findings suggest that Tau11i contribute to AD pathology by inducing neuronal senescence, pathological aggregation of RBPs, and transcriptional dysregulation that resembles the molecular signatures of NFT-free AD neurons.},
}

@article {pmid41422863,
year = {2025},
author = {Keller, M and Gallagher, C and Marengo, L and Bickenbach, K and Schmitt, U and Abukhalaf, M and Tholey, A and Kreiselmaier, S and Becker-Pauly, C and Mittmann, T and Pietrzik, CU},
title = {Meprin β elevates hippocampal soluble Aβ in the APP/V717I mouse model.},
journal = {Experimental neurology},
volume = {397},
number = {},
pages = {115600},
doi = {10.1016/j.expneurol.2025.115600},
pmid = {41422863},
issn = {1090-2430},
abstract = {The emergence of Alzheimer's disease (AD) pathology has been the focus of multiple hypotheses, with amyloid β (Aβ) playing a central role due to its presence in both familial and sporadic AD. Therefore, a crucial aspect of AD research is understanding the generation of different Aβ species. Aβ peptides result from the proteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases, with BACE1 being the most prominent β-secretase. However, BACE1-overexpressing mouse models exhibit disadvantages, making them limited for AD research. Importantly, N-terminally truncated Aβ species, which constitute up to 70 % of Aβ in AD brains, are not generated by BACE1. In recent years, alternative proteases capable of cleaving APP have been identified, bridging the gap between N-terminally truncated Aβ species and BACE1-derived Aβ. Among these novel players, the metalloprotease meprin β has emerged as a risk factor in AD pathology, generating both N-terminally truncated and full-length Aβ species. Our primary objective was to develop a mouse model that more accurately resembles the pathology of AD beyond BACE1-overexpressing models, while simultaneously confirming APP cleavage of meprin β in the hippocampus and cerebral cortex. Overexpression of meprin β led to a marked increase in soluble Aβ levels, particularly in the hippocampus, indicating a higher vulnerability or elevated meprin β activity in this region compared to the cerebral cortex. Notably, this biochemical change occurred without any observable behavioral deficits, suggesting a region-specific role of meprin β in AD pathology that may extend beyond immediate functional impairment.},
}

@article {pmid41422850,
year = {2025},
author = {Liu, R and Zhang, Q and Xian, M and Chen, Q},
title = {Identification of a novel Songorine derivative as a potent NLRP3 inflammasome inhibitor.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130511},
doi = {10.1016/j.bmcl.2025.130511},
pmid = {41422850},
issn = {1464-3405},
abstract = {As a key intracellular pattern-recognition receptor, NLRP3 senses diverse pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammasome assembly and pyroptotic cell death. Aberrant NLRP3 activation contributes to various chronic inflammatory diseases, including atherosclerosis, Alzheimer's disease, and rheumatoid arthritis, underscoring its therapeutic relevance. In this study, we designed and synthesized compound 8a, a structurally optimized derivative of the diterpenoid alkaloid songorine. In lipopolysaccharide (LPS)- and nigericin-stimulated macrophage models, 8a markedly reduced lactate dehydrogenase (LDH) release (IC50 = 2.69 μM in THP-1 cells and 1.75 μM in J774A.1 cells) and effectively inhibited gasdermin D (GSDMD) cleavage and interleukin-1β (IL-1β) secretion, demonstrating potent suppression of pyroptosis. Hydrogenation of the C16-C17 double bond afforded compound 8b, which lost inhibitory activity, indicating that the α,β-unsaturated carbonyl moiety is essential for function, likely via covalent modification of cysteine residues on NLRP3. This mechanism was further substantiated by Drug Affinity Responsive Target Stability (DARTS) assays and mass spectrometry, confirming direct binding between 8a and NLRP3. We also conducted structure-activity relationship studies by modifying the C1 position and found that such modifications did not significantly impact the compound's activity. Collectively, these findings identify 8a as a novel songorine-derived covalent NLRP3 inhibitor and provide the first elucidation of its structure-activity relationship and molecular mechanism, offering valuable insights for the rational design of safe and effective anti-inflammatory agents targeting NLRP3.},
}

@article {pmid41422841,
year = {2025},
author = {Naveh-Tassa, S and Levy, Y},
title = {Multivalency in Tau-Microtubule interactions: Heterogeneous association and functional implications.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169600},
doi = {10.1016/j.jmb.2025.169600},
pmid = {41422841},
issn = {1089-8638},
abstract = {Tau is a dynamic microtubule-associated protein essential for maintaining microtubule (MT) stability and neuronal function. Its intrinsically disordered nature, combined with its multivalent binding capacity, makes it challenging to characterize structurally. Governed largely by electrostatic interactions, both in solution and when bound to MTs, Tau exhibits highly transient and heterogeneous behavior. Here, we apply coarse-grained molecular dynamics simulations to investigate tau-MT interactions and uncover how multivalent binding is regulated at the sub-regional level. Our simulations capture interactions both with the flexible, disordered C-terminal tails of tubulin and with the structured tubulin surface. We show that distinct tau sub-regions contribute differentially to binding. Isoform variation, defined by the presence or absence of specific sub-regions, further modulates tau's interaction with tubulin, influencing both MT stability and dimer polymerization rates through electrostatic tuning. Our simulations also reveal how Alzheimer's disease-associated phosphorylation disrupts tau-MT interactions by weakening multivalent engagement. Together, our findings provide new mechanistic insight into how electrostatics and sub-regional composition regulate the dynamic, multivalent nature of tau-MT interactions, with implications for neuronal integrity and tauopathy-related dysfunction.},
}

@article {pmid41422686,
year = {2025},
author = {Benussi, A and Michelutti, M and Lombardo, TMI and Toffoletto, B and Palacino, F and Cenacchi, V and Pelusi, L and Capacchione, F and Menichelli, A and Perego, A and Sirianni, F and Cattaruzza, T and Manganotti, P},
title = {Diagnostic performance of plasma pTau217/Aβ42 ratio and a three-zone threshold model for Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {159},
number = {},
pages = {60-68},
doi = {10.1016/j.neurobiolaging.2025.12.005},
pmid = {41422686},
issn = {1558-1497},
abstract = {Early and accurate diagnosis of Alzheimer's disease (AD) typically relies on invasive or expensive methods like cerebrospinal fluid (CSF) biomarkers and amyloid PET imaging. Blood-based biomarkers, particularly plasma phosphorylated tau (pTau181, pTau217) and amyloid-beta ratios (Aβ42/40), offer a more accessible diagnostic alternative. This study assessed the diagnostic accuracy of plasma biomarkers and developed a three-zone classification model to reduce reliance on invasive confirmatory tests. We retrospectively evaluated 109 participants referred to a tertiary memory clinic. Participants underwent cognitive assessments, brain MRI, CSF biomarker analyses (pTau181, Aβ42/40), and plasma biomarker measurements (pTau181, pTau217, Aβ42/40, pTau217/Aβ42 ratio). Diagnostic performance was evaluated using ROC analyses, and thresholds achieving ≥ 95 % sensitivity and specificity were used to define low, intermediate and high-risk zones. Plasma biomarkers correlated significantly with CSF biomarkers. For identifying AD pathology (A+/T + vs. others), plasma pTau217 and the pTau217/Aβ42 ratio demonstrated the highest accuracy (both AUC=0.95), outperforming plasma pTau181 (AUC=0.88) and Aβ42/40 ratio (AUC=0.73). At optimal thresholds, plasma pTau217 showed 87.5 % sensitivity and 93.4 % specificity, whereas the pTau217/Aβ42 ratio showed higher sensitivity (95.8 %) but lower specificity (85.2 %). Using the three-zone model, plasma pTau217 enabled definitive classification in 80.7 % of patients, increasing to 84.4 % with the pTau217/Aβ42 ratio. Among patients with mild cognitive impairment, plasma pTau217 achieved excellent accuracy (AUC=0.98). Plasma pTau217, alone or combined with Aβ42, provides highly accurate and scalable identification of AD pathology, substantially reducing the need for invasive diagnostic procedures.},
}

@article {pmid41422676,
year = {2025},
author = {Matsumoto, M and Ikebukuro, K and Tsukakoshi, K},
title = {Competitive-SELEX discovery of DNA aptamers selective for neurofilament light chain in human plasma.},
journal = {Biochemical and biophysical research communications},
volume = {796},
number = {},
pages = {153151},
doi = {10.1016/j.bbrc.2025.153151},
pmid = {41422676},
issn = {1090-2104},
abstract = {Neurofilament light chain (NfL) is a blood-based biomarker closely associated with neurodegeneration and the progression of Alzheimer's disease. Here, we report the identification of novel single-stranded DNA aptamers that specifically recognise NfL with high affinity. Using a competitive SELEX strategy incorporating NfL, we enriched aptamer candidates that selectively bind the clinically relevant region of NfL. Two lead aptamers, MN711 and MN734, displayed nanomolar dissociation constants of 11 nM and 8.1 nM, respectively, comparable to those of widely used anti-NfL antibodies. Circular dichroism spectroscopy confirmed parallel G-quadruplex structures, and both aptamers showed minimal off-target binding to amyloid β40, amyloid β42, or phosphorylated tau181. Importantly, MN711 retained concentration-dependent binding to NfL spiked into human plasma. These aptamers provide promising ligand candidates for NfL biosensing platforms and blood-based diagnostic devices for neurodegenerative diseases.},
}

@article {pmid41422621,
year = {2025},
author = {Nie, Y and Cui, Q and Li, W and Lü, Y and Yu, W},
title = {A vision-language model for enhanced MCI identification in Alzheimer's disease through neuropsychological and neuroimaging data integration.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {197},
number = {},
pages = {108415},
doi = {10.1016/j.neunet.2025.108415},
pmid = {41422621},
issn = {1879-2782},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder with the progression typically spanning from mild cognitive impairment (MCI) to severe dementia. However, in clinical practice, diagnosing MCI is challenging due to conflicts between neuroimaging findings and clinical neuropsychological assessments. Structural and metabolic changes in imaging may not immediately correlate with cognitive symptoms, making early MCI detection difficult. This diagnostic complexity requires considerable clinical expertise and can lead to delays in detection. Moreover, multi-modal fusion using computer-based techniques faces challenges due to the inherent heterogeneity across different data modalities. In this study, a Vision-Language Model (VLM)-based approach is proposed to enhance the identification of Alzheimer's Disease, with a particular focus on the early detection of MCI. Our contribution is a synergistic architecture that includes domain-specific learnable abnormality tokens that function as adaptive probes for clinical pathologies, and a unique Unified Multi-Modal Attention module designed to explicitly harmonize conflicting signals between neuroimaging and clinical data. Finally, a Large Language Model synthesizes all information to generate the final diagnostic output. Evaluated on three publicly available datasets across four identification tasks, the proposed method performs robustly, outperforms state-of-the-art approaches, especially in the challenging MCI identification task, and significantly reduces diagnostic errors when dealing with conflicting data. The results underscore the practical significance of integrating multi-modal data within a VLM framework, which not only enhances diagnostic accuracy but also reduces diagnostic errors and delays in early-stage MCI identification, thereby supporting more timely and effective clinical decision-making.},
}

@article {pmid41422555,
year = {2025},
author = {Mishra, AK and Jain, S},
title = {Integrative Multiomics Insights into the Genetic and Epigenetic Architecture of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00750},
pmid = {41422555},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by complex genetic and molecular interactions. Despite major advances in genomics, current discoveries explain less than 40% of AD heritability, underscoring the need for integrative approaches that capture cross-omic regulation. Here, we propose a multiomics integration framework combining genomic, epigenomic, and transcriptomic data sets to identify convergent molecular signatures underlying AD pathogenesis. An integrated epigenome-wide association study-genome wide association study (EWAS-GWAS) analysis using GeneCards and VarElect identified 42 candidate genes, showing overlap between genetic susceptibility and epigenetic dysregulation. These include canonical AD loci (APOE, CLU, BIN1, PICALM, and TREM2) and novel regulatory genes such as AKT1, DOT1L, SREBF1, and PVT1. Network analysis revealed 32 nodes and 30 edges with an average node degree of 1.88 and a protein-protein interaction (PPI) enrichment p-value of 6.45 × 10[-6], indicating significant functional connectivity. Integrative pathway mapping highlighted mitochondrial-nuclear cross-talk, metabolic dysfunction, and noncoding RNA regulation as central pathogenic axes. This multilayered approach bridges static genomic variants with dynamic epigenetic and transcriptomic alterations, offering a systems-level view of disease mechanisms. Methodologically, the framework integrates EWAS-GWAS correlation, functional annotation, and PPI modeling to prioritize biologically relevant targets. Translationally, these findings reveal potential methylation-based biomarkers, polygenic-epigenetic risk models, and targetable molecular pathways for early detection and precision therapeutics. Overall, this integrative strategy enhances mechanistic understanding and supports the development of predictive, multiomic tools for individualized AD management.},
}

@article {pmid41422050,
year = {2025},
author = {Valletta, M and Briel, N and Yuksekel, I and Barboure, M and Coward, A and De Houwer, JFH and Fawad, A and González-Mayoral, A and Iaccarino, G and Martínez-Dubarbie, F and Moukaled, S and Andreasson, U and Gobom, J and Brinkmalm, A and Tijms, B and Zetterberg, H and Blennow, K and Suárez-Calvet, M and Schöll, M and Paterson, RW and Montoliu-Gaya, L and Sogorb-Esteve, A},
title = {Fluid biomarkers for neurodegenerative diseases: a comprehensive update.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01919-z},
pmid = {41422050},
issn = {1758-9193},
}

@article {pmid41421907,
year = {2025},
author = {Boer, D and Schmidt, C and Sterke, S and van Bodegom-Vos, L and Achterberg, W and Vlieland, TV},
title = {Novel barriers and facilitators were identified for family involvement in physiotherapy and exercise for aged care facility residents with dementia: a qualitative study.},
journal = {Journal of physiotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jphys.2025.12.003},
pmid = {41421907},
issn = {1836-9561},
abstract = {QUESTION: What barriers and facilitators do physiotherapists and aged care facility staff perceive regarding the involvement of family caregivers in physiotherapy and exercise for residents with dementia?

DESIGN: Reflexive thematic analysis with semi-structured interviews to explore the subjective experiences of physiotherapists and aged care staff, grounded in a constructivist ontology.

METHODS: We conducted 28 semi-structured interviews with 19 physiotherapists and 9 aged care facility staff members concerned with family participation. Participants were selected from Dutch aged care facilities providing care for residents with dementia. Interviews were recorded and transcribed and subsequently analysed using inductive thematic coding.

RESULTS: The perceived barriers included the burden placed on family caregivers, particularly during the transition to an aged care facility, and the need for adequate information and guidance to ensure successful involvement. In addition, it was found that an unwelcoming environment fostered by physiotherapists and staff hinder family members' participation. Facilitators included a proactive approach of physiotherapists regarding the collaboration and information provision on practical aspects of exercise, particularly when supported by technology or exergaming. Other facilitators were the family caregivers' previous healthcare experience and cultural factors emphasising the importance of family support.

CONCLUSION: The study identified barriers to family caregiver involvement, such as perceived caregiver burden and lack of role clarity, alongside facilitators such as previous caregiving experience, culturally rooted family values and strong social or religious networks. Physiotherapists and aged care facilities could improve collaboration by proactively discussing family caregiver roles, adopting flexible approaches, and using inclusive (digital) communication methods to support ongoing caregiver engagement.},
}

@article {pmid41421732,
year = {2025},
author = {Shor, Y and Said, R and Fainstein, N and Wolf, G and Stepanov, LS and Lachish, M and Ganz, T and Shwaiky, Y and Benyamini, H and Nevo, Y and Brock, Y and Gurevitz, J and Lifschytz, T and Lotan, A and Ben-Hur, T},
title = {The paradoxical protective effect of chronic stress on advanced Alzheimer's disease pathology.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106224},
doi = {10.1016/j.bbi.2025.106224},
pmid = {41421732},
issn = {1090-2139},
abstract = {BACKGROUND: Core pathology in Alzheimer's disease (AD) includes amyloid-β (Aβ) deposition, gliosis, and eventual neuronal loss. Depression during midlife increases the risk of developing AD at late life. Late-life depression is highly prevalent among AD patients, but its role in AD pathogenesis is unclear, and specifically whether it pushes the brain with established AD pathology towards degeneration. CNS myeloid cells (Microglia and CNS-associated macrophages) clear Aβ early on; however, in advanced disease stages, they adopt a neurotoxic phenotype that exacerbates neurodegeneration. It is unclear whether and how stress and depression influence CNS myeloid cells' dysfunction in AD and the neurodegenerative process.

METHODS: To investigate the impact of chronic stress on microglial function and on neurodegeneration, we utilized the 5xFAD mouse model, which exhibits extensive Aβ pathology but no neuronal loss at age 7 months, representing a late preclinical AD stage. We used a six-week chronic mild stress (CMS) paradigm to induce depressive behavior, after which CNS myeloid cell activation state was evaluated by transcriptomic analysis, activation marker expression and oxidation function. Neuronal and microglial densities were assessed histologically.

RESULTS: Transcriptomic analysis of freshly isolated CNS myeloid cells showed a basal hyper-activated state in non-stressed 5xFAD mice, whereas CMS suppressed multiple immunologic and metabolic pathways. CMS reduced CD68 expression, and reduced oxidative function in CNS myeloid cells. CMS did not induce neurodegeneration in the (behavioral-relevant) pre-frontal, primary motor, hippocampal and Amygdalar cortices in 5xFAD mice. Rather, CMS protected these regions from microglia-mediated neurodegeneration, caused by a microbial TLR2 agonist.

CONCLUSION: Chronic stress and depression attenuate CNS myeloid cells. While this has been shown to promote amyloid pathology at early stages, similar attenuation of CNS myeloid cells at the stage of established AD pathology may interfere with their transition into fully neurotoxic microglia which cause neurodegeneration. These findings highlight the importance of tailoring microglial-targeted therapies to the stage-dependent roles of these cells during AD progression.},
}

@article {pmid41421725,
year = {2025},
author = {Kumar Das, S and Bashir, B and Kolekar, KA and Harish, V and Patle, D and Vishwas, S and Mittal, N and Jha, SK and Kumar, P and Gupta, G and Dureja, H and Dua, K and Chang, D and Kuppusamy, G and Singh, SK},
title = {Protein and peptide based nanotherapeutics for the management of Alzheimer's disease: Current insights and future directions.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103000},
doi = {10.1016/j.arr.2025.103000},
pmid = {41421725},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the most chronic neurodegenerative disease. The pathological hallmark of AD includes the accumulation of amyloid-beta plaques (Aβ), oxidative stress as well as chronic inflammatory reactions. Current treatments, such as acetylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, and recently approved monoclonal antibodies, offer symptomatic relief or slightly slow down progression. However, they too are constrained by high cost, side effects and limited activity. Proteins and peptides are emerging focus of attention as promising therapeutics, due to their higher selectivity, participation in many pathological pathways, and are lesser toxicity than other therapies in recent years. These biomolecules mediate their effect by decreasing amyloid aggregation, preventing tau hyperphosphorylation, regulating oxidative damage and repairing synapses. Various proteins and peptides such as SS31, LPfFFD-PEG, SEN1576, α sheet peptides, D-(PGKLVYA), RI-OR2-TAT, TFP5, SEN304, PP-Leu, Ac-Leu-Pro-Phe-Phe-Asp-NH2 (iAb5p), and Cyclo (17, 21)- (Lys17, Asp21) Aβ (1-28) have been used in the treatment of AD. Nonetheless, these peptides have a limited clinical translatability due to their vulnerability to enzymatic degradation, systemic circulation instability, low bioavailability, and limited penetration across the blood-brain barrier (BBB). To overcome these challenges, nanotechnology-based treatments have become a revolutionary solution. Both functionalized and non-functionalized protein and peptide-loaded nanoparticles provide protection against degradation, cross the BBB, and allow sustained and targeted delivery of neuronal tissues. The ligand-functionalized nanoparticle systems increase the accumulation of therapeutics in the brain as they cross the blood-brain barrier more efficiently. These are also able to protect the circulatory proteins and peptides, and eventually lead to improved therapeutic results in preclinical models. The present review highlights the therapeutic and delivery potential of protein- and peptide-based nanocarriers as dual therapeutic and delivery vectors with disease-modifying capability and precision targeting. Together, these advances have placed nanotechnology-based protein and peptide therapeutics for better management of AD.},
}

@article {pmid41421724,
year = {2025},
author = {Pini, L and Imbimbo, BP and Griffa, A and Allali, G and Pomara, N},
title = {Targeting brain connectivity in Alzheimer's disease with repurposed drugs.},
journal = {Ageing research reviews},
volume = {114},
number = {},
pages = {103001},
doi = {10.1016/j.arr.2025.103001},
pmid = {41421724},
issn = {1872-9649},
abstract = {Neuroimaging studies have highlighted both hyperconnectivity and hypoconnectivity across the Alzheimer's disease (AD) continuum, alongside task-induced activity changes. These alterations may reflect compensatory mechanisms or network breakdowns. While connectivity-based measures are not yet established as clinical biomarkers, they hold promises for evaluating therapeutic efficacy and informing the design of targeted interventions. Based on these insights, this review explores the potential of off-label FDA-approved drug repositioning as a cost-effective strategy to identify therapeutic approaches for AD. We examine the neurophysiological effects of certain repurposed drugs that modulate synaptic activity, reduce inflammation, enhance metabolic pathways and gut-brain axis interactions, in preclinical and clinical models. Emerging evidence suggests that these drugs (e.g., anticonvulsants, anti-diabetics, anti-inflammatory, and gastrointestinal agents) can influence brain connectivity and activity, mitigating cognitive deficits. By integrating connectivity-focused biomarkers into clinical trials, researchers can advance the development of disease-modifying treatments. This review underscores the importance of a connectivity-driven framework for repurposing existing drugs to address need for new treatments for AD.},
}

@article {pmid41421688,
year = {2025},
author = {Liu, YL and Li, Y and Feng, R and Chen, J and Wang, Y and Chen, YA and Ding, N and Yuan, J and Ling, ZH},
title = {Beyond manual transcripts: Exploring the potential of automatic speech recognition errors in improving Alzheimer's disease detection.},
journal = {Journal of biomedical informatics},
volume = {173},
number = {},
pages = {104968},
doi = {10.1016/j.jbi.2025.104968},
pmid = {41421688},
issn = {1532-0480},
abstract = {OBJECTIVE: This study aims to extend the counterintuitive observation that Automatic Speech Recognition (ASR) errors can be beneficial for Alzheimer's Disease (AD) detection. Our objective is to conduct a large-scale investigation to validate this phenomenon and, more importantly, to elucidate the specific mechanisms by which ASR errors can serve as valuable diagnostic clues for distinguishing individuals with AD from Healthy Controls (HC).

METHODS: We employed 18 ASR models, in both their original and fine-tuned versions, to generate 36 sets of transcripts from the ADReSS dataset. We also synthesized speech from both manual and ASR transcripts using a text-to-speech (TTS) model. Knowledge-based features and pre-trained embeddings were extracted and fed into two proposed AD detection models : a self-attention model and a cross-attention-based interpretability model. To uncover the underlying mechanisms, we conducted a multi-faceted set of analyses, including examinations of ASR error types, words affected by ASR errors, linguistic comparisons, attention weight analysis, and case studies.

RESULTS: We demonstrate that transcripts generated by certain ASR models achieve higher AD detection accuracy than gold-standard manual transcripts. This performance gain stems not from errors in general or a high Word Error Rate (WER), but from specific and asymmetric error patterns. Our analyses reveal that these patterns amplify some pre-existing linguistic deficits in AD speech (e.g., disfluencies), thereby increasing the feature-level divergence between the AD and HC groups. Furthermore, we show that these diagnostic clues are effectively preserved when speech is synthesized from ASR transcripts, holding significant implications for data augmentation strategies in AD research.

CONCLUSION: The specific, asymmetric error patterns introduced by certain ASR models enhance the distinction between AD and HC groups by amplifying pathological linguistic deficits associated with AD. This work suggests a paradigm shift for clinical ASR development: optimizing models not merely for transcription accuracy, but for their downstream diagnostic utility.},
}

@article {pmid41421687,
year = {2025},
author = {Lin, HW and Li, SP and Wen, JX and Zhang, JX and Zhang, BM and Wang, YJ and Cui, XJ and Yao, M},
title = {Multi-target neuroprotective effects of notoginsenoside R1 in neurodegenerative diseases: From pharmacokinetics to translational prospects.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108074},
doi = {10.1016/j.phrs.2025.108074},
pmid = {41421687},
issn = {1096-1186},
abstract = {Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from Panax notoginseng (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer's disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.},
}